AH RECEPTOR INDEPENDENT CNS/REPRODUCTIVE EFFECTS OF PCBS

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Evidence that environmental exposure to polychlorinated biphenyl (PCB) mixtures adversely affects human health is compelling enough that eight epidemiological studies are currently being conducted. Toxicity of PCB mixtures is generally attributed to their coplanar and mono-ortho- chlorinated congeners that bind to the same (Ah) receptor as does 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), and risk of exposure to PCBs is currently measured in terms of how many "TCDD equivalents" are present in the mixtures. However, most PCB congeners do not bind to the Ah receptor; PCB mixtures cause numerous biological responses not mediated by binding to the Ah receptor; and potent Ah receptor agonists constitute only a tiny percentage of all PCBs in environmental samples. The possibility that perinatal exposure to PCB mixtures adversely affects health in adulthood via Ah receptor-independent mechanisms is essentially unexplored. Our hypothesis is that PCB mixtures adversely affect development of the male reproductive, female reproductive, and central nervous systems via at least three Ah receptor-independent mechanisms, and that PCB mixtures do so at occupationally if not environmentally relevant exposure levels. To test this hypothesis, pregnant/lactating rats will be treated daily with prototype congeners that are major constituents of the human PCB body burden: 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), an inducer of phenobarbital-responsive, drug and steroid metabolizing enzymes; 2,2',5,5'-tetrachlorobiphenyl (PCB 52), a congener whose major metabolite is estrogenic; and 2,3,3',4,4'-pentachlorobiphenyl (PCB 105), a congener whose metabolites bind strongly to thyroid hormone-binding proteins. A fourth congener, the Ah receptor agonist 3,3',4,4',5-pentachlorobiphenyl (PCB 126), will serve as a positive control. Effects of these congeners on development of the male reproductive,, female reproductive, and central nervous systems of offspring of treated dams will be determined. Multiple endpoints within each organ system will be evaluated. For males, these include indices of androgenic status, quantitative analysis of spermatogenesis, fertility testing, and observations of masculine sexual behaviors and potential to display feminine sexual behavior. For females, these include plasma l7beta-estradiol concentrations, estrus cycling, fertility testing, and observations of feminine sexual behaviors. Plasma T4, T3, and TSH concentrations will be measured in both sexes during the critical neonatal period when sexual differentiation of the central nervous system occurs, and regional distribution of aromatase activity, estrogen receptors, and androgen receptors in the brain will also be determined. For each congener that adversely affects one or more organ systems, a dose-response experiment will be conducted to determine how sensitive rats are to in utero and lactational exposure to this type of congener. Such results will greatly facilitate the ability of health officials to make informed decisions about whether the "TCDD equivalents" approach to PCB risk assessment is sufficient to protect public health or whether one or more Ah receptor-independent actions of PCB mixtures must also be considered. The results will also facilitate future research on mechanisms by which PCBs cause developmental and reproductive toxicity, currently handicapped by lack of knowledge as to which congener types in complex mixtures cause the various toxic responses.