1: Ann Endocrinol (Paris). 2008 Apr;69(2):116-22. Epub 2008 Apr 28.

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Environment and endocrinology: the case of thyroidology.

Köhrle J.

Institut für Experimentelle Endokrinologie und EnForCé, Charité Universitätsmedizin Berlin, Humboldt Universität, Charitéplatz 1, Berlin, Germany.

Evidence is accumulating for interference of selected endocrine disrupting chemicals (EDC) with the thyroid axis. EDC disturb thyroid hormone (TH) homeostasis leading to developmental defects, hypothyroidism and altered thyroid growth patterns. A rising incidence of papillary thyroid carcinoma (PTC) in several Western countries cannot be definitely accounted for by improved diagnosis or management of thyroid cancer or improved iodine supply. In recent studies, we and others detected, within the thyroid hormone axis, multiple molecular targets of disruption by EDC, which are used in cosmetics, as pesticides or plasticizers or consumed as plant-derived compounds with the diet or with nutritional supplements. Several of these agents exert adverse effects on thyroid growth and function in animal or in vitro cellular models. Major targets are the sodium iodide symporter (NIS), the hemoprotein thyroperoxidase (TPO), the T4 distributor protein transthyretin (TTR), the deiodinases, TH conjugating enzymes and the TR thyroid hormone receptor family. Still prevailing iodine deficiency in many parts of the world predisposes the thyroid gland to adverse effects of endocrine disrupters especially under phases of vulnerability during development and under adaptive challenges during diseases.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 18440490 [PubMed - in process]

2: Toxicol Appl Pharmacol. 2008 Mar 15;227(3):357-69. Epub 2007 Nov 28.

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Transcriptional responses in thyroid tissues from rats treated with a tumorigenic and a non-tumorigenic triazole conazole fungicide.

Hester SD, Nesnow S.

Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. [email protected]

Conazoles are azole-containing fungicides that are used in agriculture and medicine. Conazoles can induce follicular cell adenomas of the thyroid in rats after chronic bioassay. The goal of this study was to identify pathways and networks of genes that were associated with thyroid tumorigenesis through transcriptional analyses. To this end, we compared transcriptional profiles from tissues of rats treated with a tumorigenic and a non-tumorigenic conazole. Triadimefon, a rat thyroid tumorigen, and myclobutanil, which was not tumorigenic in rats after a 2-year bioassay, were administered in the feed to male Wistar/Han rats for 30 or 90 days similar to the treatment conditions previously used in their chronic bioassays. Thyroid gene expression was determined using high density Affymetrix GeneChips (Rat 230_2). Gene expression was analyzed by the Gene Set Expression Analyses method which clearly separated the tumorigenic treatments (tumorigenic response group (TRG)) from the non-tumorigenic treatments (non-tumorigenic response group (NRG)). Core genes from these gene sets were mapped to canonical, metabolic, and GeneGo processes and these processes compared across group and treatment time. Extensive analyses were performed on the 30-day gene sets as they represented the major perturbations. Gene sets in the 30-day TRG group had over representation of fatty acid metabolism, oxidation, and degradation processes (including PPARgamma and CYP involvement), and of cell proliferation responses. Core genes from these gene sets were combined into networks and found to possess signaling interactions. In addition, the core genes in each gene set were compared with genes known to be associated with human thyroid cancer. Among the genes that appeared in both rat and human data sets were: Acaca, Asns, Cebpg, Crem, Ddit3, Gja1, Grn, Jun, Junb, and Vegf. These genes were major contributors in the previously developed network from triadimefon-treated rat thyroids. It is postulated that triadimefon induces oxidative response genes and activates the nuclear receptor, Ppargamma, initiating transcription of gene products and signaling to a series of genes involved in cell proliferation.

Publication Types:

• Comparative Study

PMID: 18164361 [PubMed - indexed for MEDLINE]

3: Asian J Androl. 2008 Jan;10(1):134-45.

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Endocrine disruptors and estrogenic effects on male reproductive axis.

Sikka SC, Wang R.

Department of Urology, Tulane University Health Sciences Center, New Orleans, LA 70112-2699, USA. [email protected]

Endocrine disruptors (e.g., polychlorinated biphenyls [PCBs], dichlorodiphenyl-trichloroethane [DDT], dioxin, and some pesticides) are estrogen-like and anti-androgenic chemicals in the environment. They mimic natural hormones, inhibit the action of hormones, or alter the normal regulatory function of the endocrine system and have potential hazardous effects on male reproductive axis causing infertility. Although testicular and prostate cancers, abnormal sexual development, undescended testis, chronic inflammation, Sertoli-cell-only pattern, hypospadias, altered pituitary and thyroid gland functions are also observed, the available data are insufficient to deduce worldwide conclusions. The development of intra-cytoplasmic sperm injection (ICSI) is beyond doubt the most important recent breakthrough in the treatment of male infertility, but it does not necessarily treat the cause and may inadvertently pass on adverse genetic consequences. Many well-controlled clinical studies and basic scientific discoveries in the physiology, biochemistry, and molecular and cellular biology of the male reproductive system have helped in the identification of greater numbers of men with male factor problems. Newer tools for the detection of Y-chromosome deletions have further strengthened the hypothesis that the decline in male reproductive health and fertility may be related to the presence of certain toxic chemicals in the environment. Thus the etiology, diagnosis, and treatment of male factor infertility remain a real challenge. Clinicians should always attempt to identify the etiology of a possible testicular toxicity, assess the degree of risk to the patient being evaluated for infertility, and initiate a plan to control and prevent exposure to others once an association between occupation/toxicant and infertility has been established.

Publication Types:

• Review

PMID: 18087652 [PubMed - indexed for MEDLINE]

4: Toxicology. 2008 Jan 14;243(1-2):84-95. Epub 2007 Oct 7.

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Effect of Pyrethrins on cytochrome P450 forms in cultured rat and human hepatocytes.

Price RJ, Giddings AM, Scott MP, Walters DG, Capen CC, Osimitz TG, Lake BG.

BIBRA International Ltd., Woodmansterne Road, Carshalton, Surrey SM5 4DS, United Kingdom.

High doses of Pyrethrins produce liver and thyroid gland tumours in rats by modes of action involving the induction of hepatic xenobiotic metabolising enzymes. The aim of this study was to compare the effects of Pyrethrins with those of the rat liver and thyroid tumour promoter sodium Phenobarbital on some cytochrome P450 (CYP) forms in cultured rat and human hepatocytes. The treatment of female Sprague-Dawley rat and human (both male and female) hepatocytes for 72 h with 0-1000 microM Pyrethrins and 0-1000 microM Phenobarbital did not result in any marked cytotoxicity. In rat hepatocytes both Pyrethrins and Phenobarbital produced an induction of 7-benzyloxy-4-trifluoromethylcoumarin O-debenzylase activity (a CYP1A/2B form marker) and CYP2B1 and CYP2B1/2 mRNA levels. Pyrethrins and Phenobarbital also induced CYP3A-dependent testosterone 6beta-hydroxylase activity in rat hepatocytes. In human hepatocytes Pyrethrins and Phenobarbital induced both testosterone 6beta-hydroxylase activity and CYP3A4 mRNA levels and also increased CYP2B6 mRNA levels. The effects of Pyrethrins and Phenobarbital were concentration-dependent and exhibited a threshold. These results demonstrate that the effects of Pyrethrins on CYP forms in cultured rat and human hepatocytes are qualitatively similar to those of Phenobarbital. Pyrethrins induce CYP2B and CYP3A forms in cultured rat hepatocytes and can induce CYP3A and CYP2B forms in human hepatocytes. While CYP form induction by Pyrethrins, Phenobarbital and related compounds can be associated with liver and thyroid gland tumour formation in rodents, epidemiological data for Phenobarbital suggests that such effects do not occur in humans.

Publication Types:

• Comparative Study

• Research Support, Non-U.S. Gov't

PMID: 18022748 [PubMed - indexed for MEDLINE]

5: J Environ Biol. 2007 Apr;28(2 Suppl):475-81.

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Responses of serum calcium and inorganic phosphate levels as well as parathyroid gland and calcitonin producing C cells of Rattus norvegicus to Mipcin administration.

Rangoonwala SP, Suryawanshi SA, Pandey AK.

Department of Zoology, Institute of Science, 15 Madam Cama Raoad, Mumbai-400 032, India.

Serum calcium (Ca) level of Rattus norvegicus ranged between 13.08 +/- 0.41 - 13.25 +/- 0.39 mg/100 ml whereas serum inorganic phosphate (Pi) concentration varied between 4.21 +/- 0.28 - 4.33 +/- 0.26 mg/100 ml. Sublethal (0.50 LD50 and 0.75 LD50) administration of Mipcin induced a progressive dose-dependent decline in serum Ca level in the rat which was statistically significant at 7 and 14 days. Serum inorganic phosphate level of the treated rats did not exhibit significant fluctuation during the entire course of investigation. Parathyroid chief cells of the experimental rats exhibited degranulation, vacuolation, loss of secretory (hormone) granules and lipid droplets, decreased chromatin in nuclei and damages in the endoplasmic reticulum as well as cristae of mitochondria at 14 days of the treatment. Not much of changes could be seen in the oxyphil cells of parathyroid as well as thyroid C cells of the Mipcin-treated rats.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 17929768 [PubMed - indexed for MEDLINE]

6: Int J Hyg Environ Health. 2007 Oct;210(5):659-67. Epub 2007 Sep 17.

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Some evidence of effects of environmental chemicals on the endocrine system in children.

Rogan WJ, Ragan NB.

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. [email protected]

Pollutant chemicals that are widespread in the environment can affect endocrine function in laboratory experiments and in wildlife. Although human beings are commonly exposed to such pollutant chemicals, the exposures are generally low and clear effects on endocrine function from such exposures have been difficult to demonstrate. Human data including both exposure to the chemical agent and the endocrine outcome are reviewed here, including age at weaning, age at puberty, anogenital distance, and sex ratio at birth, and the strength of the evidence are discussed. Although endocrine disruption in humans by pollutant chemicals remains largely undemonstrated, the underlying science is sound and the potential for such effects is real.

Publication Types:

• Review

PMID: 17870664 [PubMed - indexed for MEDLINE]

PMCID: PMC2245801 [Available on 10/01/08]

7: Chemosphere. 2007 Aug;69(1):118-27. Epub 2007 May 29.

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Thyroid ultrasound volume, structure and function after long-term high exposure of large population to polychlorinated biphenyls, pesticides and dioxin.

Langer P, Tajtáková M, Kocan A, Petrík J, Koska J, Ksinantová L, Rádiková Z, Ukropec J, Imrich R, Hucková M, Chovancová J, Drobná B, Jursa S, Vlcek M, Bergman A, Athanasiadou M, Hovander L, Shishiba Y, Trnovec T, Seböková E, Klimes I.

Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlárska 3, 833 06 Bratislava, Slovakia. [email protected]

We examined 2,046 adults (834 males and 1,212 females aged 20-75 years) from polluted district in East Slovakia (POLL) and two neighboring upstream and upwind located districts of background pollution (BCGR). By ultrasound we estimated the thyroid volume (ThV), hypoechogenicity (HYE), nodules and cysts. Serum levels of thyrotropin (TSH), thyroperoxidase antibodies (TPOab) and thyroglobulin were estimated by electrochemiluminiscent assay and these of 15 PCB congeners, p,p'-DDE, p,p'-DDT, hexachlorobenzene (HCB) and hexachlorocyclohexane by high-resolution gas chromatography. In 320 subjects also selected hydroxylated and methylsulfonated PCB metabolites, polychlorinated dibenzo-dioxins (PCDDs), -furans (PCDFs), five dioxin-like coplanar and eight mono-ortho PCB congeners were estimated. Urinary iodine was measured by automatic microplate method. Reciprocal positive association was found between three major POPs (PCBs, DDE and HCB), the levels of these and also PCDDs plus PCDFs in polluted area being considerably higher than in background pollution area. ThV in groups of males and females from POLL with high PCBs level was significantly higher (p<0.001 by t-test) then in age and sex matched groups from BCGR with low PCBs level. In 1,048 males and females aged <60 years with serum PCBs level >1,000 ng g(-1) lipid (median=1,756 ng g(-1)) a significant effect of age on ThV was found (p<0.01 by ANOVA), while in 921 respective subjects with PCBs level <1,000 ng g(-1) (median=661 ng g(-1)) it was not. These findings supported the view on the additional effect of PCBs on ThV other than that of age. Since the urinary iodine in both districts showed optimal range, any interfering effect of unsatisfactory iodine intake on ThV may be excluded. The frequency of autoimmune thyroiditis signs such as HYE, increased serum level of TPOab and TSH resulting in subclinical or overt thyroid hypofunction was positively associated with sex, age and organochlorine levels. The increase of such frequency in males with POPs levels was much more abrupt than that in females. No considerable differences in the frequency of thyroid nodules as related to PCBs level were found.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 17537484 [PubMed - indexed for MEDLINE]

8: C R Biol. 2007 May;330(5):410-8. Epub 2007 Apr 9.

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[Toxicity of hexachlorobenzene in Meriones unguiculatus: effects on thyroid and liver]

[Article in French]

Bitri L, Dhaouadi N, Ouertani L, Maurel D, Ben Saad M.

Laboratoire de physiologie animale, département des sciences biologiques, UR Physiologie environnementale et biorythmes, faculté des sciences de Tunis, Tunisie. [email protected]

The effect of in vivo administered hexachlorobenzene (HCB) on liver and thyroid was studied on Meriones unguiculatus. HCB (1.6, 4, and 16 mg/kg of body weight) has been administered orally to meriones for 30 days. At the end of the experiment, the body weight of the animals did not show significant change. However, the higher dose of HCB treatment led to a pronounced hepatic hypertrophy comparatively to controls. Histological observations revealed many cytomorphological alterations. Cellular necrosis, periportal, and centrolobular vein congestion and cytoplasmic vacuolisation were noted and correlated with the administered doses of HCB. The higher dose of HCB induced modifications in the activities of hepatic transaminases and on thyroid hormones levels: ALAT activity level was more pronounced in males (170+/-24.7 U/l vs. 52.66+/-8.29 U/l in controls) than in females (120+/-12.47 U/l vs. 56+/-5 U/l in controls). However, ASAT activity increased significantly only in females (259+/-29 U/l vs. 244.66+/-18 U/l in controls). Plasma total triiodothyronine (TT3) and total thyroxine (TT4) levels seemed to be sex-dependent in intoxicated animals, since TT4 decreased significantly in males (21.95+/-7.46 nmol/l vs. 40.59+/-1.08 nmol/l in controls) and TT3 in females (1.42+/-0.11 nmol/l vs. 3.96+/-0.48 nmol/l in controls).

Publication Types:

• English Abstract

PMID: 17531791 [PubMed - indexed for MEDLINE]

9: Toxicol Pathol. 2006;34(7):895-902.

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Toxicity profiles in rats treated with tumorigenic and nontumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil.

Wolf DC, Allen JW, George MH, Hester SD, Sun G, Moore T, Thai SF, Delker D, Winkfield E, Leavitt S, Nelson G, Roop BC, Jones C, Thibodeaux J, Nesnow S.

Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, ORD, USEPA, Research Triangle Park, North Carolina 27711, USA. [email protected]

Conazoles are a class of azole based fungicides used in agriculture and as pharmaceutical products. They have a common mode of antifungal action through inhibition of ergosterol biosynthesis. Some members of this class have been shown to be hepatotoxic and will induce mouse hepatocellular tumors and/or rat thyroid follicular cell tumors. The particular mode of toxic and tumorigenic action for these compounds is not known, however it has been proposed that triadimefon-induced rat thyroid tumors arise through the specific mechanism of increased TSH. The present study was designed to identify commonalities of effects across the different conazoles and to determine unique features of the tissue responses that suggest a toxicity pathway and a mode of action for the observed thyroid response for triadimefon. Male Wistar/Han rats were treated with triadimefon (100, 500, 1800 ppm), propiconazole (100, 500, 2500 ppm), or myclobutanil (100, 500, 2000 ppm) in feed for 4, 30, or 90 days. The rats were evaluated for clinical signs, body and liver weight, histopathology of thyroid and liver, hepatic metabolizing enzyme activity, and serum T3, T4, TSH, and cholesterol levels. There was a dose-dependent increase in liver weight but not body weight for all treatments. The indication of cytochrome induction, pentoxyresorufin O-dealkylation (PROD) activity, had a dose-related increase at all time points for all conazoles. Uridine diphopho-glucuronosyl transferase (UDPGT), the T4 metabolizing enzyme measured as glucuronidation of 1-naphthol, was induced to the same extent after 30 and 90 days for all three conazoles. Livers from all high dose treated rats had centrilobular hepatocyte hypertrophy after 4 days, while only triadimefon and propiconazole treated rats had hepatocyte hypertrophy after 30 days, and only triadimefon treated rats had hepatocyte hypertrophy after 90 days. Thyroid follicular cell hypertrophy, increased follicular cell proliferation, and colloid depletion were present only after 30 days in rats treated with the high dose of triadimefon. A dose-dependent decrease in T4 was present after 4 days with all 3 compounds but only the high doses of propiconazole and triadimefon produced decreased T4 after 30 days. T3 was decreased after high-dose triadimefon after 4 days and in a dose-dependent manner for all compounds after 30 days. Thyroid hormone levels did not differ from control values after 90 days and TSH was not increased in any exposure group. A unique pattern of toxic responses was not identified for each conazole and the hypothesized mode of action for triadimefon-induced thyroid gland tumors was not supported by the data.

Publication Types:

• Comparative Study

PMID: 17178690 [PubMed - indexed for MEDLINE]

10: Toxicol Pathol. 2006;34(7):879-94.

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Transcriptional profiles in liver from rats treated with tumorigenic and non-tumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil.

Hester SD, Wolf DC, Nesnow S, Thai SF.

Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. [email protected]

Conazoles are a class of fungicides used as pharmaceutical and agricultural agents. In chronic bioassays in rats, triadimefon was hepatotoxic and induced follicular cell adenomas in the thyroid gland, whereas, propiconazole and myclobutanil were hepatotoxic but had no effect on the thyroid gland. These conazoles administered in the feed to male Wistar/Han rats were found to induce hepatomegaly, induce high levels of pentoxyresorufin-O-dealkylase, increase cell proliferation in the liver, increase serum cholesterol, decrease serum T3 and T4, and increase hepatic uridine diphosphoglucuronosyl transferase activity. The goal of the present study was to define pathways that explain the biologic outcomes. Male Wistar/Han rats (3 per group), were exposed to the 3 conazoles in the feed for 4, 30, or 90 days of treatment at tumorigenic and nontumorigenic doses. Hepatic gene expression was determined using high-density Affymetrix GeneChips (Rat 230_2). Differential gene expression was assessed at the probe level using Robust Multichip Average analysis. Principal component analysis by treatment and time showed within group sample similarity and that the treatment groups were distinct from each other. The number of altered genes varied by treatment, dose, and time. The greatest number of altered genes was induced by triadimefon and propiconazole after 90 days of treatment, while myclobutanil had minimal effects at that time point. Pathway level analyses revealed that after 90 days of treatment the most significant numbers of altered pathways were related to cell signaling, growth, and metabolism. Pathway level analysis for triadimefon and propiconazole resulted in 71 altered pathways common to both chemicals. These pathways controlled cholesterol metabolism, activation of nuclear receptors, and N-ras and K-ras signaling. There were 37 pathways uniquely changed by propiconazole, and triadimefon uniquely altered 34 pathways. Pathway level analysis of altered gene expression resulted in a more complete description of the associated toxicological effects that can distinguish triadimefon from propiconazole and myclobutanil.

PMID: 17178689 [PubMed - indexed for MEDLINE]

11: Endocr Regul. 2006 Jun;40(2):46-52.

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Multiple organochlorine pollution and the thyroid.

Langer P, Tajtaková M, Kocan A, Vlcek M, Petrik J, Chovancova J, Drobna B, Jursa S, Pavuk M, Trnovec T, Sebokova E, Klimes I.

Institute of Experimental Endocrinology, Slovak Academy of Science, Bratislava, Slovakia. [email protected]

OBJECTIVE: Although the biological effects of major persistent organochlorinated pollutants (POPs) appear to be essentially similar, some effects which would be specific for certain substance cannot be excluded. We attempted to study the thyroid volume and thyrotropin level in the population living in the area with multiple pollution by polychlorinated biphenyls (PCBs) and pesticides (DDE and hexachlorobenzene - HCB). METHODS: A total of 454 adults was examined within the pilot field survey in 1998. Among them were 237 males (age range 19-78 years, median 47) and 227 females (age range 19-78 years, median 48). Fifteen environmentally prevalent congeners of polychlorinated biphenyls and also p,p-DDE (2,2-bis(4-chlorophenyl)-1,1-dichloroethylene), p,p-DDT (2,2-bis(4-chlorophenyl)- 1,1,1-trichloro-ethane), hexachlorobenzene (HCB) as well as alpha-, beta- and gamma-hexachlorocyclohexane (HCH) were determined in serum by high resolution gas chromatography using microelectron capture detector and microcapillary column. Thyroid volume (ThV) was measured by real time sonography using the ellipsoid method with the aid of sonographic instrument Sonoline SI-400 (Siemens, Germany). The level of TSH was estimated by supersensitive immunoradiometric method using commercial kits by Immunotech (Marseille, France). Pearsons correlation coefficients after logarithmic transformation of values and Spearmans correlation coefficients were used for statistical evaluation. RESULTS: Significant positive association (p<0.01) was found between DDE and PCB, DDE and HCB, while that between PCB and HCB was not significant. Similar positive association (p<0.01) was also found between each individual organochlorine and their sum. Significant negative association (p<0.01) was found between ThV and TSH. When using categorical PCB values either >2000 (N=208) or >3000 (N=127) ng/g lipid, significant positive association (p<0.05 and p<0.01, respectively) was found between the sum of all organochlorines (PCB+DDE+HCB) and ThV, while that between PCB and ThV (p<0.01) was found only at the PCB levels >3000 ng/g lipid. When using Spearmans correlation coefficients, significant negative association appeared between PCB and TSH (p<0.05), sum of organochlorines and TSH (p<0.05) and ThV and TSH (p<0.01). CONCLUSIONS: Although several significant positive and negative associations were found, this study, like several others, could not exactly define the participation level of individual POPs in their common toxic effects, but possibly contributed to the recognition and elucidation of some problems related to this task.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 17100546 [PubMed - indexed for MEDLINE]

12: Cir Pediatr. 2006 Apr;19(2):101-5.

