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

点击翻译按钮获取中文摘要

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.