There is widespread concern that exposure to chemicals in the environment may be related to the observed increase in the incidence of breast cancer. Among the chemicals of concern are polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs), which have the potential to disrupt estrogenic responses. It is difficult to predict the health effects of exposure to complex mixtures of these chemicals because individual congeners of PCBs and PAHs can be either estrogenic or anti-estrogenic and act through a variety of mechanisms potentially leading to additive, antagonistic or synergistic effects. Furthermore, the microbial reductive dechlorination of PCBs and the metabolic transformation of both PCBs and PAHs within the body, may substantially alter the activity of these mixtures. It is hypothesized that reductive dechlorination of PCBs increases the estrogenic activity of the resulting mixture, and that metabolism of PCBs and PAHs further alters the estrogenic and anti-estrogenic activity of these mixtures. Thus, the objective of this proposal is to determine how mixtures of PCBs and PAHs may interact and modulate estrogenic activity in human cells. Specifically we will: 1) Determine the estrogenic and anti-estrogenic activity of relevant complex mixtures of PCBs and PAHs. Extracts from sediment samples and mixtures reflecting the composition of PCBs and PAHs detected in human tissue, food and water will be tested in human breast cancer cells for their estrogenic and anti-estrogenic activity. 2) Determine how mixtures of PCBs and PAHs alter estrogenic activity and assess whether knowledge of the activity of the individual components is sufficient to predict the activity of the mixture. Mechanisms to be investigated include, estrogen receptor (ER) binding, regulation of ER level, metabolism of 17-estradiol metabolism of PCBs and PAHs in breast cancer cells. The nature of the interactions will be explored using full dose-response curves and probit analysis. 3) Determine the extent to which the estrogenic and anti-estrogenic activity of a mixture is altered by metabolism in human liver microsomes, and identify the major active metabolites. Metabolites generated from incubations in human liver microsomes, and identify the major active metabolites. Metabolites generated from incubations in human liver microsomes will be tested for their estrogenic and anti-estrogenic activity in human breast cancer cells. Knowledge gained from these studies will provide insight into the relationship between exposure to environmental estrogens and health risk.
