Sex-specific disease aetiology from developmental steroid insults: mechanistic understanding and biomarker development towards disease prevention.

我们的寿命和工作时间越来越长，但利用这一点意味着享受延长的“健康寿命”和延长的寿命。发展许多成人疾病的风险是在我们在子宫中发育时设定的，因此我们在胎儿生命期间经历的环境需要“恰到好处”。了解胎儿环境的颜色如何发展有助于在怀孕期间做出决策，以确保我们的孩子有最好的健康机会。荷尔蒙驱动发育。类固醇激素指导许多过程，包括正确的男性或女性发育。不幸的是，性类固醇在发育过程中的不平衡可能会造成终身的健康后果。许多与改变早期生活类固醇暴露相关的临床条件具有直到生命后期才“沉默”的影响。其中一些后果是性别特异性的，可能是由于男性或女性发育的不同激素要求。在我们的环境中也有许多化学物质可以到达发育中的胎儿。其中一些化合物的行为像类固醇，或影响天然类固醇的作用;这些是“内分泌干扰化合物”。性类固醇激素雄激素和雌激素在发育中起着关键的男性和女性特异性作用。常见的情况，如多囊卵巢综合征（PCOS）的起源不正确的性类固醇暴露在发展过程中。内分泌干扰化合物通常模拟或改变这些性类固醇的作用。如果我们知道在胎儿生命期间不正确的性类固醇暴露的影响，并将此信息与成人疾病发展联系起来，那么我们就可以预测化学暴露的影响，以及PCOS等临床疾病对下一代的影响。通过识别成年生活中的生物标志物，这些生物标志物是不正确的胎儿类固醇暴露的遗产，我们可以识别那些有发展相关疾病风险的个体。然后，我们可以设计治疗方法，以防止疾病发生之前，在风险的个人，从而保护这些人从有'healthspans'短于他们的lifespans. While调查PCOS的起源，我们开发了这种人类条件的绵羊模型，通过改变性类固醇的环境，发展羔羊的经验。这会导致成年后胰岛素抵抗、肥胖、胰腺和肝脏功能改变。在这里，我们选择研究肝脏，因为它响应，灭活和转化类固醇。我们的工作表明，肝脏受到影响，在健康相关的方式，我们改变胎儿类固醇暴露的研究。最近的技术进步将使我们能够建立“地图”的影响改变类固醇暴露在胎儿期的发展和成人功能的肝脏，具体到男性和女性。正如我们已经知道的一些成人健康的后果改变胎儿类固醇暴露，我们现在可以发现背后的原因。一旦我们知道受影响的基因和蛋白质，我们就可以检查肝脏中某些改变在循环中可检测到的可能性。这将使我们进行血液测试，看看是否有人在早期生活中错误地暴露于改变的类固醇信号，然后我们可以考虑如何在他们生病之前帮助这些人。所需的所有绵羊样本都是从以前的科学调查中收集的，节省了时间和金钱，并减少了研究中的动物使用。我们知道我们提出的研究绵羊样本在人类相关的健康方面受到影响，因此这些样本可以回答这些影响是如何发生的。我们将揭示在发育过程中改变性类固醇暴露的后果，这种改变如何影响成人疾病的风险，开发血液测试，以确定在生命早期那些在以后的生活中风险增加，并提供有关可能的治疗途径的信息。

We are living and working longer, but capitalising on this means enjoying extended 'healthspan' as well as extended lifespan. Risks of developing many adult illnesses are set down as we develop in the womb, hence the environment we experience during fetal life needs to be 'just right'. Understanding how the fetal environment colours development helps decision making during pregnancy to ensure best health chances for our children. Hormones drive development. Steroid hormones direct numerous processes, including correct male or female development. Unfortunately, imbalance in sex steroids during development can have lifelong health consequences. Numerous clinical conditions associated with altered early life steroid exposure have effects that are 'silent' until later in life. Some of these consequences are sex-specific, likely due to differing hormonal requirements of male or female development. There are also many chemicals in our environment that can reach a developing fetus. Some of these compounds behave like steroids, or affect natural steroid actions; these are 'endocrine disrupting compounds'. The sex steroids androgens and oestrogens play critical male and female-specific roles in development. Common conditions such as Polycystic Ovary Syndrome (PCOS) have origins of incorrect sex steroid exposure during development. Endocrine disrupting compounds commonly mimic, or alter, effects of these sex steroids. If we knew what the effects of the incorrect sex steroid exposure were during fetal life, and could connect this information to adult disease development, then we could predict what the effects of chemical exposures, and clinical conditions such as PCOS would have on the next generation. By identifying biomarkers in adult life that are legacies of incorrect fetal steroid exposure, we could identify those individuals at risk of developing associated illness. We could then design treatments to prevent disease prior to its occurrence in at risk individuals, and thereby protect such people from having 'healthspans' shorter than their lifespans.Whilst investigating origins of PCOS we developed sheep models of this human condition by altering the sex steroid environment that developing lambs experience. This leads to development of insulin resistance, obesity, altered pancreatic and liver function in adulthood. Here we have chosen to study the liver since it responds to, deactivates and transforms steroids. Our work indicated that the liver was affected in a health-relevant manner by our altered fetal steroid exposure studies. Recent technological advances will let us build 'maps' of effects of altered steroid exposure during fetal life on development and adult function of liver, specific to males and females. As we already know some adult health consequences of altered fetal steroid exposure we can now discover the reasons behind them. Once we know the genes and proteins affected, we can examine the possibility of some alterations in the liver being detectable in the circulation. This will give us blood tests to see if someone has been incorrectly exposed to altered steroid signalling during their early life, and then we can consider how to help such individuals prior to them getting ill. All sheep samples required are already collected from previous scientific investigations, saving time, money, and reducing animal use in research. We know the sheep samples we propose for study are affected in terms of human-relevant health, so these samples hold answers to how these effects occur. We will reveal the consequences of altered sex steroid exposure during development, how such alterations affect adult disease risk, develop blood tests to identify during early life those at increased risk in later life, and provide information regarding possible treatment routes.