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[Thyroid C cells are decreased in experimental CDH]

[Article in Spanish]

Martínez L, De Ceano-Vivas M, González-Reyes S, Fernández-Dumont V, Calonge WM, Ruiz E, Rodríguez JI, Tovar JA.

Departamento de Cirugía Pediátrica, Hospital Universitario La Paz, Madrid. [email protected]

BACKGROUND/AIM: Experimental CDH is often associated with malformations of neural crest origin. Several of these features are present in human CDH and therefore likely similar pathogenic mechanisms should be explored. The aim of the present study is to examine whether thyroid C-cells, another neural crest derivative, are abnormal in this rat model. METHODS: Pregnant rats were exposed either to 100 mg of 2-4-dichlorophenyl-p-nitrophenyl ether (nitrofén) or vehicle (controls) on 9.5 day of gestation. Fetuses were recovered on day 21st and the thyroids of those with CDH (68%) were immuno-histochemically stained with anti-calcitonin antibody. The number of positively stained cells per high power field were counted using a computer-assisted image analysis method in at least 5 sections per thyroid. The distribution of the cells within the gland was assessed as well. Comparisons between CDH and control rats were made by non-parametric tests with a significance threshold of p<0.05. RESULTS: The number of c-cells was dramatically reduced in CDH animals in comparison with controls (101.2 +/- 61.3 vs 23.1 +/- 37, p<0.0001). Histology of the thyroid was similar in both groups, but the distribution of positive C-cells within the gland followed an abnormal pattern in CDH rats with the cells tending to be located at the periphery rather than at the core of the lobes. CONCLUSIONS: Nitrofén induces a severe decrease in thyroid C cells accompanied by abnormal distribution patterns. These results add further evidence of the involvement of a neural crest dysregulation as a component of the pathogenesis of experimental CDH. Whether there is or not a clinical counterpart to these findings is still unknown, but the nature of the cardiovascular and craneo-facial malformations in some babies with CDH strongly support further research in this field.

Publication Types:

• English Abstract

• Research Support, Non-U.S. Gov't

PMID: 16846133 [PubMed - indexed for MEDLINE]

13: Nippon Eiseigaku Zasshi. 2006 Jan;61(1):19-31.

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[Exposure to endocrine disrupting chemicals and children's health: problems in epidemiological studies]

[Article in Japanese]

Kishi R, Sata F, Saijo Y, Kurahashi N, Kato S, Nakajima S, Sasaki S.

Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan. [email protected]

Most endocrine disrupting chemicals are characterized by their properties to induce marked phenotypic changes in offspring such as congenital anomalies and neurodevelopmental dysfunctions. Although an increase in the prevalence of hypospadias or cryptorchidism has been reported in various countries, improvement in diagnostic techniques and more attention to the features of the diseases have also been emphasized. Although there have been a few reports that hypospadias or cryptorchidism had been associated with diethylstilbestrol (DES), pesticides and so on, the associations between these diseases and endocrine disrupting chemicals remain unclear. Recently, the association between maternal metabolic polymorphism or paternal smoking during pregnancy and these diseases has been reported. There are also variable clinical features in children's neurobehavioral development, and thyroid and immune functions in relation to exposure to endocrine disrupting chemicals such as polychlorinated biphenyls (PCBs) and dioxins. Only a few Dutch studies have suggested that perinatal exposure to background level of PCB/dioxin confers immunity to allergy development. Genetic susceptibility to environmental endocrine disrupting chemicals may be related to adverse pregnancy outcomes. It is suggested that well-designed epidemiological studies such as prospective cohort studies should be performed to elucidate this association.

Publication Types:

• English Abstract

• Review

PMID: 16506651 [PubMed - indexed for MEDLINE]

14: Toxicol Pathol. 2005;33(7):776-83.

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A mixture of ammonium perchlorate and sodium chlorate enhances alterations of the pituitary-thyroid axis caused by the individual chemicals in adult male F344 rats.

Khan MA, Fenton SE, Swank AE, Hester SD, Williams A, Wolf DC.

National Research Council, Environmental Carcinogenesis Divisions, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.

Ammonium perchlorate (AP) and sodium chlorate (SC) have been detected in public drinking water supplies in many parts of the United States. These chemicals cause perturbations in pituitary-thyroid homeostasis in animals by competitively inhibiting iodide uptake, thus hindering the synthesis of thyroglobulin and reducing circulating T(4) (thyroxine). Little is known about the short-term exposure effects of mixtures of perchlorate and chlorate. The present study investigated the potential for the response to a mixture of these chemicals on the pituitary-thyroid axis in rats to be greater than that induced by the individual chemicals. Adult male F-344 rats were exposed, via their drinking water, to the nominal concentrations of 0.1, 1.0, 10 mg/L AP or 10, 100, 1000 mg/L SC and their mixtures for 7 days. Serum T(4) levels were significantly (p < 0.05) reduced in rats following exposure to the mixtures, but not after exposure to the individual chemicals. Serum T(3) (triiodothyronine) was not altered by treatment and TSH (thyroid stimulating hormone) was only increased after the high-dose chlorate treatment. Histological examination of the thyroid gland showed colloid depletion and hypertrophy of follicular epithelial cells in high-dose single chemical and all mixture-treated rats, while hyperplasia was observed only in some of the rats treated with mixtures (AP 10 + SC 100, AP 0.1 + SC 1000, and AP 10 + SC 1000 mg/L). These data suggest that short-term exposure to the mixture of AP and SC enhances the effect of either chemical alone on the pituitary-thyroid axis in rats.

PMID: 16392172 [PubMed - indexed for MEDLINE]

15: Natl Toxicol Program Tech Rep Ser. 2005 Dec;(517):1-255.

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Toxicology and carcinogenesis studies of sodium chlorate (Cas No. 7775-09-9) in F344/N rats and B6C3F1 mice (drinking water studies).

National Toxicology Program.

BACKGROUND: Sodium chlorate occurs when drinking water is disinfected by chlorine dioxide. We studied the effects of sodium chlorate in rats and mice to identify potential toxic or carcinogenic hazards to humans. METHODS: We gave groups of male and female rats drinking water containing 125, 1,000, or 2,000 milligrams (mg) of sodium chlorate per liter (L) of water for two years. Male and female mice received 500, 1,000, or 2,000 mg/L. Other groups of animals received plain tap water and served as the control groups. At the end of the study, tissues from more than 40 sites were examined for every animal. RESULTS: Male and female rats receiving sodium chlorate had higher rates of follicular cell hypertrophy of the thyroid gland, and the groups receiving 2,000 mg/L had higher rates of thyroid gland cancer, compared with the control groups. Female mice exposed to sodium chlorate had a few pancreatic islet cell tumors. CONCLUSIONS: We conclude that sodium chlorate caused some thyroid gland neoplasms in male and female rats. The pancreatic islet cell tumors in female mice may have been related to sodium chlorate exposure.

Publication Types:

• Comparative Study

PMID: 16362061 [PubMed - indexed for MEDLINE]

16: Endocr Regul. 2005 Jan;39(1):13-20.

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Human thyroid in the population exposed to high environmental pollution by organochlorinated pollutants for several decades.

Langer P, Kocan A, Tajtakova M, Petrik J, Chovancova J, Drobna B, Jursa S, Pavuk M, Trnovec T, Seböková E, Klimes I.

Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska, Slovakia. [email protected]

OBJECTIVE: To study possible effects of long-time exposure of chemical factory employees and population of surrounding polluted area to polychlorinated biphenyls and pesticides on the thyroid volume and function as compared to the population from the area of background pollution. METHODS: A total of 461 adults consisting of 239 men and 222 women was examined and divided into four groups according to their permanent domicile as related to the level of environmental pollution, e.g. SR (area of background pollution, n = 207), SI (slightly polluted area, n = 59), MI (polluted city of Michalovce, n = 94) and CH (employees of chemical factory subjected to high PCB exposure, n = 101), combined first three groups being also called LPA (less polluted areas, n = 360). Thyroid volume (ThV) and echogenicity were measured by real time sonography. The level of polychlorinated biphenyls (PCB) and pesticides (hexachlorbenzene--HCB, DDE (2,2'-2-bis(4-chlorobiphenyl)- 1,1-dichloroethylene), p,p'-DDT (2,2'-bis(4-chlorophenyl)- 1,1,1-trichloroethane) and alpha-, beta- and gamma-hexachlorcyclohexane--HCH) was estimated by congener specific analysis using HP 5890 gas chromatograph with a 63Ni electron capture detector. Serum levels of thyrotropin (TSH) and thyroid peroxidase antibodies (anti-TPO) were measured by specific sensitive immunoassays. RESULTS: The association of very high PCB level (e.g. 7300 +/- 871 ng/g lipid; mean +/- S.E.) with increased ThV (e.g. 16.3 +/- 0.73 ml) in CH has been found, the values being significantly higher than these of 360 subjects in LPA (e.g. 2045 +/- 147 ng/g, p < 0.001 for PCB and 14.0 +/- 0.32 ml, p < 0.001 for ThV). In 23 subjects from CH with PCB level > 10000 ng/g the ThV was 18.7 +/- 2.32 ml, while that in 251 subjects from LPA with PCB level of < 2000 ng/g was 13.8 +/- 0.35 ml (p < 0.05). In addition, ThV as well as PCB levels were strikingly increasing with age. In parallel with PCB levels, also the levels of other organochlorines estimated (namely these of DDE) were increasing. Although the participation of these substances in the development of adverse effects cannot yet be defined, it cannot be excluded. The association of increased levels of episodic congener PCB 101 with increased ThV appeared to be more pronounced than that of stable congeners PCB 153 and 180. Finally, significant increase in the frequency of thyroid hypoechogenicity by ultrasound, ThV > 20.0 ml and thyroperoxidase antibodies in CH area was observed as compared to LPA. CONCLUSIONS: Several associations of high PCB and pesticides level with characteristics of thyroid disorders (e.g. increased thyroid volume, frequency of hypoechogenicity and frequency of positive thyroperoxidase antibodies level in blood) were observed in the area with heavy industrial pollution by PCB.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 16107134 [PubMed - indexed for MEDLINE]

17: Toxicology. 2005 Feb 28;207(3):349-62.

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The role of type I and type II 5' deiodinases on hexachlorobenzene-induced alteration of the hormonal thyroid status.

Alvarez L, Hernández S, Martinez-de-Mena R, Kolliker-Frers R, Obregón MJ, Kleiman de Pisarev DL.

Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Buenos Aires 1121, Argentina. [email protected]

Treatment of male Wistar rats with hexachlorobenzene (HCB) (1000 mg/kg b.w.) for 3-30 days decreases circulating levels of thyroxine (T4) but does not affect triiodothyronine (T3). Time courses were determined for 5' deiodinase type I (5' D-I) activity in thyroid, liver, and kidney and 5' deiodinase type II (5' D-II) activity in brown adipose tissue (BAT) to test the possibility that increased deiodinase activity might contribute to the maintenance of the serum T3 level. Specific 5' D-I activity was increased in the thyroid at 21 days and thereafter. No significant changes were observed in the liver, however, total 5' D-I activity in this tissue was increased at 30 days of treatment as a consequence of liver weight enhancement. HCB decreased kidney 5' D-I activity after 15 days, and BAT 5' D-II activity after 21 days of treatment. Total body 5' D-I activity was significantly increased by 30 days of HCB-treatment. HCB increased the activity of hepatic T4 uridine diphosphoglucuronosyl transferase (UDPGT) in a time-dependent manner, without changes in T3 UDPGT. We propose that increased T4 to T3 conversion in the thyroid and in the greatly enlarged liver may account for the maintenance of serum T3 concentration in hypothyroxinemic HCB-treated rats.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 15664263 [PubMed - indexed for MEDLINE]

18: Sichuan Da Xue Xue Bao Yi Xue Ban. 2004 Nov;35(6):770-3.

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[Time course of the disruption of rat's thyroid function by pesticide N'N-methylene-bis]

[Article in Chinese]

Wang JT, Sun D, Zhang H, Cheng WB, Wu DS.

Department of Environmental Health, West China School of Public Health, Sichuan University, Chengdu 610041, China.

OBJECTIVE: To study the effect of pesticide N'N-methylene-bis on thyroid function in rats, and the time-effect relationship. METHODS: N'N-methylene-bis dimethylsulfoxide solution was administered to rats by gavage at a dose of 50 mg/kg body weight for 1, 3, and 5 days respectively. The rats in the control group were given solvent dimethylsulfoxide by oral gavage at the same volume. All animals were sacrificed 1 day after the last dosage, and the levels of FT4 and TSH in serum were measured by radioimmunoassay. The histological changes of thyroid gland were observed, and the expression of PCNA in thyroid was detected by immunohistochemistry. RESULTS: Compared with the solvent control group, the serum FT4 level in rats given N'N-methylene-bis for 3 days significantly decreased, while the TSH level significantly increased in the 3 d and 5 d groups (P<0.05). Hyperplasia of thyroid follicular epithelium was observed in the 3 d and 5 d groups. PCNA positive cells in thyroid of the 3 d and 5 d groups were significantly higher than that of control (P<0.05). CONCLUSION: The effect of N'N-methylene-bis on the level of serum FT4 and TSH in rats appeared on the 2nd or 3rd day of the experiment. Histopathologic examination showed thyroid gland proliferation of follicular epithelium within 3 days. The combined use of serologic test and histopathologic examination for screening thyroid hormone disruptors may be an effective method.

Publication Types:

• English Abstract

• Research Support, Non-U.S. Gov't

PMID: 15573750 [PubMed - indexed for MEDLINE]

19: G Ital Med Lav Ergon. 2004 Jul-Sep;26(3):171-9.

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[Occupational exposure to endocrine disruptors: state of the art]

[Article in Italian]

Papaleo B, Caporossi L, De Rosa M, Chiovato L, Ferrari M, Imbriani M, Signorini S, Pera A.

ISPESL - Dipartimento di Medicina del Lavoro, Roma. [email protected]

Research into how exposure to "endocrine disrupters chemicals" affects human health is attracting increasing attention among European and international scientists since these contaminants are so widespread in the home and work environment and can have far-reaching effects on mental and physical health. Here we draw a general picture of studies to date on specific occupational exposures to single chemicals such as bisphenol A, styrene, etc., or homogeneous groups such as pesticides, metals, dioxins, phthalates and others. Although the exposure occurs in different ways, the toxic mechanisms of action vary widely, and it is hard to establish precisely the conditions of occupational exposure, significant correlations are nevertheless evident between the potential dose and its effects and further studies are certainly needed. There is still much debate on the epidemiological methods employed, which may overestimate exposure. The "measure" or at least an accurate description of exposure conditions is critical to the whole question and attempts to ensure this involve standardized procedures and statistical tests as the basis for a protocol for assessing the risk of occupational exposure. Investigations to date have focused on the effects on the reproductive system, in males in particular. However, considering the broad range of equilibria and systems on which endocrine destructive compounds can act, the international scientific community needs to persist in its efforts to develop methods for checking the effects on other endocrine organs--particularly the thyroid gland--and on the immune and neurological systems.

Publication Types:

• Comparative Study

• English Abstract

• Review

PMID: 15551945 [PubMed - indexed for MEDLINE]

20: Toxicol Sci. 2004 Oct;81(2):443-53. Epub 2004 Jul 22.

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Evaluation of the developmental and reproductive toxicity of methoxychlor using an anuran (Xenopus tropicalis) chronic exposure model.

Fort DJ, Thomas JH, Rogers RL, Noll A, Spaulding CD, Guiney PD, Weeks JA.

Fort Environmental Laboratories, 1414 South Sangre Road, Stillwater, Oklahoma 74074, USA. [email protected]

The chronic toxicity of methoxychlor to the South African clawed frog, Xenopus (Silurana) tropicalis, was evaluated using a life cycle approach. The chronic exposure period ranged from mid-cell blastula stage [NF (Nieuwkoop and Faber, 1994) stage 8] to 90 days of exposure, during which time the organisms generally completed metamorphosis and emerged as juvenile frogs. Methoxychlor concentrations ranged from 1 to 100 micrograms/l. Methoxychlor concentrations >10 micrograms/l caused delayed development. Organisms exposed to 10 micrograms/l methoxychlor for 30 days showed enlarged thyroid glands with follicular hyperplasia. No increase in mortality or external malformation was observed at any of the test concentrations during early embryo-larval development (NF stage 8 to NF stage 46; ca. 2 days exposure). A concentration-dependent increase in external malformations and internal abnormalities of the liver and gonads were noted after 90 days of exposure, however. Skewing of the sex ratio toward the female gender decreased ovary weight and number of oocytes, and increased oocyte immaturity and necrosis were noted at methoxychlor concentrations of 100 micrograms/l. Reductions in testis weight and sperm cell count were also detected at 100 micrograms/l methoxychlor. Results from these studies suggested that methoxychlor was capable of altering the rate of larval development, but did not adversely affect early embryo-larval development (2 days of exposure) as manifested in external malformations. Internal malformations, increases in the ratio of phenotypic females, were induced by chronic methoxychlor exposure. In addition, reproductive endpoints, most notably in the female specimens, were adversely affected by methoxychlor exposure. These studies add to the standardization and validation of a useful amphibian test methods capable of evaluating both reproductive and developmental effects of potential endocrine disrupting chemicals over a life cycle exposure.

Publication Types:

• Research Support, Non-U.S. Gov't

• Research Support, U.S. Gov't, Non-P.H.S.

PMID: 15272137 [PubMed - indexed for MEDLINE]

21: Reprod Toxicol. 2003 Sep-Oct;17(5):617-23.

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Histological and histomorphometric alterations in thyroid and adrenals of CD rat pups exposed in utero to methyl thiophanate.

Maranghi F, Macrí C, Ricciardi C, Stazi AV, Rescia M, Mantovani A.

Laboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanità, Viale Regina Elena, 299-00161 Rome, Italy. [email protected]

Pregnant CD rats were treated with an initial dose of 0, 310 or 560 mg/kg bw per day of the fungicide methyl thiophanate (MT) on gestational days 10-14, corresponding to formation of thyroid and adrenal primordia; newborns were sacrificed on postnatal days (PNDs) 10 and 23. No apparent maternal toxicity and no effects on litter size, viability or weight gain were present. Delayed ear pinna detachment and eye opening were present at top dose level.Thyroid histology showed increased irregular nuclei and/or mitoses (PND 10-both doses), cells with necrotic or hydropic changes (PND 23-top dose). The adrenal cortex showed increased karyomegaly and hydropic degeneration (PND 23-both doses). Thyroid histomorphometry showed reduced follicular density, moderately increased follicular cell height and number of nuclei/follicle (PND 10-top dose and PND 23-both doses), suggesting retarded follicular maturation. The adrenal cortex relative area was slightly decreased (PND 10-top dose and PND 23-both doses).MT may act as weak endocrine disrupter, suggesting that attention should be paid to delayed endocrine alterations elicited by agrochemicals.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 14555200 [PubMed - indexed for MEDLINE]

22: Toxicol Sci. 2004 Jan;77(1):51-62. Epub 2003 Sep 26.

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Early developmental neurotoxicity of a PCB/organochlorine mixture in rodents after gestational and lactational exposure.

Bowers WJ, Nakai JS, Chu I, Wade MG, Moir D, Yagminas A, Gill S, Pulido O, Meuller R.

Systemic Toxicology and Pharmacokinetics Section, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario K1A 0L2, Canada. [email protected]

The developmental and neurobehavioral effects of gestational and lactational exposure to a mixture of 14 polychlorinated biphenyls (PCBs) and 11 organochlorine pesticides was examined and compared against the commercial PCB mixture Aroclor 1254. The mixture was based on blood levels reported in Canadian populations living in the Great Lakes/St. Lawrence basin. Pregnant Sprague-Dawley rats were dosed orally with 0.013, 0.13, 1.3, or 13 mg/kg of the chemical mixture or 15 mg/kg of Aroclor 1254 from gestation day (GD) 1 to postnatal day (PND) 23. The highest mixture dose decreased maternal gestation and lactation body weight, and produced high mortality rates (80% overall) and reductions in offspring weight that persisted to adulthood. Aroclor 1254 produced smaller but persistent decreases in offspring weight without affecting maternal weight or offspring mortality. Aroclor 1254 and 13 mg/kg of the mixture produced comparable decreases in maternal and offspring serum T4 levels and comparable alterations to maternal thyroid morphology. Aroclor 1254 delayed the righting reflex and ear opening, accelerated eye opening, and reduced grip strength at PNDs 10-14. The mixture at 13 mg/kg delayed negative geotaxis in addition to delaying righting reflex and ear opening and reducing grip strength but had no effect on eye opening. Lower mixture doses (0.13 and 1.3 mg/kg) also delayed ear opening but affected no other parameters. Developmental exposure to the chemical mixture was found to be more toxic than exposure to Aroclor 1254 and produced a different profile of effects on early neurodevelopment. This PCB/organochlorine pesticide mixture affects mortality, growth, thyroid function, and neurobehavioral development in rodents.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 14514954 [PubMed - indexed for MEDLINE]

23: Int J Toxicol. 2003 Jul-Aug;22(4):287-95.

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The herbicide metolachlor induces liver cytochrome P450s 2B1/2 and 3A1/2, but not thyroxine-uridine dinucleotide phosphate glucuronosyltransferase and associated thyroid gland activity.

Dalton SR, Miller RT, Meyer SA.

Department of Toxicology, North Carolina State University, Raleigh, North Carolina, USA.

