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Targeted RNA-sequencing of testes from fetal rats exposed to dicyclohexyl phthalate informs potency and adverse outcome pathway development

ABSTRACT: The US EPA is refining long-term animal testing to increase the pace of chemical risk assessments. One approach involves using benchmark dose (BMD) response modeling of gene expression data from short term adult animal studies to indicate longer term chemical risk. Whether this approach works with developmental and reproductive toxicants is less certain. Dicyclohexyl phthalate (DCHP) is a high production volume phthalate ester with known effects on testes. Despite knowledge on several key events in phthalate testicular dysgenesis, the molecular initiating event is still unknown. The present study aims to assess how well gene expression-based BMD analysis of fetal testes from an in utero exposure performs at predicting developmental and reproductive toxicity endpoints for DCHP while applying, whole transcriptome, targeted RNA-Sequencing (RNA-Seq) to inform new molecular targets involved in phthalate-induced testicular dysgenesis. BMD analysis of targetd RNA-Seq data identified gene-set based BMD values that were 4 and 6-fold lower than development-related decreased anogenital distance and reproductive-related testis atrophy measures (101 and 144 mg/kg-day, respectively). Further analysis of top differentially expressed genes from targeted RNA-Seq identified Testin, Svs5, Lrrc39, etc. that may warrant further investigation in DCHP-induced testicular dysgenesis. Canonical pathway comparisons (Ingenuity Pathway Analysis) indicated suppression of steroid/cholesterol biosynthesis processes while biological function comparisons identified disrupted reproductive and genitourinary development processes across dose groups consistent with known DCHP effects. These results show promise in using targeted RNA-Seq from short-term in utero exposures to rapidly and quantitatively indicate developmental and reproductive effects, thereby helping EPA more quickly assess chemical impacts across a range of adverse effects. This abstract does not represent US EPA policy and mention of products does not constitute endorsement.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE293297 | GEO | 2025/07/31

REPOSITORIES: GEO

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Project description:The purpose of this study is to assess the potential of TOTM to induce testicular maldevelopment in the rat. We studied the effects of TOTM on the expression of genes in pathways involved in steriodogenesis and testes development. Certain phthalate esters have previously been shown to be involved in the induction of rat testicular mal-development (TMD) through effects on the expression of genes in pathways involved in steroidogenesis and testes development. In order to assess the effects of a potential alternate plasticizer, tris(2-ethylhexyl)trimellitate (TOTM), rats were exposed daily, in utero, to TOTM in order to assess the potential of this compound to induce developmental effects on the fetal testes. Pregnant rats were exposed between gestational day 12 and 19 and fetal testes RNA was analysed using whole genome microarrays. The effects of TOTM on the expression of genes in pathways involved in steroidogenesis and testes development were examined. The effects of TOTM were also compared with di(2-ethylhexyl)phthalate (DEHP), mono(2-ethylhexyl)phthalate (MEHP), an active metabolite of DEHP, and 2-ethylhexanol (2-EH), which were used as positive and negative controls, respectively. MEHP & DEHP (500mg/kg) caused a repression of genes in TMD pathways involved in cholesterol synthesis and transport (HMGCS, HMGCR, StAR, SCARB1, FDFT1, FDPS), steroidogenesis (Cyp11a, HSD3B1, SC4MOL) and testes development (INSL3, INHA). 2-EH caused minor repression of some of the genes in the TMD pathway. This was rationalised on the basis that 2-EH, a DEHP metabolite, is also a weak PPARα agonist. It has been shown that in utero treatment with DBP will repress the genes from fetal testes involved in steroidogenesis and that this effect is associated with direct DBP-mediated binding of PPARα to the promoters of these genes (Plummer et. al. 2010). TOTM did not cause a significant repression of genes in the TMD pathway. Based on these data, it is highly unlikely that TOTM will cause testicular dysgenesis in rats. Rats were exposed to TOTM in utero by the administration of daily oral gavage doses to pregnant dams between gestational day 12 and 19. The foetal testes were obtained by micro-dissection and prepared to facilitate the isolation of RNA, which was subsequently analysed using whole rat genome microarrays.

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Targeted RNA-sequencing of testes from fetal rats exposed to dicyclohexyl phthalate informs potency and adverse outcome pathway development

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