Effect of DEHP on adult mouse Leydig cells

BACKGROUND: Phthalates are manmade industrial additives used mostly as plasticizers. In addition to their deleterious effects on male genital development, population studies have recently documented correlations between phthalates exposure and subtle impacts on reproductive tract development and on the metabolic syndrome in male adults. In mature rodents liver di-(2-ethylhexyl)-phthalate (DEHP) activates the peroxisome proliferators-activated receptor (PPARalpha), a member of the nuclear receptor (NR) superfamily. OBJECTIVES: Using a systems biology approach, we aimed at defining potential mechanisms underlying the impacts of DEHP on adult mouse liver and testis. METHODS: Thus, we performed a parallel analysis of transcript and metabolic profiles in the liver from adult mice exposed to varying DEHP doses. Moreover, we obtained pangenomic mRNA profiles of laser-captured Leydig and Sertoli cells from mature animals exposed to DEHP. RESULTS: Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of some prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways. Integration of hepatic transcriptomic and metabonomic profiles further revealed a correlation between the impacts of DEHP on a cluster of genes and metabolites linked to heme synthesis and on a cluster of Rev-erbalpha target genes related to metabolic and circadian clock pathways. Cell-specific effects of DEHP were investigated in the adult testis and a noticeable impact of DEHP was observed on Leydig cells transcriptome. CONCLUSIONS: We report a detailed analysis of DEHP interference with hepatic Constitutive Androstane Receptor (CAR) and Rev-erbalpha pathways and a novel transcriptional impact of DEHP on adult endocrine cells of the testis. Keywords: Treatment effect two condition experiment, Leydig cells from DEHP-treated mice vs. Leydig cells from vehicle-treated mice. Biological replicates: 2 DEHP-treated samples and 3 vehicle-treated samples. Each treated sample has been hybridized against each vehicle-treated sample in a dye-swap design. N=2 DEHP-treated x 3 vehicle-treated x 2 microarrays=12 microarrays