Metolachlor (2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl) acetamide) is widely used internationally as a corn and cotton herbicide. The metolachlor effects noted in rats during testing for U.S. pesticide registration include increased liver weight and hepatocarcinogenicity associated with eosinophilic foci. These properties, plus nongenotoxicity, are also characteristic of the prototypical rat liver tumor promoter, phenobarbital. Phenobarbital induces hepatic cytochrome P450s CYP2B1/2 and CYP3A1/2 and thyroxine (T(4))-UDP-glucuronosyltransferase (T(4)-UGT), which enhances thyroxine clearance and thus indirectly increases thyroid gland activity. Because other chloroacetanilide herbicides are known to similarly affect rat thyroid gland, this study tested the hypothesis that metolachlor would have these additional phenobarbital-like effects on liver, especially that of T(4)-UGT induction with consequential stimulation of thyroid gland. Effects of metolachlor, fed to male Sprague-Dawley rats for 14 days at the carcinogenic dose of 3000 ppm, were compared to those of equimolar phenobarbital. Liver microsomal CYP2B1/2 and CYP3A1/2 were probed by immunoblotting and T(4)-UGT was measured enzymatically. Serum T(4), triiodothyronine (T(3)), and thyroid-stimulating hormone (TSH) and thyroid follicular epithelial cell morphology and proliferation were used to assess thyroid gland activity. Metolachlor induced CYP2B1/2 and CYP3A1/2 proteins, but unlike phenobarbital, did not affect T(4)-UGT activity. In agreement, serum T(4), T(3), or TSH were unaffected by metolachlor. Also, no significant effects of metolachlor on thyroid gland morphology or follicular epithelial cell height or proliferation were observed. These data demonstrate that metolachlor is an inducer of hepatic CYP2B1/2 activity. But unlike the prototypical CYP2B1/2 inducer phenobarbital, metolachlor does not cause an increase in T(4)-glucuronidation and thyroid gland activation.

Publication Types:

• Research Support, Non-U.S. Gov't

• Research Support, U.S. Gov't, P.H.S.

PMID: 12933323 [PubMed - indexed for MEDLINE]

24: Mol Cell Endocrinol. 2003 Jul 31;205(1-2):185-92.

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Effect of thyroid state on H2O2 production by rat liver mitochondria.

Venditti P, De Rosa R, Di Meo S.

Dipartimento di Fisiologia Generale ed Ambientale, Università di Napoli, I-80134 Napoli, Italy.

It has been suggested that activation of mitochondrial respiration by thyroid hormone results in oxidative tissue injury secondary to increased reactive oxygen species production. In order to throw light on this subject, the effects of thyroid state on O2 consumption and H2O2 release by rat liver mitochondria were investigated. Hypothyroidism decreased the rates of O2 consumption and H2O2 release by succinate or pyruvate/malate-supplemented mitochondria during both State 4 and State 3 respiration, whereas hyperthyroidism increased such rates. Conversely, with both substrates and during either respiration phase, the percentage of O2 released as H2O2 was not significantly affected by thyroid state. On the other hand, the capacity of mitochondria to remove H2O2 increased by about 17% in hyperthyroid rats and decreased by about 35% in hypothyroid ones. This result indicates that the ratio between H2O2 production and release and so the percentage of O2 turned into H2O2 instead of being reduced to water increase in the transition from hypothyroid to hyperthyroid state. In light of previous observations that mitochondrial content of cytochromes and ubiquinone also increases in such a transition, the modifications of H2O2 production appear to be due to a modulation by thyroid hormone of the mitochondrial content of the autoxidisable electron carriers. This view is supported by measurements of H2O2 release in the presence of respiratory inhibitors, which show that the thyroid state-linked changes in H2O2 production occur at H2O2 generator sites of both Complex I and Complex III.

PMID: 12890580 [PubMed - indexed for MEDLINE]

25: J Occup Environ Med. 2003 May;45(5):526-32.

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Possible effects of polychlorinated biphenyls and organochlorinated pesticides on the thyroid after long-term exposure to heavy environmental pollution.

Langer P, Kocan A, Tajtáková M, Petrík J, Chovancová J, Drobná B, Jursa S, Pavúk M, Koska J, Trnovec T, Seböková E, Klimes I.

Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlarska 3, 833 06 Slovakia. [email protected]

The purpose of this work was to study the effects of high environmental exposure to polychlorinated biphenyls (PCBs) and other organochlorines on the thyroid. Thyroid volume, hypoechogenicity and nodules (by ultrasound), presence of antithyroid peroxidase (anti-TPO) antibodies, and abnormal thyroid-stimulating hormone (TSH) levels in serum (by radioimmunoassay) were examined in 101 adults from the PCB-polluted area in 360 controls. Serum levels of PCBs, hexachlorobenzene, gamma-hexachlorocyclohexane (HCH), p,p'-DDT(1,1,1-trichloro-2,2'-bis(p-chlorophenyl)ethane), and p,p'-DDE(1,1-dichloro-2,2'-bis(p-chlorophenyl)ethene) were measured by high-resolution gas chromatography. Very high levels of PCBs were found in the polluted area (7300 +/- 871 ng/g lipids) compared with controls (2045 +/- 147 ng/g). Positive correlations (P < 0.001) were found between the levels of all organochlorines and their total except for hexachlorocyclohexane (HCH). In the polluted area, the highest thyroid volumes (18.7 +/- 2.32 mL; mean +/- SE) were clustered among 23 subjects (17 males and six females) with PCB levels above 10,000 ng/g (range 10,000-58,667 ng/g). In the remaining 438 subjects the thyroid volume was 14.2 +/- 0.29 mL. These data suggest that there might be a threshold serum PCB level of approximately 10,000 ng/g that may influence the thyroid volume. A two-way ANOVA showed that all thyroid volumes in the polluted area were significantly higher (P < 0.001) than in the control area. In males from the polluted area, the frequencies of thyroid hypoechogenicity, thyroid nodules, positive anti-TPO, and abnormal TSH level were higher than in males from the control area, whereas such differences were not observed in females. Increased thyroid volume and indicators of potential thyroid dysfunction were associated with long-term environmental exposure to PCBs. These effects on the thyroid were confined to subjects with PCB levels above 10,000 ng/g of lipid (thyroid volume) and to males from the polluted area (thyroid hypoechogenicity, thyroid nodules, positive anti-TPO, and abnormal TSH).

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 12762077 [PubMed - indexed for MEDLINE]

26: Occup Environ Med. 2003 Apr;60(4):301-3.

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Organochlorine compounds and concentrations of thyroid stimulating hormone in newborns.

Ribas-Fitó N, Sala M, Cardo E, Mazón C, De Muga ME, Verdú A, Marco E, Grimalt JO, Sunyer J.

Respiratory and Environmental Health Research Unit, Institut Municipal d'Investigació Mèdica, Barcelona, Spain.

AIMS: To assess the association between prenatal exposure to organochlorine compounds and thyroid status in newborns from an area with high levels of hexachlorobenzene (HCB). METHODS: A total of 98 mother-infant pairs (83.1% of all children born during the period 1997-99 in a specific area polluted with HCB) were recruited. Levels of organochlorine compounds were measured in 70 cord serum samples. Concentrations of thyroid stimulating hormone (TSH) were measured in plasma of all newborns three days after birth. RESULTS: All newborns had concentrations of TSH within the range of normal reference values (<25 mU/l). Dichlorodiphenyl dichloroethylene (p,p'DDE), beta-hexachlorocyclohexane (beta-HCH), polychlorinated biphenyl (PCB) 138 and 118 were related to higher concentrations of TSH, although only significant for beta-HCH. Levels of HCB were not associated with TSH. CONCLUSIONS: Although this community is highly exposed to HCB, no association was found between this organochlorine and TSH concentrations at birth.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 12660379 [PubMed - indexed for MEDLINE]

PMCID: PMC1740513

27: Ann N Y Acad Sci. 2002 Dec;982:123-36.

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Results of long-term experimental studies on the carcinogenicity of ethylene-bis-dithiocarbamate (Mancozeb) in rats.

Belpoggi F, Soffritti M, Guarino M, Lambertini L, Cevolani D, Maltoni C.

Cancer Research Center, European Ramazzini Foundation for Oncology and Environmental Sciences, Bologna, Italy.

Mancozeb, an ethylene-bis-dithiocarbamate (EBDC), has been one of the most commonly used fungicides in commercial use for several decades. Nevertheless, up to now, no adequate published experimental studies on the carcinogenicity of Mancozeb have been published. Because of the importance of the compound and of the number of people potentially exposed (workers engaged in the production and use of the fungicide, people living in agricultural areas where the compound is sprayed, and people consuming polluted products), a long-term experimental study of Mancozeb was begun at the Cancer Research Center of the Ramazzini Foundation. Groups of 150 male and female Sprague-Dawley rats, 8 weeks old at the start of the treatment, were administered Mancozeb at the concentration of 1000, 500, 100, 10, and 0 ppm in feed supplied ad libitum for 104 weeks. At the end of the treatment, animals were kept under controlled conditions until spontaneous death. Mancozeb caused an increase in (1) total malignant tumors, (2) malignant mammary tumors, (3) Zymbal gland and ear duct carcinomas, (4) hepatocarcinomas, (5) malignant tumors of the pancreas, (6) malignant tumors of the thyroid gland, (7) osteosarcomas of the bones of the head, and (8) hemolymphoreticular neoplasias. On the basis of these data, Mancozeb must be considered a multipotent carcinogenic agent.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 12562632 [PubMed - indexed for MEDLINE]

28: Sci Total Environ. 2002 Aug 5;295(1-3):207-15.

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Burden of organochlorine pesticides in blood and its effect on thyroid hormones in women.

Rathore M, Bhatnagar P, Mathur D, Saxena GN.

Department of Zoology, University of Rajasthan, Jaipur, India.

Man has utilized a wide variety of pesticides to combat the crop pests and vectors of human diseases. However, in this process, he has overlooked the darker side of these noxious chemicals, the concentrations of which have reached the environment and pose serious threats, such as mutagenesis, teratogenesis, carcinogenesis and endocrine dysfunction in various components of the ecosystem. The present study was planned to assess the burden of organochlorine pesticides and their influence on thyroid function in women. The study included a total of 123 women from Jaipur City who visited the Thyroid clinic in SMS Medical College and Hospital. One hundred women showed normal thyroid hormone levels while the remaining 23 women had depleted T4 and high TSH levels. The qualitative and quantitative estimation of organochlorine pesticides was carried out by gas chromatography. Out of the analyzed pesticides, the concentration of p,p'-DDT and its metabolites was higher in all the subjects, but dieldrin was found to be significantly high in the hypothyroid women. The correlation analysis for dieldrin and depleted T4 levels in hypothyroid women elicited an inverse relationship between them.

PMID: 12186288 [PubMed - indexed for MEDLINE]

29: Hum Exp Toxicol. 2002 Apr;21(4):217-21.

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Effects of carbendazim on rat thyroid, parathyroid, pituitary and adrenal glands and their hormones.

Barlas N, Selmanoglu G, Koçkaya A, Songür S.

