Alteration of the expression and 17, 20 lyase activity of cytochrome P450 17-hydroxylase/17, 20 lyase and of the expression of other Leydig cells genes in the rat fetal testis directly exposed to Mono-ethyl hexyl phthalate in culture.
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ABSTRACT: This study aimed to investigate the direct mechanism(s) of action ofMono-(Ethyl-Hexyl) phthalate (MEHP) on the rat fetal testis with particular emphasis to Leydig cell steroidogenesis, by means of an in vitro system based on culture for 3 days of fetal testes from 14.5 days post-coïtum old rats. We first confirmed that an exposure to MEHP led to a dose-dependent decrease of testosterone and demonstrated that dihydrotestosterone (DHT) production was also inhibited. We then demonstrated that in 10µM MEHP-exposed testis basal 17alpha-hydroxy-progesterone (17OHP) production was increased (+40%) while androstenedione levels decreased (-55%). Furthermore, the addition of the latter steroid but none of the other precursors rescued testosterone thus establishing further that MEHP specifically blocked steroidogenesis at the level of the 17,20 lyase activity of the P450c17 enzyme (CYP17), which converts 17OHP to androstenedione. Furthermore and accordingly, both levels of testicular CYP17 protein (western blot) and cyp17a1 gene (qPCR, microarrays) were found to decrease under MEHP exposure. The microarray analysis also showed that among the few other testicular genes cyp17a1 whose expression was inhibited by MEHP were the genes encoding for the Leydig cell insulin-like peptid 3 (INSL3), involved in the control of testicular descent, and for inhibin A (INHA), that regulates follicular-stimulating hormone secretion.Under in vitro conditions where MEHP is not metabolized and remains at low intratesticular concentration, our findings show in particular that this phthalate directly inhibits several important Leydig cell factors involved in testis development and function.
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE22218 | GEO | 2011/06/01
SECONDARY ACCESSION(S): PRJNA128773
REPOSITORIES: GEO
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