Environmental contaminants that act by disrupting endocrine action have been hypothesized to be responsible for a number of significant human reproductive/developmental disorders. A distinct class of these compounds interacts with estrogen receptors (i.e., xenoestrogens). The proposed research seeks to examine how xenoestrogens could affect human reproduction, by exploiting the advantages of a vertebrate surrogate (rainbow trout) to investigate key questions. The central hypothesis for this proposal is that: Xenoestrogens decrease male fertility by altering male germ cell development that negatively affects spermatozoa produced upon sexual maturation. These alterations are the result of epigenetic changes and are transmitted transgenerationally.
The Specific Aims are as follows:
Specific Aim 1 : Study the reproductive consequences of discrete xenoestrogen exposure on male rainbow trout during three different periods of development (i.e., embryonic, juvenile, sexually maturing). A known xenoestrogenic effect in male rainbow trout, reduced fertility, will be tracked for heritability in F1 male progeny.
Specific Aim 2 : Examine the direct effect(s) of xenoestrogen exposure on the testes of juvenile isogenic rainbow trout using an in vitro gonad culture system and transplantation procedure.
Specific Aim 3 : Investigate methylation changes (i.e. epigenetic alterations) in the genomic DNA of the brain, pituitary gland, and testis in isogenic male rainbow trout in response to in vivo xenoestrogen exposure. The degree and location of changes in methylation patterns would be compared during three different periods of development (i.e., embryonic, juvenile, sexually maturing); determine whether methylated changes in sperm DNA (in exposed fathers) due to xenoestrogen exposure are heritable and transmitted to F1 and F2 male progeny. A major unknown is the impact of xenoestrogens to cause effects in the male that are transmitted to the next generation. Information obtained from this proposal will begin to dissect the mechanisms of xenoestrogen action in the rainbow trout as they relate to epigenetic changes and provide insights that can be extended to the human male. ? ?
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