Grant: Operating Grant

Epidemiological and experimental studies suggest that disruption of embryonic programming and fetal gonadal development can result in undescended testis, hypospadias, poor semen quality, or testicular cancer. Among these conditions, some appear only later in life. Phthalates are plasticizers that are ubiquitously found in the environment and shown to alter male sexual organ development and to decrease testosterone production in the fetus. Di-(2-ethylhexyl) phthalate (DEHP) is among the most prevalent of the plasticizers, and its active metabolites are present from fetal development to adulthood. In men, there is an inverse correlation between DEHP metabolites and circulating androgen levels. In rats, we have shown that fetal exposure to DEHP results in reduced circulating testosterone and aldosterone levels in the adult offspring. It is our hypothesis that in utero exposure of rats to DEHP leads to changes in testis and adrenal function, and that it is the interaction of the testes and adrenals in the adult that results in reduced testicular testosterone production. Using a combination of in vivo, ex vivo and in vitro experiments together with morphological, biochemical, pharmacological, genetic and epigenetic tools, we propose to determine the endocrine and metabolic changes occurring in the adult male following in utero exposure to environmentally relevant concentrations of DEHP, and to identify the mechanisms underlying the long-term effects of DEHP exposure leading to inhibition of steroid biosynthesis. Reduced testosterone (primary hypogonadism) has been linked to infertility, erectile dysfunction, obesity, osteoporosis and cardiovascular diseases. Moreover, changes in adrenal function could lead to changes in blood pressure, a common disease for which the origins remain unknown in most cases. It is critical to determine whether exposure to a highly prevalent environmental toxicant such as DEHP could be a risk factor in the origin of these disorders.