The role of endocrine disrupting chemicals and weight in the onset of female puberty via epigenetic mechanisms

哺乳动物的青春期是由位于下丘脑的一组特殊神经元脉冲性地释放促性腺激素释放激素（GnRH）引起的。抑制和刺激神经递质的网络，由上游转录调节精心策划，控制这一过程。越来越多的证据表明，青春期的时间和进程受到外源性（内分泌干扰化学物质，EDCs）和内源性（体重/肥胖）因素的影响，这些因素不仅会对第一代健康造成严重损害，而且会对后代造成严重损害。潜在的机制尚不清楚。在这一应用中，我们提出了一个高度创新的概念，即表观遗传机制，如DNA甲基化、染色质修饰和Polycomb组沉默子的成员，可能是EDC和超重的靶标，随后影响参与GnRH神经元功能调节的基因表达，并改变雌性啮齿动物的青春期开始时间。

Mammalian puberty is initiated by the pulsatile release of Gonadotropin-releasing hormone (GnRH) from a specialized group of neurons located in the hypothalamus. A network of inhibitory and stimulatory neurotransmitters, orchestrated by upstream transcriptional regulators, controls this process. Evidence has accumulated that timing and progression of puberty are affected by exogenous (endocrine disrupting chemicals, EDCs) and endogenous (weight/obesity) factors resulting in profound impairment of health not only in the first but additionally in further generations. The underlying mechanism is unknown. In this application we propose the highly innovative concept that epigenetic mechanisms, such as DNA methylation, chromatin modifications and members of Polycomb group silencers, might be targets for EDC and overweight subsequently affecting the expression of genes involved in the functional regulation of GnRH neurons and modifying the timing of pubertal onset in female rodents.