The hypothalamus plays key roles in regulating reproduction and energy balance. We determined the transcriptional profile of the hypothalamus (F0 and F1) to identify its relationship with the reproductive function and metabolic phenotypes of rats under BPA exposure and the paternal contribution. Male rats received 35 μg/kg bw/day BPA, 5 μg/kg bw/day ethinylestradiol (EE2) or vehicle via diet. At PND 170, the sexual behaviour of male F0 rats was assessed before mating. The metabolic and reproductive phenotypes and the transcriptional profiles of the testis (F0) and hypothalamus were tested in F0 and F1 rats. Male rats exposed to BPA exhibited no changes in fertility, metabolic phenotypes, sperm quality or serum sex hormones, but none of them ejaculated during the test period. Four differentially expressed genes (DEGs) in the F0 hypothalamus and 51 DEGs in the F0 testis were identified in the BPA group. Paternal BPA and EE2 exposure increased the body weight and food intake of male offspring, and 164 and 3433 DEGs were identified in the hypothalamus of BPA- and EE2-treated rats (F1, male), respectively. The highest-ranked function impaired by BPA and EE2 in the F1 hypothalamus was immune function. BPA and EE2 exposure induced alterations in the metabolic phenotype in F1-generation males, and this effect may be related to the altered inflammatory-related signalling pathways in the hypothalamus but neither treatment affected the F0 hypothalamus. Hundreds of genes in the F1 hypothalamus showed changes upon BPA and EE2 treatment. Concern regarding paternal environmental endocrine disruptor exposure should be raised.

下丘脑在调节生殖和能量平衡中起关键作用。我们确定了下丘脑（F0和F1）的转录谱，以鉴定其与BPA暴露和父本作用下大鼠生殖功能和代谢表型的关系。雄性大鼠通过饮食接受35μg/ kg bw /天BPA，5μg/ kg bw /天乙炔雌二醇（EE2）或赋形剂。在PND 170处，在交配前评估雄性F0大鼠的性行为。在F0和F1大鼠中测试了睾丸（F0）和下丘脑的代谢和生殖表型以及转录谱。暴露于BPA的雄性大鼠在生育力，代谢表型，精子质量或血清性激素方面无变化，但在测试期间均未射精。在BPA组中，在F0下丘脑中发现了四个差异表达基因（DEG），在F0睾丸中发现了51 DEG。父亲暴露于BPA和EE2会增加雄性后代的体重和食物摄入量，在BPA和EE2处理的大鼠（F1，雄性）的下丘脑中分别鉴定到164和3433 DEG。F1下丘脑中BPA和EE2损害最高的功能是免疫功能。BPA和EE2暴露引起F1代男性代谢表型的改变，这种作用可能与下丘脑中炎症相关的信号通路改变有关，但两种治疗均不影响F0下丘脑。F1下丘脑中的数百个基因在BPA和EE2处理后显示出变化。应提高对父亲环境内分泌干扰物暴露的关注。