The goals of this project are: (1) to apply the biomarkers which have been developed for human reproductive epidemiology in experiments with a non-human primate model; (2) to carry out experiments in vivo which are relevant to the mechanisms of toxicity to primate reproductive physiology; (3) to test the utility of the in vivo biomarkers for detecting and characterizing reproductive toxicity of TCDD, an environmental chemical which has been shown to cause early fetal loss (EFL) in macaques; and (4) to initiate pilot studies on the reproductive toxicity of 13-cis retinoic acid, a vitamin A analogue, which is a potent human teratogen that also causes increased EFL. In vivo biomarkers will be validated for the animal model through surgical and chemical interventions which mimic ovarian and fetal toxicity. Animals will be treated with TCDD during the early post-implantation period and the biomarkers which characterize the resulting reproductive toxicity will be measured. This will include established ultrasonographic techniques for monitoring early development and distinguishing between the various forms of fetal loss after exposure to toxic agents, and endocrine parameters (progesterone, 17beta-estradiol, chorionic gonadotropin, relaxin) which will be assessed simultaneously. Collectively, the results of these experiments will permit a comparison between the physiologic events of early pregnancy in humans and nonhuman primates and will address the following questions: (1) whether spontaneous early fetal losses in humans are a model for toxicant-induced pregnancy failures; (2) whether biomarkers for human surveillance are valid for toxicant-induced events in the nonhuman primate; (3) whether the mechanism of action of suspected reproductive toxicants can be evaluated in whole animal experiments using the macaque model.
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