Department of Biology, Science Faculty, Hacettepe University, Beytepe, Ankara, Turkey. [email protected]

The purpose of this study is to determine the effects of low and high dose of carbendazim on the level of certain hormones and endocrine glands (thyroid, parathyroid, adrenal and pituitary glands) of male rats. Carbendazim is a systemic fungicide with activity against a number of plant pathogens. In this study, daily doses of 0, 150, 300 and 600 mg/kg per day carbendazim were applied to male rats by gavage for 15 weeks. At the end of the experiment, T3, T4, TSH, ACTH and GH levels in rat serum were analysed. Thyroid, parathyroid, adrenal and pituitary glands of rats were taken. A significant increase was observed in serum T3 levels of the rats, which were exposed to 300 mg/kg per day carbendazim doses, compared to the serum T3 levels of the control group. There were no differences between the control and carbendazim-treated group of rats regarding serum TSH, T4, ACTH and growth hormone levels. This showed us that carbendazim caused histopathological damages in thyroid, parathyroid and adrenal glands of rats. No changes were observed in pituitary glands of treated rats. These results suggest that a high quantity of subchronic carbendazim exposure affects thyroid, parathyroid and adrenal glands.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 12099623 [PubMed - indexed for MEDLINE]

30: Toxicol Sci. 2002 Jun;67(2):207-18.

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Thyroid toxicity due to subchronic exposure to a complex mixture of 16 organochlorines, lead, and cadmium.

Wade MG, Parent S, Finnson KW, Foster W, Younglai E, McMahon A, Cyr DG, Hughes C.

Growth and Development Section, Environmental and Occupational Toxicology Section, Environmental Health Directorate, Health Canada, Tunney's Pasture, Ottawa, Ontario, Canada K1A 0L2. [email protected]

The human population in the industrialized world is ubiquitously exposed to complex mixtures of persistent pollutants that contaminate food, water, and air. A large number of these contaminants have been shown to cause significant toxicity to the hypothalamic-pituitary-thyroid (HPT) axis in laboratory animal studies, through a variety of mechanisms, although these effects occur at levels of exposure greatly in excess of common human exposure. While many of the mechanisms of thyroid toxicity of these substances are potentially complementary, little is known of the degree of interaction of common persistent contaminants on responses of the HPT axis. To investigate the potential effects of a complex, environmentally relevant mixture on the HPT axis, sexually mature male rats were administered a mixture of 16 common organochlorines (dichlorodiphenoxytrichloroethane [DDT], p,p'-dichlorodiphenoxydichloroethylene [p,p'-DDE], hexachlorobenzene [HCB], tetrachlorodibenzo-p-dioxin [TCDD], polychlorinated biphenyls [PCBs], methoxychlor, endosulfan, heptachlor, hexachlorocyclohexane, dieldrin, aldrin, mirex, and several chlorinated benzenes, and metal contaminants [lead, cadmium]). The doses of the mixture that were administered were related to minimum risk levels or tolerable daily intakes of these substances, as derived by risk assessment with the 1x, 10x, 100x, and 1000x groups receiving mixture components at doses equivalent to 1x, 10x, 100x, or 1000x the minimum risk level (or tolerable daily intake, reference dose), respectively. After 70 daily treatments by gavage, endpoints related to circulating thyroid hormone (serum thyroxine [T(4)], triiodothyronine [T(3)], thyroid stimulating hormone [TSH], and serum T(3) uptake [T(3)-up]), thyroid gland histomorphology (thyroid follicle cross sectional area, epithelial height, follicle roundness or aspect ratio, colloid/epithelial ratio) and hepatic metabolism of thyroid hormone (UDP-glucuronyl transferase [UGT] and outer-ring deiodinase [ORD]) were assessed. All examined endpoints were significantly altered by the mixture albeit with great variability between endpoints in the sensitivity. While most endpoints examined did not show significant changes at mixture doses below 1000x, 2 endpoints, TSH and hepatic outer ring deiodinase activity, were significantly increased and decreased, respectively, by 1x dose and showed dose-related increases in severity with increasing dose. Median thyroid follicle cross sectional area was also increased by the lowest dose of the mixture but decreased with subsequent increases in dose until, at the highest dose, this parameter was significantly reduced relative to control. The relative sensitivity of endpoints of thyroid function in detecting toxicity of the mixture was TSH = ORD = median follicle area >> T(3) > all other endpoints. These results demonstrate that low doses of ubiquitous environmental contaminants can alter HPT physiology in sexually mature males.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 12011480 [PubMed - indexed for MEDLINE]

31: Environ Health Perspect. 2002 Jun;110 Suppl 3:363-7.

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Clues from wildlife to create an assay for thyroid system disruption.

Colborn T.

Wildlife and Contaminants Program, World Wildlife Fund, 1250 24th Street NW, Washington, DC 20037-9736, USA. [email protected]

In 1996 the U.S. Congress charged the U.S. Environmental Protection Agency to develop a screening program to test chemicals for their possible estrogenic and other endocrine effects. Shortly thereafter, the Chemical Guidelines Program of the Organisation for Economic Co-operation and Development's (OECD) Environmental Directorate organized a Task Force on Endocrine Disruption Testing and Assessment to coordinate development of internationally harmonized screening and testing protocols. Most of the research devoted to this effort has focused on detecting impaired estrogenicity, androgenicity, and/or steroidogenesis, with little progress toward developing assays to detect chemicals that might interfere with thyroid function. Despite the fact that wildlife biologists have been reporting abnormal thyroid gland development and unusual thyroid hormone (TH) and retinoid ratios in fish and birds since the early 1960s, few studies have demonstrated an association between an environmental contaminant and a particular health end point other than reduced reproductive success at the population level. This article is a review of the literature that specifically examines THs and their role in normal behavior and development in wildlife. It presents several studies that associated changes in the thyroid gland, TH concentrations, and behavior with contaminant exposure. The goal of this article is to provide fodder for the creation of simple screens to detect possible thyroid system agonists and antagonists.

Publication Types:

• Research Support, Non-U.S. Gov't

• Review

PMID: 12060830 [PubMed - indexed for MEDLINE]

PMCID: PMC1241184

32: Cancer Lett. 2002 Apr 8;178(1):1-9.

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Improvement of a two-stage carcinogenesis model to detect modifying effects of endocrine disrupting chemicals on thyroid carcinogenesis in rats.

Takagi H, Mitsumori K, Onodera H, Nasu M, Tamura T, Yasuhara K, Takegawa K, Hirose M.

Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-Ku, Tokyo 158-8501, Japan.

In order to improve the sensitivity of our previously established thyroid carcinogenesis model and to clarify whether endocrine disrupting chemicals with weak estrogenic activity have any modifying effects on the development of thyroid proliferative lesions, 6-week-old female castrated F344 rats were first given a single subcutaneous injection of 2000 mg/kg body weight of N-bis(2-hydroxypropyl)nitrosamine. From 1 week later, they received diets with: no supplement (basal diet (BD) group); cholesterol pellets containing 0.5 mg 17 beta-estradiol 3-benzoate (EB); or diet admixed with 1000 ppm methoxychlor (MXC) or 10,000 ppm bisphenol A (BPA) for 20 weeks. Furthermore, additional groups were administered 200 ppm sulfadimethoxine (SDM) in the drinking water simultaneously with the BD, EB, MXC or BPA treatments. Thyroid follicular cell hyperplasias, adenomas and/or carcinomas were induced only in the EB+SDM group, the incidences of non-malignant lesions being significantly increased, as compared with the BD+SDM group values. Furthermore, the serum level of thyroid stimulating hormone (TSH) was significantly increased in this group. No significant variation in quantitative values for thyroid proliferative lesions or TSH levels were observed in the other treated groups. The results of the present study convincingly indicate that EB, with strong estrogenic activity, but not MXC and BPA, with weak estrogenic activities, exerts promoting effects on thyroid carcinogenesis in rats. The present modified rat two-stage thyroid carcinogenesis model appears to have advantages over our previous model for screening purposes.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 11849735 [PubMed - indexed for MEDLINE]

33: Sci Total Environ. 2002 Feb 4;284(1-3):75-84.

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Association between chronic exposure to pesticides and recorded cases of human malignancy in Gaza Governorates (1990-1999).

Safi JM.

Faculty of Agriculture, Al-Azhar University, Gaza, Palestinian National Authority. [email protected]

Epidemiological association between chronic exposure to pesticides and recorded cases of human malignancy in Gaza Governorates during the years 1990-1999 was studied. The pesticide usage in Gaza Governorates was recorded in detail. It ranged from 216.9 to 393.3 t from 1990 to 1999, respectively. Banned and extremely hazardous pesticides are identified according to their carcinogenicity, genotoxicity and cytotoxicity. Hospital cases of cancers in men and women were recorded. Each tumor type was grouped according to sex and age group from 0 to > 65 years. Total cases recorded in males were 2277, with average annual incidence and age-adjusted rate/100,000 was 53.2 and 96.8 respectively, whereas the total for females was 2458 cases, average annual incidence and age-adjusted rate/100,000 was 59.7 and 105.3, respectively, over the same 10 years. Lung cancer, lymphomas, leukemia, cancers of the urinary bladder, prostate, brain, colon, stomach and liver were the most abundant among males, while breast cancer, leukemia, lymphomas, cancers of the brain, uterus, lung, thyroid gland and liver were the most abundant in females. Statistical analysis using correlation coefficients and P values showed highly significant positive correlations between the type of pesticide and cancer incidence for male, female and both sexes. Correlation coefficients and P values, respectively, for both sexes were: 0.992 and 0.000 for insecticides; 0.952 and 0.000 for fungicides; 0.812 and 0.004 for herbicides; 0.925 and 0.000 for nematicides; 0.992 and 0.000 for others; and 0.994 and 0.000 for all types of pesticides. In the densely populated agricultural areas, it is not possible to separate or differentiate between occupational and general public exposure. Consequently, the introduction of and heavy use and misuse of pesticides and other toxic substances in the Gaza environment is suspected to correlate with the growing incidence of cancer. Precise determination of the effects of chronic exposure is, therefore, urgently needed. Future legislation to stop and regulate the use of extremely hazardous compounds will be essential. Continuous records for chronic diseases and cancers are also required for future follow-ups and periodical risk-assessment evaluations. Hence, further epidemiological studies are needed with detailed exposure assessment for individual pesticides, taking measures to reduce risk into consideration.

PMID: 11846176 [PubMed - indexed for MEDLINE]

34: Toxicol Sci. 2002 Feb;65(2):288-98.

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Spinosad insecticide: subchronic and chronic toxicity and lack of carcinogenicity in Fischer 344 rats.

Yano BL, Bond DM, Novilla MN, McFadden LG, Reasor MJ.

