The long term objective of this project is to determine mechanisms by which TCDD causes reproductive and developmental toxicity in animals so as to better understand the potential hazards TCDD and related compounds pose to human health. Previous data from this laboratory have shown that the rat male reproductive system is exceptionally sensitive to maternal TCDD exposure. Effects include impaired prostate growth, reduced sperm numbers, and demasculinized sexual behaviors. The proposed project will continue to elucidate mechanisms for the male reproductive effects as well as extend the assessment of potential TCDD adverse effects and mechanisms to the female reproductive system and preimplantation embryo. Because the prostate is so vulnerable, effects on prostate budding, cell differentiation and proliferation, androgen metabolism, and mRNA abundance will be determined. Because TCDD decreases ejaculated sperm numbers far more than it impairs spermatogenesis, sperm release in urine and spontaneous ejaculates, and excurrent duct sperm and fluid transit will be assessed. A major emphasis of the proposed project is to evaluate the potential role of the aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) in both normal reproductive system development and TCDD-mediated reproductive and developmental toxicity. Because TCDD might act directly on reproductive organs, the ontogeny and distribution of AhR and ARNT in rat male and female reproductive organs and humans will be characterized. Because the AhR and ARNT are highly expressed in oocytes and TCDD can affect preimplantation development, the expression of AhR and ARNT and subsequent receptor-mediated responses following TCDD exposure will be assessed in mouse preimplantation embryos. Finally, the use of AhR and ARNT knockout mice are proposed to determine the role of these receptor proteins in both normal reproductive system and early embryo development, and in mediating TCDD effects on these processes. The results from the proposed studies should contribute to our mechanistic understanding of the reproductive and developmental risks associated with maternal exposure to TCDD and possibly related compounds.
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