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

发育性类固醇损伤引起的性别特异性疾病病因：疾病预防的机制理解和生物标志物开发。

• 批准号: MR/P011535/1
• 负责人: Mick Rae
• 金额: $ 81.1万
• 依托单位: Edinburgh Napier University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP011535%2F1
• 关键词: Sex; specific; disease; aetiology; developmental

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.

我们的生活和工作时间越来越长，但利用这一点意味着享受更长的“健康寿命”和更长的寿命。当我们在子宫里发育时，罹患许多成人疾病的风险就已经确定，因此我们在胎儿时期经历的环境需要“恰到好处”。了解胎儿环境颜色的发育如何有助于怀孕期间的决策，以确保我们的孩子获得最佳的健康机会。激素推动发育。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，发育过程中性类固醇的不平衡可能会产生终生的健康后果。许多与生命早期类固醇暴露改变相关的临床病症会产生“沉默”的影响，直到晚年。其中一些后果是因性别而异的，可能是由于男性或女性发育的荷尔蒙需求不同所致。我们的环境中还有许多化学物质可以影响发育中的胎儿。其中一些化合物的行为类似于类固醇，或影响天然类固醇的作用；这些是“内分泌干扰化合物”。性类固醇雄激素和雌激素在男性和女性的发育过程中发挥着关键的作用。多囊卵巢综合症（PCOS）等常见疾病的根源是发育过程中不正确的性类固醇暴露。内分泌干​​扰化合物通常会模仿或改变这些性类固醇的作用。如果我们知道不正确的性类固醇暴露在胎儿时期会产生什么影响，并且可以将这些信息与成人疾病的发展联系起来，那么我们就可以预测化学物质暴露以及多囊卵巢综合症等临床状况会对下一代产生什么影响。通过识别成人生活中因胎儿类固醇暴露不当而产生的生物标志物，我们可以识别那些有患相关疾病风险的个体。然后，我们可以设计治疗方法，在高危个体出现疾病之前进行预防，从而保护这些人的“健康寿命”不会短于其寿命。在研究多囊卵巢综合症的起源时，我们通过改变发育中的羔羊所经历的性类固醇环境，开发了这种人类疾病的绵羊模型。这会导致成年后出现胰岛素抵抗、肥胖、胰腺和肝功能改变。在这里，我们选择研究肝脏，因为它对类固醇有反应、失活和转化。我们的工作表明，我们改变的胎儿类固醇暴露研究以与健康相关的方式影响了肝脏。最近的技术进步将使我们能够绘制胎儿期类固醇暴露改变对男性和女性肝脏发育和成年功能的影响的“地图”。由于我们已经知道胎儿类固醇暴露改变对成人健康的一些影响，我们现在可以发现其背后的原因。一旦我们知道受影响的基因和蛋白质，我们就可以检查在循环中可检测到肝脏中某些变化的可能性。这将为我们提供血液测试，以了解某人在其早期生活中是否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这些人生病之前帮助他们。所有所需的绵羊样本均已从之前的科学研究中收集，节省了时间、金钱，并减少了研究中的动物使用。我们知道我们建议研究的绵羊样本会受到人类相关健康的影响，因此这些样本可以解答这些影响是如何发生的。我们将揭示发育过程中性类固醇暴露改变的后果，这种改变如何影响成人疾病风险，开展血液测试以识别生命早期那些在晚年风险增加的人，并提供有关可能的治疗途径的信息。

项目成果

Maternal exposure to ambient black carbon particles and their presence in maternal and fetal circulation and organs: an analysis of two independent population-based observational studies.

• DOI: 10.1016/s2542-5196(22)00200-5
• 发表时间: 2022-10
• 期刊: The Lancet. Planetary health
• 作者: Bongaerts E;Lecante LL;Bové H;Roeffaers MBJ;Ameloot M;Fowler PA;Nawrot TS
• 通讯作者: Nawrot TS

Nutrient transporter expression in both the placenta and fetal liver are affected by maternal smoking.

胎盘和胎儿肝脏中营养转运蛋白的表达均受到母亲吸烟的影响。

• DOI: 10.1016/j.placenta.2019.02.010
• 发表时间: 2019
• 期刊: Placenta
• 影响因子: 3.8
• 作者: Walker N

The human fetal adrenal produces cortisol but no detectable aldosterone throughout the second trimester.

• DOI: 10.1186/s12916-018-1009-7
• 发表时间: 2018-02-12
• 期刊: BMC medicine
• 影响因子: 9.3
• 作者: Johnston ZC;Bellingham M;Filis P;Soffientini U;Hough D;Bhattacharya S;Simard M;Hammond GL;King P;O'Shaughnessy PJ;Fowler PA
• 通讯作者: Fowler PA

Hepatic Mitochondrial Dysfunction and Risk of Liver Disease in an Ovine Model of "PCOS Males".

• DOI: 10.3390/biomedicines10061291
• 发表时间: 2022-05-31
• 期刊: Biomedicines
• 影响因子: 4.7