The human fetal liver: development and response to maternal drug use.

人类胎儿肝脏：发育和对母体药物使用的反应。

• 批准号: MR/L010011/1
• 负责人: Paul Fowler
• 金额: $ 75万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL010011%2F1
• 关键词: human; fetal; liver; development; response

It is well known that if a woman smokes while pregnant there are bad consequences for the resulting offspring, especially slowed growth in the womb. However, other serious problems are also likely to occur in children exposed to their mothers' cigarette smoke chemicals during pregnancy. These include an impaired immune system (e.g. increased asthma), poorer educational performance and a raised chance of developing obesity, diabetes and heart disease (called metabolic syndrome). Many of these effects also happen if the mother regularly drinks alcohol while pregnant, even if not to the extent of addiction. We do not know exactly how much the chance of somebody developing metabolic syndrome is altered if their mother smoked and/or drank while pregnant. However, a recent study of 74,000 women found that if their mothers smoked while pregnant, the women had a 53% higher chance of becoming obese. This would be a major added drain on the NHS and would mean that many more people would be likely to suffer these debilitating conditions since smoking and/or alcohol use during pregnancy continues in 20-40% of women. In 2006-07 costs to the English NHS of lifestyle and related conditions were: smoking £3.3 billion, alcohol £3.3 billion, overweight/obesity £5.1 billion and diabetes £3.5 billion annually.Adult health is partly programmed by events during fetal life when the individual is still in the womb and an individual may be badly adjusted for life if the mother uses recreational drugs. Growth restriction is important in this process and the liver is one of the organs most affected by disturbed growth before birth. The fetal liver is a key organ, protecting the fetus from harmful chemicals and controlling fetal growth. Progress in understanding the effects of maternal drug use on fetal development suffers from two problems: firstly, our ignorance of the levels of drugs to which the fetus is exposed and, secondly, the mechanisms by which these drugs affect development. Two factors contribute to our ignorance. Firstly, very little research uses normal human fetuses. Secondly, there is a lack of low-cost means with which to measure how much/which chemicals (nicotine, alcohol, cannabis etc.) are getting into the human fetus during pregnancy. This project aims to resolve these issues using our uniquely large collection of normal, second trimester human fetal livers and by collecting both the liver and the placenta from further terminations of normal pregnancies.We will use highly sophisticated methods at the National Institute on Drug Abuse (USA) to measure chemicals from tobacco, cannabis, cocaine and alcohol in the fetal liver and in matched pairs of fetal livers and placentas. This will tell us how much the fetus has been exposed to drugs taken by the mother and whether the placenta can be used to measure the fetal burden of drugs and chemicals from the mother. This would allow us to carry out much larger studies of newborn babies to measure exposure levels in the placenta and their contribution to adult ill-health.At the same time as measuring drug levels in the fetal liver we will work out how those drugs have affected liver function. Then, by using cell culture, it will be possible to re-create the effects of drug exposure in the culture dish with a view to understanding the long-term consequences. We will also be able to find out more about how liver function develops and how it differs between male and female babies Overall, our aim is to relate changes in the control of fetal liver development to the effects of chemicals in cigarette smoke. This will allow us to understand liver mal-development turns to metabolic syndrome. The information from this study will allow us to measure, and to understand, the effects of exposing the developing fetus to its mother's recreational drug use. This will enable treatments to be designed to reverse these effects and to lower the incidence of the modern scourge of metabolic syndrome.

