The Association of the Polychlorinated Biphenyl Class of Endocrine Disruptors With Polycystic Ovary Syndrome and Thyroid Dysfunction

Introduction:. Polychlorinated biphenyls (PCBs) are a class of endocrine disruptors with a long half-life in the body that are associated with irregular menses, growth and development delay, increased cancer risk, thyroid disorders and an increased risk of diabetes. Higher levels of PCBs have been related to polycystic ovary syndrome (PCOS). PCB toxicity depends on their structure, with coplanar PCBs being most toxic (akin to dioxins); therefore, PCB subtypes were determined to see if they differed in women with PCOS compared to normal controls. Methods:. PCB levels were compared in Caucasian women with (n=29) and without (n=30) PCOS and related to metabolic features. PCBs were fractionated then analysed by high-resolution gas chromatography-unit resolution mass spectrometry. Results:. The control and PCOS groups were age and BMI matched (p=ns); insulin resistance was not different (HOMA 1.7±1.0 v 2±1.6, p=ns) but free androgen index was increased in PCOS (p<0.004). PCB-118, 138, 153 and 180 were found in all subjects, whilst fewer subjects showed PCB-28(15/59), PCB-52(4/59) or PCB-101(26/59). There was no difference for PCB-188,138,153 and 180 between controls and PCOS, but all correlated with increasing age (p<0.01) and decreasing estimated glomerular filtration rate (p<0.05); no correlations with BMI, HOMA, testosterone, TSH or T3 were found; however, PCB-118 (the only coplanar PCB detected) associated with an increased T4/T3 ratio (p<0.01). Conclusion. Despite PCBs being banned over a decade ago, PCBs were detected, but did not differ between age and BMI matched women with and without PCOS. Thyroid dysfunction may be only associated with toxic coplanar PCBs, such as PCB-118 that was associated with a higher T4/T3 ratio.

Genetic differences in the aryl hydrocarbon receptor and CYP1A2 affect susceptibility to developmental polychlorinated biphenyl exposure in mice: Relevance to studies of human neurological disorders

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that remain a human health concern with the discovery of new sources of contamination and ongoing bioaccumulation and biomagnification. Children exposed during early brain development are at highest risk of neurological deficits, but there is some evidence that high PCB exposure in adults increases the risk of Parkinson’s disease. Our previous studies found allelic differences in the aryl hydrocarbon receptor and cytochrome P450 1A2 (CYP1A2) affect susceptibility to developmental PCB exposure, resulting in cognitive deficits and motor dysfunction. High-affinity AhrbCyp1a2(-/-) mice were most susceptible compared with poor-affinity AhrdCyp1a2(-/-) and wild type AhrbCyp1a2(+/+) mice. Our follow-up studies assessed biochemical, histological and gene expression changes to identify the brain regions and pathways affected. We also measured PCB and metabolite levels in multiple tissues to determine if genotype altered toxicokinetics. We found evidence of AHR-mediated immune suppression with reduced thymus and spleen weights and significantly reduced thyroxine at P14. In the brain, the greatest changes were seen in the cerebellum where a foliation defect was over-represented in Cyp1a2(-/-) mice. In contrast, we found no difference in tyrosine hydroxylase immuno-staining in the striatum. Gene expression patterns varied across the three genotypes, but there was clear evidence of AHR activation. Distribution of parent PCB congeners also varied by genotype with strikingly high levels of PCB 77 in poor-affinity AhrdCyp1a2(-/-) while AhrbCyp1a2(+/+) mice effectively sequestered coplanar PCBs in the liver. Together, our data suggest that the AHR pathway plays a role in developmental PCB neurotoxicity, but we found little evidence that developmental exposure is a risk factor for Parkinson’s disease.