Converging Effects of Three Different Endocrine Disrupters on Sox and Pou Gene Expression in Developing Rat Hippocampus: Possible Role of microRNA in Sex Differences

ABSTRACT: Abstract. Transcriptomes of developing, early postnatal rat hippocampus were compared after gestational and lactational exposure to different environmental chemicals exhibiting endocrine activity (endocrine disrupters) at doses impairing memory in adult offspring: Aroclor 1254 (PCB mixture) and bisphenol A, 5 or 0.5 mg/kg administered in chow, and chlorpyrifos, 3 or 1 mg/kg injected subcutaneously. All three chemicals exhibited a common effect on Sox6, Sox11, Pou2f2/Oct2, and Pou3f2/Brn2 in male hippocampus at the higher dose level. Additional Sox and Pou genes were affected by two treatments. Real time RT PCR in samples not used for transcriptomics confirmed the transcriptomics data and showed a comparable expression change for bisphenol A also at the lower dose. No changes were seen in female hippocampus. In the case of Sox6, gene network analyses indicated that miR-24 may be involved in the sexual dimorphism. This miR, which represses Sox6 and is repressed by estrogen receptor-alpa in other tissues, was downregulated by all chemicals in male but not female hippocampus. Sox6 expression levels of individual hippocampus samples (FPKM) were inversely correlated with expression levels of Pvalb, a downstream target of Sox6 and marker of an interneuron subpopulation, but not with markers of Sox6-independent interneuron subpopulations, Nos1 and 5HT3aR, indicating a selective effect on a hippocampal interneuron subpopulation. Effects on interneuron development are further suggested, in males, by changes in Nrg1 and Erbb4 expression controlling interneuron migration. Our investigation disclosed genes involved in cell-autonomous regulation of developmental processes as potential targets of endocrine disrupters. If corroborated by additional studies, they may serve as markers of early developmental effects in regulatory test development.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE180054 | GEO | 2021/11/08

REPOSITORIES: GEO