Toxicology and Environmental Research and Consulting, The Dow Chemical Company, 1803 Building, Midland, Michigan, 48674, USA. [email protected]

Spinosad is an insecticide derived from a naturally occurring bacterium via fermentation. The toxicity of spinosad was characterized in subchronic and chronic toxicity/oncogenicity studies conducted according to standard toxicology regulatory guidelines. Subchronic toxicity was evaluated in groups of 10 Fischer 344 rats/sex given feed containing 0, 0.05, 0.1, 0.2, or 0.4% spinosad (Study 1) or 0, 0.003, 0.006, 0.012, or 0.06% spinosad (Study 2) for 13 weeks. Lower body weights and increased mortality occurred in rats given 0.4% spinosad. Microscopic effects were observed in the adrenal glands, liver, lymphoid cells, reproductive tissues, kidney, thyroid, stomach, lung, and skeletal muscle of rats given > or = 0.05% spinosad, and consisted primarily of vacuolation of cells; however, degenerative, regenerative, and/or inflammatory changes were also noted in some tissues. Vacuolation within a number of tissues was ultrastructurally characterized by an increase in size and number of lysosomes that contained extensive membranous whorls consistent with phospholipidosis. The no observed effect level (NOEL) in the 13-week studies was 0.012% (24 mg/kg/day) spinosad. Chronic toxicity and oncogenicity were evaluated in groups of 60 Fischer 344 rats/sex given feed containing 0, 0.005, 0.02, 0.05, or 0.1% spinosad for up to 2 years. Rats given 0.1% spinosad for 1 year had microscopic effects similar to those observed in the subchronic studies. Vacuolation and inflammation of the thyroid gland also occurred in rats given 0.05% spinosad for 1 year. Excessive mortality occurred in rats from the oncogenicity study given 0.1% spinosad by 21 months, and surviving rats were euthanized because the maximum tolerated dose had been exceeded. Rats given 0.05% spinosad for 2 years had vacuolation and/or inflammation involving the thyroid, lymphoid tissue, and lung. Rats given 0.05% spinosad had similar numbers of neoplasms as control rats, indicating that spinosad was not carcinogenic at dose levels up to 0.05%. The NOEL at 2 years was 0.005% (2.4 mg/kg/day) spinosad.

PMID: 11812933 [PubMed - indexed for MEDLINE]

35: Environ Toxicol Chem. 2001 Aug;20(8):1709-15.

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Effects of fungicides on thyroid function, metabolism, and thermoregulation in cotton rats.

Tomasi TE, Ashcraft J, Britzke E.

Department of Biology, Southwest Missouri State University, Springfield 65804, USA. [email protected]

Among the myriad of recent studies on endocrine-disrupting chemicals, relatively few involve thyroid disruption, and most of these address exposure/disruption during embryonic life. Of those involving adult vertebrates, the endpoints examined are thyroid measurements. Even though thyroid disruption could potentially interfere with energy metabolism and thermoregulation such that over-winter survival might be compromised, the possible energetic consequences of these thyroid perturbations have not been investigated. We assessed thyroid function and measured resting metabolic rates of cotton rats chronically exposed to the fungicides vinclozolin or mancozeb. In addition, we measured norepinephrine-induced nonshivering thermogenesis and cold-induced thermogenesis and then cold-acclimated the mancozeb animals. Although thyroid hormone concentrations generally decreased, this was compensated for by an increase in thyroxine turnover (vinclozolin study only) such that thyroxine utilization rate was not different. In addition, there was no difference between the treated and control animals in any of the metabolic parameters measured. It is concluded that wild rodents exposed to these compounds are not energetically compromised.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 11491553 [PubMed - indexed for MEDLINE]

36: Toxicol Pathol. 2001 Mar-Apr;29(2):250-9.

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Subchronic sodium chlorate exposure in drinking water results in a concentration-dependent increase in rat thyroid follicular cell hyperplasia.

Hooth MJ, Deangelo AB, George MH, Gaillard ET, Travlos GS, Boorman GA, Wolf DC.

Environmental Carcinogenesis Division, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.

Chlorine dioxide (ClO2) is an effective drinking water disinfectant, but sodium chlorate (NaClO3) has been identified as a potentially harmful disinfection by-product. Studies were performed to describe the development of thyroid lesions in animals exposed to NaClO3 in the drinking water. Male and female F344 rats and B6C3F1 mice were exposed to 0, 0.125, 0.25, 0.5, 1.0, or 2.0 g/L NaClO3 for 21 days. Additional male F344 rats were exposed to 0, 0.001. 0.01. 0.1, 1.0. or 2.0 g/L NaClO3 for 90 days. Female F344 rats were exposed to 0, 0.5, 1.0, 2.0, 4.0, or 6.0 g/L of NaClO3 for 105 days. Thyroid tissues were processed by routine methods for light microscopic examination, and follicular cell hyperplasia was diagnosed using a novel method. Thyroid hormone levels were altered significantly after 4 and 21 days. NaClO, treatment induced a concentration-dependent increase in the incidence and severity of thyroid follicular cell hyperplasia. Male rats are more sensitive to the effects of NaClO3 treatment than females. Follicular cell hyperplasia was not present in male or female B6C3F1 mice. These data can be used to estimate the human health risk that would be associated with using ClO2, rather than chlorine, to disinfect drinking water.

Publication Types:

• Research Support, U.S. Gov't, Non-P.H.S.

PMID: 11421493 [PubMed - indexed for MEDLINE]

37: Hum Exp Toxicol. 2000 Sep;19(9):497-501.

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Assessment of thyroid function in pesticide formulators.

Zaidi SS, Bhatnagar VK, Gandhi SJ, Shah MP, Kulkarni PK, Saiyed HN.

National Institute of Occupational Health (Indian Council of Medical Research), Meghani Nagar, Ahmedabad.

Thirty male pesticide formulators exposed to the dust and liquid formulation of endosulfan, quinalphos, chlorpyriphos, monocrotophos, lindane, parathion, phorate, and fenvalerate and 20 comparable control subjects from the same area of study were examined for the evaluation of thyroid function tests. The level of TSH was elevated (about 28%) in pesticide formulators as compared to a control group, but the increase was statistically insignificant. Based on the individual TSH measurement, 3 of 30 formulators had isolated elevated levels of TSH and seem to have acquired sub-clinical hypothyroidism; five had TSH values slightly elevated to the upper boarder line (4.03 muIU/ml); and the majority of formulators (N= 22) had TSH values in the normal range varying from 1.29 to 3.9 muIU/ml. Total T3 was suppressed significantly (P< 0.01) in formulators, while marginal decrease (about 7%) was noticed in T4 level. This study indicated thyroid function impairment in few pesticide formulators.

PMID: 11204551 [PubMed - indexed for MEDLINE]

38: Nippon Rinsho. 2000 Dec;58(12):2527-32.

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[Endocrine disrupting chemicals and carcinogenesis--breast, testis and prostate cancer]

[Article in Japanese]

Imaida K, Shirai T.

1st Department of Pathology, Nagoya City University Medical School.

Since exogenous hormones, including hormonal medicines such as diethylstilbestrol (DES), have been shown carcinogenic potentials in human and animals, it has been worried about whether endocrine disrupting chemicals(EDCs) have also carcinogenic potentials at their target organs, such as prostate, mammary gland, testes, uterus, ovary, thyroid, etc. In experimental animals, mammary tumors are induced by some pesticides, such as DDT and atrazine. Although testicular tumors are also induced by some EDCs, such as DES and E2, most of tumors are interstitial cell tumors, but not germ cell tumors, which are most common testicular tumors in man. Epidemiological studies showed that there is no EDC which clearly possess carcinogenic potentials in man, except dioxin and hormonal medicines.

Publication Types:

• English Abstract

• Review

PMID: 11187749 [PubMed - indexed for MEDLINE]

39: Toxicol Sci. 2000 Dec;58(2):366-76.

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The effects of atrazine on female wistar rats: an evaluation of the protocol for assessing pubertal development and thyroid function.

Laws SC, Ferrell JM, Stoker TE, Schmid J, Cooper RL.

National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. [email protected]

The effects of atrazine (ATR), a chlorotriazine herbicide, on the onset of puberty were evaluated in Wistar rats. Female rats were dosed by oral gavage from postnatal day(s) (PND) 22 through PND 41 with 0, 12.5, 25, 50, 100, or 200 mg ATR/kg. Vaginal opening (VO) was significantly delayed 3.4, 4.5, or greater than 6.8 days by 50, 100, and 200 mg/kg, respectively. VO had not occurred in 4 of 15 females in the 200 mg/kg group by the time of necropsies (PND 41). Body weight (bw) at necropsy was reduced in the 200 mg/kg group by 11.6%, but was not different from the control (0) in the 50 and 100 mg/kg groups. To examine the influence of reduced bw on pubertal development, a group of pair-fed controls was included whose daily food intake was dependent upon the amount consumed by their counterpart in the 200 mg/kg group. Although necropsy bw was reduced to the same extent as the ATR females, VO in the pair-fed controls was not significantly delayed. Adrenal, kidney, pituitary, ovary, and uterine weights were reduced by 200 mg/kg ATR. Serum T(3), T(4), and TSH were unaltered by ATR, which was consistent with no histopathologic/morphologic changes in the thyroid. Estrous cyclicity was monitored in a second group of females from VO to PND 149. The number of females displaying regular 4- or 5-day estrous cycles during the first 15-day interval after VO was lower in the 100 and 200 mg/kg ATR and pair-fed controls. Irregular cycles were characterized by extended periods of diestrus. By the end of the second 15-day interval (PND 57-71), no effects on estrous cyclicity were observed. These data show that ATR can delay the onset of puberty and alter estrous cyclicity in the female Wistar rat ( NOAEL of 25 mg/kg). Reduced food consumption and bw did not account for the delay in VO, because this effect was not observed in the pair-fed controls. In addition, the effect on estrous cyclicity was observed in the 100 mg/kg ATR group where no significant reduction in bw was observed.

PMID: 11099648 [PubMed - indexed for MEDLINE]

40: Mol Cell Endocrinol. 2000 Oct 25;168(1-2):127-34.

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Effect of thyroid hormones on mitochondrial oxygen free radical production and DNA oxidative damage in the rat heart.

López-Torres M, Romero M, Barja G.

Department of Animal Biology II (Animal Physiology), Faculty of Biology, Complutense University, 28040, Madrid, Spain. [email protected]

Mitochondria seem to be involved in oxygen radical damage and aging. However, the possible relationships between oxygen consumption and oxygen radical production by functional mitochondria, and oxidative DNA damage, have not been studied previously. In order to analyze these relationships, male Wistar rats of 12 weeks of age were rendered hyper- and hypothyroid by chronic T(3) and 6-n-propyl-2-thiouracil treatments, respectively. Hypothyroidism decreased heart mitochondrial H(2)O(2) production in States 4 (to 51% of controls; P<0.05) and 3 (to 21% of controls; P<0.05). In agreement with this, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) decreased in the heart genomic DNA of hypothyroid animals to 40% of controls (P<0.001). Studies with respiratory inhibitors showed that the decrease in oxygen radical generation observed in hypothyroidism occurred at Complex III (mainly) and at Complex I; that decrease was due to the presence of a lower free radical leak in the respiratory chain (P<0.05). Hyperthyroidism did not significantly change heart mitochondrial H(2)O(2) production since the increase in State 4 oxygen consumption in comparison with control and hypothyroid animals (P<0.05) was compensated by a decrease in the free radical leak in relation to control animals (P<0.05). In agreement with this, heart 8-oxodG was not changed in hyperthyroid animals. The lack of increase in H(2)O(2) production per unit of mitochondrial protein will protect mitochondria themselves against self-inflicted damage during hyperthyroidism.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 11064159 [PubMed - indexed for MEDLINE]

41: Toxicol Sci. 2000 Nov;58(1):50-9.

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The effect of atrazine on puberty in male wistar rats: an evaluation in the protocol for the assessment of pubertal development and thyroid function.

Stoker TE, Laws SC, Guidici DL, Cooper RL.

