Effect of the Metabolic Modification of Environmental Chemicals on Endocrine-disrupting Activity

Abstract

The endocrine-disrupting activities of various environmental chemicals are metabolically activated. For example, diphenyls, styrene oligomers, chalcones, trans-stilbene and 2-nitrofluorene are not estrogens, but after incubation with liver microsomes, their metabolites show estrogenic activities. Thus, these chemicals are estrogenically activated by the cytochrome P450 system. In contrast, the antiandrogenic activity of fenthion, an organophosphorus insecticide, is abolished after metabolism to sulfoxide and sulfone derivatives. Structural requirements of twenty bisphenol A related compounds, as well as various benzophenones, for estrogenic and antiandrogenic activities have been investigated. The estrogenic and antiandrogenic activities of Benzophenone 3, a representative UV absorbant, are activated by oxidative metabolism. Parabens (used as antimicrobial agents) exhibit estrogenic activity, and their potency shows a bell-shaped curve between C1 (methylparaben) and C12 (dodecylparaben) parabens. The AhR ligand activity of indirubin is decreased by metabolism. Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDE) are activated by hydroxylation to show estrogenic and thyroid hormone-disrupting activities. Halogen adjacent to a hydroxyl group is essential for thyroid hormone-disrupting activity. Tetrabromobisphenol A, tetrachlorobisphenol A and tetramethylbisphenol A also exhibit thyroid hormone-disrupting activity. Amphibian metamorphosis of tadpoles to frogs is affected by hydroxylated PCB, hydroxylated PBDE and bisphenol A derivatives. These chemicals suppress thyroid hormone-dependent metamorphosis, acting as antagonists of thyroid hormone. Thus, metabolic modification can have a dramatic impact on the endocrine-disrupting activities of environmental chemicals.