Transcriptomic Changes Across the HPG Axis Following Prenatal Exposure to the EDC Mixture NeuroMix

Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that are ubiquitous in our environment and found in everyday items. We previously reported that prenatal exposure of rats to a human-relevant mixture of EDCs, NeuroMix (NMX), led to alterations in physiological and behavioral phenotypes. Here, we used hypothalamic-pituitary-gonadal (HPG) tissues from these same male and female rats and conducted 3' Tag-based RNA sequencing (TagSeq) to investigate underlying molecular mechanisms. TagSeq revealed unique tissue- and sex-specific differentially expressed genes (DEGs). In males, among the HPG tissues, NMX had the greatest effects in the hypothalamic arcuate nucleus (ARC), with 613 DEGs. Gene ontology (GO) enrichment analysis revealed that genes upregulated in the ARC of NMX males were involved in synaptic plasticity, while genes downregulated related to responses to estradiol and glucocorticoids. In females, prenatal NMX exposure induced the largest transcriptome change in the ovaries, with 1295 DEGs. GO-enrichment analysis revealed upregulation of genes involved in cilium organization and movement, while genes downregulated in this region were related to immune-related processes. Using Qiagen Ingenuity Pathway Analysis, we identified the β-estradiol pathway to be activated in all NMX female tissues and the NMX male pituitary, and inhibited in NMX male ARC, ventromedial nucleus, and testes. To our knowledge, this is one of the first studies to conduct transcriptomic profiling across HPG tissues, with these results demonstrating that prenatal exposure to NMX affects gene expression across the HPG axis in a sex-dependent manner.