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COMBINATION DOSE OF TWO PHTHALATES ADDITIVELY DEPRESSES TESTOSTERONE PRODUCTION AND INSL3 GENE EXPRESSION IN MALE RAT FETUSES
Citation:
HOWDESHELL, K., J. FURR, C. R. LAMBRIGHT, V. S. WILSON, AND L. E. GRAY. COMBINATION DOSE OF TWO PHTHALATES ADDITIVELY DEPRESSES TESTOSTERONE PRODUCTION AND INSL3 GENE EXPRESSION IN MALE RAT FETUSES . Presented at Society for the Study of Reproduction, Quebec, QC, CANADA, July 24 - 27, 2005.
Description:
Diethylhexyl phthalate (DEHP) and di(n-butyl) phthalate (DBP) are phthalate esters used to modify plastic and polymer textures. Individually,in uteroexposure to DEHP and DBP inhibit reproductive tract development,induce reproductive organ malformations, and reduce testosterone (T) productionin male rats.In addition,in utero exposure to DEHP decreases expression of insulin-like factor 3 (insl3), a gene responsible for gubernacular ligament development. In the current study, we hypothesized that co-administered DEHP and DBPwould act in a dose-additive fashion to inhibit fetal T production, and suppress expression of genes involved in gonad differentiation [steroidogenic factor 1 (Sf-1)] and steroid hormone production[steroidogenic acute regulatory protein (StAR) and cyp11a]as well as insl3 expression.Pregnant rats were gavaged on gestation days (GD) 14-18 with 500 mg/kg DEHP, DBP or a combination of both chemicals (500 mg/kg each).In experiment one, male offspring were necropsied on postnatal day90 and reproductive malformations were recorded. In experiment two, fetal testeswereremoved on GD18 and incubated in media for T production. Fetal testes RNA was also harvested and analyzed by qrt-PCR. As expected, androgen-dependent reproductive malformations increased in a cumulative fashion with the combination dose resulting in more malformations than either single chemical alone.Individually, both DBP and DEHP reducedfetal T production. When combined, T production was reduced further, indicating that the effects were additive. Regarding gene expression, DBP and DEHP reducedStAR and insl3,while the combination of the two doses further suppressed gene expression.The expression of cyp11a was decreased by DEHP, but not DBP; however, the combination dose suppressed cyp11a expression further. No significant treatment differences were seen in Sf-1 expression.These results support the hypothesis that DEHP and DBP together act in an additive fashion to decrease T production and the expression of insl3 and steroidogenesis pathway genes.These results suggest that endocrine and gene expression changes in fetal testes can accurately predict the incidenceof reproductive malformations in adulthood. Disclaimer: Abstract does not necessarily reflect EPA policy. University/US EPA Cooperative Training Agreement CT826512010