Teratogenic effects of alcohol during embryonic development are well known. An organ system influenced by alcohol is male reproductive system. There are reports of decreased testosterone production and subnormal sperm production. Diverse mechanisms have been proposed to account for the toxic effects of alcohol. One mechanism is altered retinoid signaling due to alcohol's influence on retinoid metabolism and the function of retinoic acid receptors. The proposed research is designed to better understand the cellular signaling mechanisms by which alcohol may affect retinoic acid receptors, which are essential for testicular development and spermatogenesis. The hypothesis to be tested is that prenatal and early postnatal alcohol exposures inappropriately alter retinoid signaling and, this is partially responsible for abnormal testicular proliferation and may lead to lowered sperm output. The PI's studies demonstrate that retinoic acid increased TGF beta levels in testicular cells and increased cell proliferation. Since transforming growth factor-B (TGF beta) has been shown to decrease testosterone levels in fetal testicular cells, retinoic acid, similar to alcohol, has the potential to decrease testosterone production. Even transient changes in testosterone levels at critical times in fetal and neonatal times can produce long-term effects on sperm output in the adult because Sertoli cell proliferation only occurs in early testicular development. The research design consists of the following specific aims.
Specific Aim #1 examines the effect of alcohol on testicular proliferation the expression of retinoic acid receptor, the production of TGFB, and retinoic acid and adult sperm output.
Specific Aim #2 examines the role of retinoic acid receptors in mediating the effects of alcohol during embryonic and neonatal testis development.
Specific Aim #3 examines the molecular signaling pathways by which alcohol influences retinoic acid receptor signaling. The PI will use novel embryonic and early postnatal mixed testicular cultures proven to be very useful in our preliminary studies as well as pregnant rats. The dose-and developmental-specific impact of alcohol on these testicular cultures and the fetus of pregnant rats will be investigated. The completion of these specific aims will provide insights into fetus of pregnant rats will be investigated. The completion of these specific aims will provide insights into the when alcohol can have adverse action during testis development and develop a molecular model of alcohol action in testis. The PI will show that alcohol inappropriately alters the activity of retinoic acid receptors and then changes retinoid metabolism, and this leads to alteration in testicular cell proliferation. A better understanding of the mechanism of alcohol action may lead to novel drug design to help victims of maternal alcohol abuse.
| Li, Hui; Kim, Kwan Hee (2003) Effects of ethanol on embryonic and neonatal rat testes in organ cultures. J Androl 24:653-60 |
