PNAS：男性健康在出生前就已注定

一项新研究发现，胎儿在子宫中接触到的睾酮水平，决定了男性成年后对疾病的敏感程度。这项研究提前发表在美国国家科学院院刊PNAS杂志的网站上。

　　

生物通报道：一项新研究发现，胎儿在子宫中接触到的睾酮水平，决定了男性成年后对疾病的敏感程度。

英国爱丁堡大学的研究团队发现，成年男性体内的睾酮水平在出生之前就已注定。这项研究提前发表在美国国家科学院院刊PNAS杂志的网站上。

男性可以说是由雄性激素（睾酮）塑造的，这种激素遍布全身，维持着个体的男性性征和男性性功能。睾酮不仅能促使精子发育，还有助于机体内的合成代谢，具有直观重要的作用。

为何某些男性体内的睾酮比其他人少呢？理解这一现象的原因很重要，因为睾酮的水平对于男性一生的健康状况至关重要。据统计，西方国家的心血管代谢疾病都与男性的睾酮水平较低有关。人们认为，睾酮水平低的男性更容易患上肥胖症、糖尿病和心脏病。（推荐阅读：PNAS：为何男性更易受感染）

在成年人体内负责睾酮生产的细胞，被称为间质细胞（Leydig cell）。间质细胞呈多角形或圆形，有研究指出，这些功能强大的细胞来自于睾丸中的特定干细胞群体。

研究团队对人类、大鼠、小鼠和狨猴(Marmoset)进行研究，他们发现当这些动物的胎儿在子宫中发育时，睾丸部位都会出现上述干细胞。虽然间质细胞要到青春期才开始发育，但研究显示，一旦间质细胞的干细胞前体受到影响，间质细胞的功能就会受损。

这是首次证明，子宫中的事件能够影响男性日后的健康情况。研究人员总结道，胎儿在子宫内发育时接触的睾酮水平较低，会对特定干细胞造成影响，进而损害个体成年后的睾酮水平。因为这些干细胞在青春期后，会发育成为生产睾酮的间质细胞。

“有越来越多的证据表明，母亲的饮食情况、生活方式、接触药物和化合物，都会对子宫中的睾酮水平产生显著的影响。人们需要深入理解这些影响因素，以便为孕妇们提供可靠的建议，帮助她们守护自己后代的健康。”

这项研究向人们展示，子宫内的胎儿发育会通过表观遗传学改变，决定个体成年后的雄激素合成，进而影响男性一生的患病风险。

 

生物通推荐原文摘要：

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.