Testis

Gene Expression Profiling Following In Utero Exposure to Phthalate Esters Reveals New Gene Targets in the Etiology of Testicular Dysgenesis

Abstract
Male reproductive tract abnormalities associated with testicular dysgenesis in humans also occur in male rats exposed gestationally to some phthalate esters. We examined global gene expression in the fetal testis of the rat following in utero exposure to a panel of phthalate esters. Pregnant Sprague-Dawley rats were treated by gavage daily from gestation days 12 through 19 with corn oil vehicle (1 ml/kg) or diethyl (DEP), dimethyl (DMP), dioctyl tere- (DOTP), dibutyl (DBP), diethylhexyl (DEHP), dipentyl (DPP), or benzyl butyl (BBP) phthalate at 500 mg/kg/day. Testes were isolated on gestation day 19, and global changes in gene expression were determined. Of the approximately 30,000 genes queried, expression of 391 genes was significantly altered following exposure to the developmentally toxic phthalates (DBP, BBP, DPP, DEHP) relative to the control. The developmentally toxic phthalates were indistinguishable in their effects on global gene expression. No significant changes in gene expression were detected in the non-developmentally toxic phthalate group (DMP, DEP, and DOTP). Gene pathways disrupted include those previously identified as targets for DBP, including cholesterol transport and steroidogenesis, as well as newly identified pathways involved in intracellular lipid and cholesterol homeostasis, insulin signaling, transcriptional regulation, and oxidative stress. Additional gene targets include alpha Inhibin, essential for normal Sertoli cell development, and genes involved in Sertoli cell -- gonocyte communication. The common targeting of these genes by a select group of phthalates indicates a role for their associated molecular pathways in testicular development and offers new insight into the molecular mechanisms of testicular dysgenesis.

Key words: Testis • Toxicology • Developmental biology • Male sexual function • Testosterone

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