Adverse trends in male reproductive health may result, at least in part, from exposure to environmental chemicals during development. The overall objective of this proposal is to characterize the impact of di-(2-ethylhexyl) phthalate (DEHP), the most widely used plasticizer, on neonatal development of the testis and to identify mechanisms underlying the observed toxicant-induced injury. The investigator's preliminary findings, along with published data, suggest the DEHP reduces Sertoli cell/gonocyte numbers in neonatal rats, damages the testis permanently and impairs fertility of the adult. Based on pilot data, they hypothesize that exposure to low levels of DEHP in neonates reduces Sertoli cell and gonocyte population size  by inhibiting proliferation and inducing apoptosis through perturbation of cell cycle machinery and altered expression of immediate-early response genes and  by disrupting critical Sertoli cell-gonocyte interactions.
The specific aims to be addressed are:  to identify the precise effects of low levels of phthalates on neonatal development of Sertoli cells and gonocytes in vivo and in vitro.  To evaluate the effects of phthalates on cell cycle machinery and determine how these effects impact on development of the Sertoli cell population.  To investigate the potential involvement of immediate-early response genes in phthalate-induced impairment of Sertoli cell development.  To determine whether phthalates impair Sertoli cell and/or gonocyte development by interfering with normal NCAM-and/or c-kit-based cell-cell interactions. Male rats 3-15 days old will be treated orally with DEHP and its impact on Sertoli cell/gonocyte maturation at the cellular and molecular level determined by evaluating proliferation, apoptosis and, for gonocytes, directed migration. An in vitro model system, neonatal Sertoli cell-gonocyte co-cultures, will also be used to explore mechanism(s) underlying these effects. The overall goal of this research is to increase our understanding of basic mechanisms important for testicular development and of how environmental toxicants interfere with these mechanisms and injure developing testes. In the long term, the findings will improve the investigator's ability to safeguard developing human males from the risks of exposure to the these toxicants.
|Li, L H; Jester Jr, W F; Laslett, A L et al. (2000) A single dose of Di-(2-ethylhexyl) phthalate in neonatal rats alters gonocytes, reduces sertoli cell proliferation, and decreases cyclin D2 expression. Toxicol Appl Pharmacol 166:222-9|
|Li, L H; Jester Jr, W F; Orth, J M (1998) Effects of relatively low levels of mono-(2-ethylhexyl) phthalate on cocultured Sertoli cells and gonocytes from neonatal rats. Toxicol Appl Pharmacol 153:258-65|
|Barkovskii, A L; Adriaens, P (1996) Microbial dechlorination of historically present and freshly spiked chlorinated dioxins and diversity of dioxin-dechlorinating populations. Appl Environ Microbiol 62:4556-62|