众所周知，如果一个女人在怀孕期间吸烟，对所生的后代会有不良后果，特别是减缓子宫内的生长。然而，在怀孕期间暴露于母亲香烟烟雾化学物质的儿童也可能出现其他严重问题。这些包括免疫系统受损（例如哮喘增加），教育表现较差以及患肥胖症，糖尿病和心脏病（称为代谢综合征）的机会增加。如果母亲在怀孕期间经常饮酒，即使没有成瘾的程度，也会发生许多这些影响。我们不知道如果母亲在怀孕期间吸烟和/或饮酒，那么他们患代谢综合征的几率会有多大。然而，最近一项针对74，000名女性的研究发现，如果她们的母亲在怀孕期间吸烟，那么这些女性患肥胖症的几率会高出53%。这将是NHS的一个主要额外消耗，并意味着更多的人可能会遭受这些衰弱的条件，因为吸烟和/或饮酒在怀孕期间继续在20-40%的妇女。在2006-07年的生活方式和相关条件的英国国民保健服务的成本是：吸烟33亿英镑，酒精33亿英镑，超重/肥胖51亿英镑和糖尿病35亿英镑每年。成人健康部分是由胎儿生命期间的事件编程时，个人还在子宫里，一个人可能会很难适应生活，如果母亲使用娱乐性药物。生长限制在这个过程中很重要，肝脏是出生前受生长干扰影响最大的器官之一。胎儿肝脏是一个关键器官，保护胎儿免受有害化学物质的伤害，并控制胎儿生长。在了解母体药物使用对胎儿发育的影响方面的进展存在两个问题：首先，我们对胎儿暴露的药物水平的无知，其次，这些药物影响发育的机制。有两个因素导致了我们的无知。首先，很少有研究使用正常的人类胎儿。其次，缺乏低成本的手段来衡量有多少/哪些化学品（尼古丁、酒精、大麻等）。会在怀孕期间进入胎儿体内该项目旨在解决这些问题，使用我们独特的大量正常妊娠中期人类胎儿肝脏，并从进一步终止正常妊娠中收集肝脏和胎盘。我们将在美国国家药物滥用研究所（National Institute on Drug Abuse，USA）使用高度复杂的方法来测量胎儿肝脏以及配对的胎儿肝脏和胎盘中来自烟草、大麻、可卡因和酒精的化学物质。这将告诉我们胎儿暴露于母亲服用的药物的程度，以及胎盘是否可以用来测量胎儿从母亲那里获得的药物和化学物质的负担。这将使我们能够对新生儿进行更大规模的研究，以测量胎盘中的暴露水平及其对成年人健康状况的影响，同时测量胎儿肝脏中的药物水平，我们将研究这些药物如何影响肝功能。然后，通过使用细胞培养，可以在培养皿中重现药物暴露的影响，以期了解长期后果。我们还将能够了解更多关于肝功能如何发展以及男女婴儿之间的差异。总的来说，我们的目标是将胎儿肝脏发育控制的变化与香烟烟雾中化学物质的影响联系起来。这将使我们能够了解肝脏发育不良会转化为代谢综合征。这项研究的信息将使我们能够测量和理解，将发育中的胎儿暴露于母亲的娱乐性药物使用的影响。这将使治疗方法能够逆转这些影响，并降低现代代谢综合征的发病率。

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

Additional file 1: of Maternal smoking and high BMI disrupt thyroid gland development

附加文件1：母亲吸烟和高BMI会扰乱甲状腺发育

• DOI: 10.6084/m9.figshare.7238495
• 发表时间: 2018
• 作者: Filis P

Additional file 3: of Maternal smoking and high BMI disrupt thyroid gland development

附加文件3：母亲吸烟和高BMI会扰乱甲状腺发育

• DOI: 10.6084/m9.figshare.7238516
• 发表时间: 2018
• 作者: Filis P

The human fetal adrenal proteome: development, sex, and maternal smoking link in utero smoke-exposure to offspring disease

人类胎儿肾上腺蛋白质组：发育、性别和母亲吸烟与子宫烟雾暴露与后代疾病的关系

• DOI: 10.1530/endoabs.44.p34
• 发表时间: 2016
• 期刊: Endocrine Abstracts
• 作者: Filis P

Additional file 2: of Maternal smoking and high BMI disrupt thyroid gland development

附加文件2：母亲吸烟和高BMI会扰乱甲状腺发育

• DOI: 10.6084/m9.figshare.7238507
• 发表时间: 2018
• 作者: Filis P