Summary (2005-2012)

The scientific theme for this competitive renewal continues the theme from the previous grant submission: effects of exposures to environmentally hazardous substances on reproduction and development in humans and wildlife. Special emphasis is placed on substances commonly encountered as a result of improperly managed waste disposal. The chemicals under study are all organics, both halogenated and nonhalogenated compounds. This program will focus on the underlying mechanics of xenobiotic/endocrine interactions and their effects to allow a better understanding of the implications of perturbations of reproductive and developmental processes by hazardous substances in the environment. Nine projects, 5 biomedical and 4 non-biomedical will study:

1. Epidemiological studies of effects on neurodevelopment of a population exposed to perchloroethylene (PCE, a peroxisome proliferator) in drinking water, and epidemiological techniques to study similar environmental problems (two biomedical projects);
2. Receptor based mechanistic studies of the role of intracellular receptors and signaling pathways in the development of organisms and tissues (receptors/pathway: Ah receptor, AhR; peroxisome proliferator activated receptor, PPAR; estrogen receptor, ER; androgen receptor, AR; MAP kinase pathway) for important xenobiotics (planar halogenated aromatic hydrocarbons, PHAHs; polycyclic aromatic hydrocarbons, PAHs; and peroxisome proliferators, especially phthalates) (three biomedical projects);
3. Mechanisms of toxicity and resistance of fish populations to PHAHs and xenoestrogens involving receptors (AhRs, PPARs, and ERs) and cytochrome P450s (one non-biomedical and two biomedical projects);
4. Studies of the mechanistic basis for reproductive and developmental effects observed in wildlife (including those mediated by receptors such as AhR and ER) exposed to a complex mixture in surface water from a Superfund site via groundwater and sediment (one non-biomedical project);
5. Mechanisms of oxidative dechlorination by an abiotic non-Heme iron catalyst for remediation of a wide variety of xenobiotics, including all those under study in other projects. The use of chlorinated ethylenes as a probe to study the oxidative mechanism of this biomimetic catalyst will also shed light on metabolism of these compounds by P450s (one non-biomedical project).