Epidemiological and experimental studies suggest that disruption of embryonic programming and gonadal development during human fetal life can result in testicular dysgenesis, manifested as undescended testis, hypospadias, poor semen quality, and testicular cancer. The central objective of this proposal is to gain greater understanding of the fetal basis of male reproductive disorders by elucidating the mechanisms by which exposure of the fetus to two distinct environmental antiandrogens, DEHP and atrazine, suppress fetal testosterone production and later, testosterone production by the adult. Our major goals are to identify the cellular targets and the molecular mechanisms underlying the responses of the fetus to DEHP and atrazine, and to reveal the mechanisms by which effects on the fetus lead to pathologies of the male reproductive tract in the adult. The overarching hypothesis is that in utero exposures to DEHP or atrazine suppress fetal testosterone production by direct effects on fetal Leydig cells and/or on the mesenchymal cells that are the precursors of adult Leydig cells, and by doing so, suppress postnatal development and function of the adult Leydig cell population. ? We will test this hypothesis with the following specific aims: (1) identify the cellular and molecular targets of gestational DEHP and atrazine in the fetal testis; (2) identify, compare and contrast the mechanism(s) by which gestational exposure to DEHP or atrazine results in reduced testosterone production by the fetal testis; and (3) determine the effects of fetal exposure to DEHP or atrazine on the formation and function of the adult population of Leydig cells. Taken together the proposed studies will unveil the endocrine disruptor-sensitive steps in the steroidogenic pathway that are affected by these antiandrogens, and the mechanisms and consequences of endocrine disruption on the endocrine milieu of the adult. By studying both antiandrogenic compounds at once, we expect to gain broad understanding of the mechanism or mechanisms by which antiandrogens disrupt androgen production by the testis, and by which this disruption affects processes later in life. ? ?
