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IN VITRO CONAZOLE EXPOSURE INHIBITS TESTOSTERONE PRODUCTION IN THE ADULT AND NEONATAL RAT TESTIS THROUGH THE INHIBITION OF CYP17 ACTIVITY
Citation:
BLYSTONE, C., J. C. ROCKETT, AND D. J. DIX. IN VITRO CONAZOLE EXPOSURE INHIBITS TESTOSTERONE PRODUCTION IN THE ADULT AND NEONATAL RAT TESTIS THROUGH THE INHIBITION OF CYP17 ACTIVITY. Presented at Society for the Study of Reproduction, Vancouver, British Columbia, Canada, August 1-4, 2004.
Description:
IN VITRO CONAZOLE EXPOSURE INHIBITS TESTOSTERONE PRODUCTION IN THE ADULT AND NEONATAL RAT TESTIS THROUGH THE INHIBITION OF CYP17 ACTIVITY
Chad R. Blystone1, David J. Dix2, and John C. Rockett2
1Department of Environmental and Molecular Toxicology, NC State University, Raleigh, NC, USA, and 2National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, RTP, NC, USA.
ABSTRACT
Identifying endocrine disrupting chemicals (EDCs) and understanding their mechanism of action is important for human and ecological risk assessment. The conazoles are a large family of fungicides with widespread pharmaceutical and agricultural applications. Conazole fungicides are known cytochrome P450 (CYP) modulators that may affect steroidogenesis. We hypothesized that two agricultural conazoles in current use, myclobutanil and triadimefon, are EDCs that inhibit testosterone (T) production in the adult and neonatal testis. To test this hypothesis, sliced adult or whole neonatal Sprague-Dawley rat testis was incubated in medium (M199, with 10% FBS and 100mU hCG) containing 1, 10, or 100 ?M of myclobutanil or triadimefon. T and lactate dehydrogenase (LDH), a marker of cytotoxicity, were measured in the medium at 0.5, 1.5 & 2.5h. In adult and neonatal testis, both chemicals inhibited T production at the highest concentrations after 1.5 hr(50-60% inhibition) and 2.5 hr (39-64% inhibition). Neither chemical affected LDH levels, indicating that these compounds inhibit T by modulating synthesis through a non-cytotoxic mechanism. To understand this inhibition further, progesterone (P) and androstenedione (A) levels were measured from the adult testis. The highestconcentrations of both myclobutanil and triadimefon increased levels of P and decreased levels of A, indicating that CYP17 was the target of inhibition.Though this mechanism of action remains to be confirmed in the neonatal testis, these data provide evidence that myclobutanil and triadimefon are EDCs that can affect testosterone production in the neonatal and adult testis through inhibition of CYP17 activity. This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.