Milewski Tyler M, Streifer Madeline, Thompson Lindsay M, Sheinhaus Dana, Hynes Andrew, Gore Andrea C
Division of Pharmacology & Toxicology, The University of Texas at Austin, Austin, TX 78712, USA.
Endocrinology. 2025 Sep 8;166(10). doi: 10.1210/endocr/bqaf135.
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.
内分泌干扰化学物质（EDCs）是环境中普遍存在且存在于日常用品中的外源性化学物质。我们之前报道过，大鼠在孕期暴露于与人类相关的内分泌干扰化学物质混合物NeuroMix（NMX）中，会导致生理和行为表型发生改变。在此，我们使用了来自这些相同雄性和雌性大鼠的下丘脑 - 垂体 - 性腺（HPG）组织，并进行了基于3'标签的RNA测序（TagSeq），以研究潜在的分子机制。TagSeq揭示了独特的组织和性别特异性差异表达基因（DEGs）。在雄性大鼠的HPG组织中，NMX对下丘脑弓状核（ARC）影响最大，有613个差异表达基因。基因本体（GO）富集分析表明，NMX雄性大鼠ARC中上调的基因参与突触可塑性，而下调基因与对雌二醇和糖皮质激素的反应有关。在雌性大鼠中，孕期NMX暴露在卵巢中诱导了最大的转录组变化，有1295个差异表达基因。GO富集分析显示，参与纤毛组织和运动的基因上调，而该区域下调的基因与免疫相关过程有关。使用Qiagen Ingenuity Pathway Analysis，我们发现β - 雌二醇通路在所有NMX雌性组织和NMX雄性垂体中被激活，而在NMX雄性ARC、腹内侧核和睾丸中被抑制。据我们所知，这是首批对HPG组织进行转录组分析的研究之一，这些结果表明，孕期暴露于NMX会以性别依赖的方式影响HPG轴上的基因表达。
