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CHANGES IN FETAL TESTIS GENE EXPRESSION AND STEROID HORMONE SYNTHESIS INDUCED IN MALE OFFSPRING AFTER MATERNAL TREATMENT WITH DEHP (DI-N-ETHYLHEXYL PHTHALATE)
Citation:
WILSON, V. S., C. R. LAMBRIGHT, J. R. FURR, K. L. BOBSEINE, C. R. WOOD, G. A. HELD, K. HOWDESHELL, AND L. E. GRAY. CHANGES IN FETAL TESTIS GENE EXPRESSION AND STEROID HORMONE SYNTHESIS INDUCED IN MALE OFFSPRING AFTER MATERNAL TREATMENT WITH DEHP (DI-N-ETHYLHEXYL PHTHALATE). Presented at Society of Toxicology, New Orleans, LA, March 6-10, 2005.
Description:
Phthalate estersare high production volume, ubiquitous environmental chemicals some of which induce reproductive malformations in rats when administered during sexual differentiation. Recently we have shown that malformations in gubernacular ligament development induced by high doses of DEHP are associated with decreased insl3 gene expression, a gene critical for proper gubernacular ligament formation. In study one, DEHP (0, 100, 300, 600, or 900 mg/kg/day) was administered orally to Sprague Dawley dams on gestation days (GD) 8 through 18. On GD18, fetal testes were evaluated for hormone production and changes in gene expression. Results indicate that DEHP induced a dose dependent linear decrease in testosterone production that was significant at 300, 600 and 900 mg/kg. Progesterone production was decreased at 900 mg/kg. Insl3 gene expression was also decreased in a dose dependent manner. To investigate the ontogeny of gene changes associated with these effects, a second study dosed dams orally with 0 (vehicle only) or 750 mg/kg/day DEHP beginning on GD8. Testes RNA was prepared from fetuses of 3 litters each on GD 16.5, 17, and 18. Microarray analysis was conducted on these samples using Affymetrix gene chips. Preliminary results indicate significant (p< 0.05) changes in several genes associated with Leydig cell steroidogenesis and peptide hormone production such as CYP17, StAR and Insl3 beginning, in some cases, as early as GD 16.5. A more thorough analysis of gene chip results is underway but, thus far, the changes demonstrated are consistent with the malformations previously observed in male offspring after in utero exposure to similar doses of DEHP.