Phthalates, widely used as plasticizers in food and biomedical packing, present a hazard to male reproductive health. DEHP, the most common phthalate, is metabolized to its active monoester, MEHP. In the testis, MEHP's primary testicular target is Sertoli cells (SC). However, germ cells (GC) undergo dramatic MEHP-induced changes such as detachment from SC and subsequent GC apoptosis. The long-term objective of this study is to elucidate the role of oxidative stress-induced GC mitochondrial dysfunction in MEHP toxicity and characterize the molecular targets involved.
The specific aims to carry out this objective are to: (1) test the postulate that MEHP affects testicular expression of the antioxidant peroxiredoxins (Prx), (2) determine whether MEHP exposure leads to Prx3 inactivation in GC, but not in SC, (3) establish whether Prx3 inactivation leads to increased ROS generation and mitochondrial dysfunction in GC, but not in SC, and (4) characterize whether Prx3 plays a role in toxicant-mediated cytochrome c release from GC mitochondria. Mechanistic studies involving state of the art molecular cell biology techniques will be used to elucidate the role that mitochondrial dysfunction plays in phthalate-induced testicular toxicity and infertility.
| Onorato, Thomas M; Brown, Petrice W; Morris, Patricia L (2008) Mono-(2-ethylhexyl) phthalate increases spermatocyte mitochondrial peroxiredoxin 3 and cyclooxygenase 2. J Androl 29:293-303 |
