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The overall aim of the proposed research is to understand the nature, extent and mechanisms of reproductive and endocrine toxicity of a representative xenobiotic estrogen, o,p'-DDT, and a putative xenobiotic antiandrogen, p,p'-DDE, in an established vertebrate model, the teleost Atlantic croaker. The following specific hypotheses will be tested: (1) Embryological development, gonadal differentiation, puberty and gonadal growth are sensitive stages of the teleost reproductive life history cycle to disruption by estrogenic and antiandrogenic chemicals; (2) The reproductive toxicities of o,p'-DDT and p,p'-DDE in both male and female croaker are primarily due to their estrogenic and antiandrogenic activities, respectively; (3) Endocrine disruption in males by xenoestrogens is mediated by their binding to the testicular estrogen receptor (ER) and disruption by antiandrogens in females is caused by binding to the ovarian androgen receptor (AR) in addition to the more traditional sites of estrogen and androgen action on the hypothalamus-pituitary-gonadal-liver axis; (4) Males in general are more sensitive than females to the reproductive effects of estrogenic chemicals.

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The effects of in vivo administration o,p'-DDT will be compared to those of a synthetic estrogen, diethylstilbestrol and the effects of o,p'-DDE will be compared to those of an antiandrogen, cyproterone acetate (hypothesis 2). The effects of both DDT analogs will be compared to those of p,p'-DDD which does not bind to either the ER or AR in croaker (hypothesis 2) and a DDT mixture which approximates the analog composition in fish samples collected from the Southern California Bight. Both male and females will be exposed to the model compounds throughout their life cycles to obtain a comprehensive understanding of how chemicals impair teleost reproduction (hypothesis 1) and which reproductive life cycle stage is the most sensitive (hypothesis 4). Indices of reproductive function such as gametogenesis, sex differentiation, hatching success and sperm motility, as well as indices of endocrine function such as steroid and gonadotropin secretion and receptor concentrations will be measured after exposure to the model compounds. The sites of estrogen action will be determined by in situ hybridization of the ER mRNA and androgen action by AR assays (hypothesis 3). Estrogenic and antiandrogenic actions of the model compounds will be assessed by specific assays (hypothesis 2). Interactions of the model compounds with the ER and AR and will be examined in competition studies (hypothesis 2 and 3).

Cost :$862,290.00

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