人类暴露于一系列内分泌干扰化学物质(EDC)。许多研究表明,在关键的发育窗口中暴露于EDCs可以永久影响内分泌健康结果。大多数实验研究涉及性腺产生的激素分泌的变化,甲状腺和肾上腺,对EDC产生下丘脑-垂体(HP)控制轴长期变化的能力知之甚少。这里,我们研究了三种常见的EDC对雄性小鼠HP基因表达的长期影响,在发育暴露之后。怀孕的小鼠暴露于0.2mg/ml的双酚S(BPS)溶液,2,2\',4,4'-四溴二苯醚(BDE-47),或3,3\',从怀孕第8天到哺乳第21天(断奶日)的5,5'-四溴双酚A(TBBPA)。雄性后代不加治疗,直到出生后第140天,在那里收集垂体和下丘脑。通过RNA测序评估垂体的基因表达,同时通过RT-qPCR评估下丘脑中特定基因的表达。差异表达,以及基因富集和通路分析,表明所有三种化学物质都会引起长期变化,(主要是抑制)涉及其内分泌功能的垂体基因。BPS和BDE-47在受影响的基因和途径水平上产生了显着重叠的作用。所有三种化学物质都改变了性腺和肝脏HP轴的途径,而BPS改变了HP-肾上腺,BDE-47改变了HP-甲状腺途径。所有三种化学物质都降低了垂体中免疫基因的表达。下丘脑中的靶向基因表达表明BPS和BDE-47组下调下丘脑内分泌控制基因,与垂体的变化相一致,这表明这些化学物质会抑制HP的整体内分泌功能。有趣的是,所有三种化学物质都改变了GPCR介导的细胞内信号分子的垂体基因,许多垂体对激素反应常见的关键信号。这项研究的结果表明,常见EDC的发育暴露对下丘脑-垂体水平的激素反馈控制具有长期影响。
Humans are exposed to a range of endocrine disrupting chemicals (EDCs). Many studies demonstrate that exposures to EDCs during critical windows of development can permanently affect endocrine health outcomes. Most experimental studies address changes in secretion of hormones produced by gonads, thyroid gland and adrenals, and little is known about the ability of EDCs to produce long-term changes in the hypothalamic-pituitary (HP) control axes. Here, we examined the long-term effects of three common EDCs on male mouse HP gene expression, following developmental exposures. Pregnant mice were exposed to 0.2 mg/ml solutions of bisphenol S (BPS), 2,2\',4,4\'-tetrabromodiphenyl ether (BDE-47), or 3,3\',5,5\'-tetrabromobisphenol A (TBBPA) from pregnancy day 8 through lactation day 21 (weaning day). Male offspring were left untreated until postnatal day 140, where pituitaries and hypothalami were collected. Pituitaries were assed for gene expression via RNA sequencing, while specific genes were assessed for expression in hypothalami via RT-qPCR. Differential expression, as well as gene enrichment and pathway analysis, indicated that all three chemicals induced long-term changes, (mostly suppression) in pituitary genes involved in its endocrine function. BPS and BDE-47 produced effects overlapping significantly at the level of effected genes and pathways. All three chemicals altered pathways of gonad and liver HP axes, while BPS altered HP-adrenal and BDE-47 altered HP-thyroid pathways specifically. All three chemicals reduced expression of immune genes in the pituitaries. Targeted gene expression in the hypothalamus indicates down regulation of hypothalamic endocrine control genes by BPS and BDE-47 groups, concordant with changes in the pituitary, suggesting that these chemicals suppress overall HP endocrine function. Interestingly, all three chemicals altered pituitary genes of GPCR-mediated intracellular signaling molecules, key signalers common to many pituitary responses to hormones. The results of this study show that developmental exposures to common EDCs have long-term impacts on hormonal feedback control at the hypothalamic-pituitary level.