Gamete and Early Embryo Biology Branch, and Endocrinology Branch, Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.

Since atrazine (ATR), a chlorotriazine herbicide, has been shown previously to alter the secretion of luteinizing hormone (LH) and prolactin (PRL) through a direct effect on the central nervous system (CNS), we hypothesized that exposure to ATR in the EDSTAC male pubertal protocol (juvenile to peripubertal) would alter the development of the male rat reproductive system. We dosed intact male Wistar rats from postnatal day (PND) 23 to 53 and examined several reproductive endpoints. ATR (0, 12.5, 25, 50, 100, 150, or 200 mg/kg) was administered by gavage and an additional pair-fed group was added to compare the effects of any decreased food consumption in the high dose group. Preputial separation (PPS) was significantly delayed in the 12.5, 50, 100, 150, and 200 mg/kg ATR dose groups. PPS was also delayed in the pair-fed group, although significantly less than in the high dose-ATR group. The males were killed on PND 53 or 54, and pituitary, thyroid, testes, epididymides, seminal vesicles, and ventral and lateral prostates were removed. ATR (50 to 200 mg/kg) treatment resulted in a significant reduction in ventral prostate weights, as did the reduced food consumption of the pair-fed group. Testes weights were unaffected by atrazine treatment. Seminal vesicle and epididymal weights were decreased in the high dose-ATR group and the control pair-fed group. However, the difference in epididymal weights was no longer significantly different when body weight was entered as a covariable. Intratesticular testosterone was significantly decreased in the high dose-ATR group on PND 45, but apparent decreases in serum testosterone were not statistically significantly on PND 53. There was a trend for a decrease in luteinizing hormone (LH) as the dose of ATR increased; however, dose group mean LH was not different from controls. Due to the variability of serum prolactin concentrations on PND 53, no significant difference was identified. Although prolactin is involved in the maintenance of LH receptors prior to puberty, we observed no difference in LH receptor number at PND 45 or 53. Serum estrone and estradiol showed dose-related increases that were significant only in the 200 mg/kg-ATR group. No differences were observed in thyroid stimulating hormone (TSH) and thyroxine (T4) between the ATR groups and the control; however triiodothyronine (T3) was elevated in the high dose-ATR group. No differences in hormone levels were observed in the pair-fed animals. These results indicate that ATR delays puberty in the male rat and its mode of action appears to be altering the secretion of steroids and having subsequent effects on the development of the reproductive tract, which appear to be due to ATR's effects on the CNS. Thus, ATR tested positive in the pubertal male screen that the Endocrine-Disrupter Screening and Testing Advisory Committee (EDSTAC) is considering as an optional screen for endocrine disrupters.

Publication Types:

• Evaluation Studies

PMID: 11053540 [PubMed - indexed for MEDLINE]

42: Clin Exp Obstet Gynecol. 1999;26(3-4):207-10.

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Disposition of pesticides and toxicants in the human reproductive system in cases of acute poisoning.

Relakis K, Sifakis S, Froudarakis G, Papadopoulou E, Michalodimitrakis EN, Koumantakis E, Tsatsakis A.

Department of Obstetrics and Gynecology, University Hospital of Heraklion, Crete, Greece.

The aim of this study was to estimate the penetration of some of the pesticides and toxicant substances in the human reproductive system. This knowledge is valuable because of the possible adverse influence of these substances on the human reproduction system and the development of the foetus during pregnancy. The existing data is mainly concerned with the results of experimental studies on animals or epidemiological studies. Here we report data concerning the disposition of several toxic xenobiotics (pesticides and solvents) in the tissues of the human reproductive system as well as in other organs and glands. Data was collected from cases of acute poisonings and derived mostly from autopsy materials. Xenobiotics were found to penetrate sampled tissues such as the testes, ovaries, epididymis, uterus, thyroid gland, as well as other human tissues. Further studies will clarify and confirm peculiarities of the penetration of a wide range of substances in various body tissues and will be the base of the estimation of the role of these toxicants in human reproductive ability and the outcome of pregnancy in humans.

PMID: 10668158 [PubMed - indexed for MEDLINE]

43: Crit Rev Toxicol. 2000 Mar;30(2):197-252.

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Endocrine-disrupting chemicals: prepubertal exposures and effects on sexual maturation and thyroid function in the male rat. A focus on the EDSTAC recommendations. Endocrine Disrupter Screening and Testing Advisory Committee.

Stoker TE, Parks LG, Gray LE, Cooper RL.

Gamete and Early Embryo Biology Branch, Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA.

Puberty in mammalian species is a period of rapid interactive endocrine and morphological changes. Therefore, it is not surprising that exposure to a variety of pharmaceutical and environmental compounds has been shown to dramatically alter pubertal development. This concern was recognized by the Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) that acknowledged the need for the development and standardization of a protocol for the assessment of the impact of endocrine-disrupting compounds (EDC) in the pubertal male and recommended inclusion of an assay of this type as an alternative test in the EDSTAC tier one screen (EPA, 98). The pubertal male protocol was designed to detect alterations of pubertal development, thyroid function, and hypothalamic-pituitary-gonadal (HPG) system peripubertal maturation. In this protocol, intact 23-day-old weanling male rats are exposed to the test substance for 30 days during which pubertal indices are measured. After necropsy, reproductive and thyroid tissues are weighed and evaluated histologically and serum taken for hormone analysis. The purpose of this review was to examine the available literature on pubertal development in the male rat and evaluate the efficacy of the proposed protocol for identifying endocrine-disrupting chemicals. The existing data indicate that this assessment of puberty in the male rat is a simple and effective method to detect the EDC activity of pesticides and toxic substances.

Publication Types:

• Review

PMID: 10759431 [PubMed - indexed for MEDLINE]

44: Endocrinology. 1999 Sep;140(9):4142-51.

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Hexachlorobenzene, a dioxin-type compound, increases malic enzyme gene transcription through a mechanism involving the thyroid hormone response element.

Loaiza-Pérez AI, Seisdedos MT, Kleiman de Pisarev DL, Sancovich HA, Randi AS, Ferramola de Sancovich AM, Santisteban P.

Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas y Universidad Autónoma de Madrid, Spain.

Hexachlorobenzene (HCB) is a dioxin-type chemical that acts mainly through the aryl hydrocarbon receptor. Chronic exposure of rats to HCB increases the activity of malic enzyme (ME). In this report, we show that this increase is correlated with an induction of ME messenger RNA (mRNA) levels, with the maximal HCB effect achieved after 9 days of intoxication. This effect is specific for ME, as other liver enzymes, such as glyceraldehyde-3-phosphate dehydrogenase, phosphoenol pyruvate carboxykinase, and mitochondrial alpha-glycerol-3-phosphate dehydrogenase, are not affected by HCB. The induction of ME mRNA levels is accompanied by an increase in ME promoter activity, as demonstrated by transient transfection experiments performed in rat hepatoma H35 cells. In an attempt to identify the cis-regulatory elements responsible for the HCB effect, different promoter deletions and mutations were used. The results obtained localize the responsive region between positions -315 and -177. This region does not contain either consensus xenobiotic response or activating protein-1 elements, the two main mediators of dioxin compounds described to date. In contrast, a thyroid hormone response element (TRE) is located between -281 to -261. Deletions and mutations of the TRE element do not respond to HCB, demonstrating that this element mediates the response of this dioxin-type compound. As ME gene expression is regulated mainly by thyroid hormones, we next investigated the role of T3 receptor (T3R) in the ME gene transcriptional induction mediated by HCB. Using Scatchard analysis, we show that neither T3R binding features for its ligand nor alpha1 or beta1T3R mRNA levels are changed with the toxic. In gel shift assays, however, we observed that protein/DNA complexes formed on TRE from the ME promoter were induced by HCB. Using an oligonucleotide with a mutation that eliminates the TRE function, we demonstrate a loss of the induced protein/DNA complexes. Together, these data suggest that the dioxin-type compound HCB increases ME gene transcription by modulating the levels of still unidentified nuclear proteins that bind to the TRE element of the ME promoter.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 10465287 [PubMed - indexed for MEDLINE]

45: Environ Res. 1999 May;80(4):383-8.

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Pentachlorophenol exposure in women with gynecological and endocrine dysfunction.

Gerhard I, Frick A, Monga B, Runnebaum B.

Department of Gynecological Endocrinology and Reproduction, University Hospital of Obstetrics and Gynecology, Voss-Strasse 9, Heidelberg, 69115, Germany.

Exposure to wood preservatives containing pentachlorophenol (PCP) was detected in 65 women who consulted the Endocrinological Department of the University Hospital of Obstetrics and Gynecology, Heidelberg, Germany, because of gynecological problems. Blood PCP levels ranged from 20.7 to 133 microg per liter of serum. One hundred and six women with similar clinical conditions, corresponding age and body weight, no PCP exposure in history, and PCP levels below 20 microg per liter of serum served as control group. Significant associations were found between serum PCP concentrations, age, and different parameters of the endocrine system. PCP may act centrally on a hypothalamic or suprahypothalamic level which may result in mild ovarian and adrenal insufficiency. PCP may, therefore, play a role in the increasing infertility problem. Copyright 1999 Academic Press.

PMID: 10330312 [PubMed - indexed for MEDLINE]

46: Thyroid. 1998 Sep;8(9):827-56.

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Effects of environmental synthetic chemicals on thyroid function.

Brucker-Davis F.

Wildlife and Contaminants Program, World Wildlife Fund, Washington, DC 20037, USA.

Synthetic chemicals are released into the environment by design (pesticides) or as a result of industrial activity. It is well known that natural environmental chemicals can cause goiter or thyroid imbalance. However, the effects of synthetic chemicals on thyroid function have received little attention, and there is much controversy over their potential clinical impact, because few studies have been conducted in humans. This article reviews the literature on possible thyroid disruption in wildlife, humans, and experimental animals and focuses on the most studied chemicals: the pesticides DDT, amitrole, and the thiocarbamate family, including ethylenethiourea, and the industrial chemicals polyhalogenated hydrocarbons, phenol derivatives, and phthalates. Wildlife observations in polluted areas clearly demonstrate a significant incidence of goiter and/or thyroid imbalance in several species. Experimental evidence in rodents, fish, and primates confirms the potentiality for thyroid disruption of several chemicals and illustrates the mechanisms involved. In adult humans, however, exposure to background levels of chemicals does not seem to have a significant negative effect on thyroid function, while exposure at higher levels, occupational or accidental, may produce mild thyroid changes. The impact of transgenerational, background exposure in utero on fetal neurodevelopment and later childhood cognitive function is now under scrutiny. There are several studies linking a lack of optimal neurological function in infants and children with high background levels of exposure to polychlorinated biphenyls (PCBs), dioxins, and/or co-contaminants, but it is unclear if the effects are caused by thyroid disruption in utero or direct neurotoxicity.

Publication Types:

• Review

PMID: 9777756 [PubMed - indexed for MEDLINE]

47: Biull Eksp Biol Med. 1997 Dec;124(12):676-7.

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[Morphologic and histochemical changes in the thyroid gland induced by single exposure to 2,4-DA]

[Article in Russian]

Malysheva LN, Zhavoronkov AA.

PMID: 9483326 [PubMed - indexed for MEDLINE]