Impact/Purpose:

A critical risk assessment issue is the impact of developmental exposures on function later in life. Development is a period when hormone-mediated organizational changes in gene expression can have permanent consequences rather than simply mediating transient alterations. These organizational changes may not be apparent until later in life because functional changes do not occur until puberty or adulthood. Finally, it has been suggested that there are processes for which there may be no apparent threshold due to limitations in the kinds of regulatory, surveillance, and repair processes that create biological thresholds in adults. Studies with exposure doses spanning several orders of magnitude will need to be undertaken to address questions about developmental versus adult sensitivity and their dose-response relationships.

These studies will 1) provide hazard identification and dose response (to identify NOAELS and LOAELS) on critical EDCs, 2) identify data gaps in current test protocols, 3) identify useful endpoints for EDSTAC Tier 2 Testing protocols using enhanced multigenerational studies and 4) hopefully, identify the concentrations of the active toxicants in the fetal and maternal tissues during sexual differentiation for comparison to human exposures.

Description:

This project will determine the critical factors that account for exposures to endocrine disrupting chemicals, or EDCs (ER, AR, AhR mediated and inhibitors of steroidogenesis) during development resulting in adverse effects seen later in life in male and female offspring. Such factors include the period of vulnerability, tissue dosimetry, and cellular and molecular mechanisms of action, which ultimately will provide data for risk assessments on individual and mixtures of EDCs. Chemicals of interest have included antiandrogens, androgens, estrogens and TCDD-like chemicals. While the major focus of our research is on in utero or early post-natal exposures and subsequent evaluation of the organism during juvenile or adult life, the effects of exposure during puberty on maturation and subsequent function of the reproductive system also are considered. Mechanistic in vitro and in vivo studies are used because they provide the important information for understanding interspecies extrapolation of endpoints, windows of vulnerability, and dose-response relationships. Typically, after a chemical is positive in in vivo and/or in vitro "hazard identification studies", dose-response studies follow to identify the shape of the dose response curve and identify NOAELS and LOAELS, if they exist. We also are interested in obtaining data at low doses which raises several important issues associated with proper statistical and experimental design. Efforts to develop broad dose-response data will continue to determine biological-thresholds exist for all EDC effects.

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