Impact of Pcbs On Thyroid Hormone Directed Brain Development

Analyses of steroid receptors are important for understanding molecular details of transcriptional control, as well as providing insight as to how an individual transacting factor contributes to cell identity and function. These studies have led to the identification of a superfamily of regulatory proteins that include receptors for thyroid hormone and the vertebrate morphogen retinoic acid. Although animals employ complex and often distinct ways to control their physiology and development, the discovery of receptor-related molecules in a wide range of species suggests that mechanisms underlying morphogenesis and homeostasis may be more ubiquitous than previously expected.

Commercial polychlorinated biphenyls (PCBs) and environmental extracts contain complex mixtures of congeners that can be unequivocally identified and quantitated. Some PCB mixtures elicit a spectrum of biochemical and toxic responses in humans and laboratory animals and many of these effects resemble those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatic hydrocarbons, which act through the aryl hydrocarbon (Ah)-receptor signal transduction pathway. Structure-activity relationships developed for PCB congeners and metabolites have demonstrated that several structural classes of compounds exhibit diverse biochemical and toxic responses. Structure-toxicity studies suggest that the coplanar PCBs, namely, 3,3',4,4'-tetrachlorobiphenyl (tetraCB), 3,3',4,4',5-pentaCB, 3,3',4,4',5,5'-hexaCB, and their monoortho analogs are Ah-receptor agonists and contribute significantly to the toxicity of the PCB mixtures. Previous studies with TCDD and structurally related compounds have utilized a toxic equivalency factor (TEF) approach for the hazard and risk assessment of polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) congeners in which the TCDD or toxic TEQ = sigma([PCDFi x TEFi]n)+sigma([PCDDi x TEFi]n) equivalent (TEQ) of a mixture is related to the TEFs and concentrations of the individual (i) congeners as indicated in the equation (note: n = the number of congeners). Based on the results of quantitative structure-activity studies, the following TEF values have been estimated by making use of the data available for the coplanar and monoortho coplanar PCBs: 3,3',4,4',5-pentaCB, 0.1; 3,3',4,4',5,5'-hexaCB, 0.05; 3,3',4,4'-tetraCB, 0.01; 2,3,3',4,4'-pentaCB, 0.001; 2,3',4,4',5-pentaCB, 0.0001; 2,3,3',4,4',5-hexaCB, 0.0003; 2,3,3',4,4',5'-hexaCB, 0.0003; 2',3,4,4',5-pentaCB, 0.00005; and 2,3,4,4',5-pentaCB, 0.0002. Application of the TEF approach for the risk assessment of PCBs must be used with considerable caution. Analysis of the results of laboratory animal and wildlife studies suggests that the predictive value of TEQs for PCBs may be both species- and response-dependent because both additive and nonadditive (antagonistic) interactions have been observed with PCB mixtures. In the latter case, the TEF approach would significantly overestimate the toxicity of a PCB mixture. Analysis of the rodent carcinogenicity data for Aroclor 1260 using the TEF approach suggests that this response is primarily Ah-receptor-independent. Thus, risk assessment of PCB mixtures that uses cancer as the endpoint cannot solely utilize a TEF approach and requires more quantitative information on the individual congeners contributing to the tumor-promoter activity of PCB mixtures.

The fact that neonates who subsequently have severe hypothyroidism have no evidence of the condition at birth suggests the possibility of the placental transfer of thyroid hormones. Recent studies have demonstrated the existence of such transfer in hypothyroid rats. To determine whether there is a transfer of thyroxine (T4) from mother to fetus, we studied 25 neonates born with a complete inability to iodinate thyroid proteins and therefore to synthesize T4. This total organification defect is an autosomal recessive disorder with an incidence of approximately 1 in 60,000 neonates in the Netherlands. In the cord serum of affected neonates, T4 levels ranged from 35 to 70 nmol per liter. Since these patients were unable to produce any T4, the T4 must have originated in their mothers. The estimated biologic half-life of serum T4 was 3.6 days (95 percent confidence interval, 2.7 to 5.3). In 15 neonates with thyroid agenesis, the serum levels and the disappearance kinetics of T4 were the same as those in the neonates with a total organification defect, suggesting that in these infants, the T4 also had a maternal origin. We conclude that in infants with severe congenital hypothyroidism, substantial amounts of T4 are transferred from mother to fetus during late gestation.