Consequences of prenatal toxicant exposure on fetal brain function

 描述(由申请人提供)：数十年的研究强调了产前暴露于常见环境毒物(即烟草烟雾、铅和汞)对后来的健康结果的破坏性影响。胎儿和婴儿对这种接触特别敏感，这既是因为发育的早期中断可能会产生长期的影响，也是因为许多神经毒物很容易通过胎盘和胎儿的血脑屏障转移。因此，毫不奇怪，出生在污染物水平较高地区的儿童(例如， 贫穷的城市社区)遭受大量不良健康后果的比率明显更高，包括儿童行为问题(BP)，如攻击性、反社会行为和多动症。虽然现在很少有人会质疑产前接触污染物的行为后遗症，但推动这些影响的机制(S)尚不清楚。对胎儿期静息功能连接性(RSFC)改变的研究是这类研究的一个特别有前途的途径，因为RSFC最初是在子宫中发展起来的，并与青年BP和儿童时期的毒物接触有关。R21的目标是检查产前暴露于三种常见毒物(烟草烟雾、铅和汞)与妊娠35周时胎儿呼吸道合并症之间的联系，以及这些联系对儿童BP的纵向影响。我们将首先确定产前暴露于铅、汞和/或可替宁作为发育中胎儿大脑中呼吸窘迫综合征的预测因子(S)。接下来，我们将评估胎儿RSFC作为3岁时血压的预测因子。然后，我们将检查胎儿RSFC是否在儿童血压和产前毒物暴露之间起中介作用。因此，我们将能够有意义地评估产前毒物暴露是否以及如何影响发育中的胎儿大脑的功能神经电路，以及这些联系的长期行为后果。这项工作将大大提高我们对产前毒物暴露的长期影响，以及儿童BP的起源的理解。

 DESCRIPTION (provided by applicant): Decades of research have highlighted the damaging effects of prenatal exposure to common environmental toxicants (i.e., tobacco smoke, lead, and mercury) on later health outcomes. Fetuses and infants are particularly sensitive to such exposure, both because early disruptions in development can have long-lasting effects, but also because many neurotoxicants are readily transferred across the placenta and the fetal blood brain barrier. Not surprisingly, then, children born in areas with high levels of pollutants (e.g., poor urban neighborhoods) suffer from notably higher rates of a number of adverse health outcomes, including child behavior problems (BP) such as aggression, antisocial behavior, and hyperactivity. Although few would now contest the behavioral sequelae of prenatal pollutant exposure, the mechanism(s) driving these effects are as yet unclear. Studies of alterations in resting-state functional connectivity (RSFC) during the fetal period represent a particularly promising avenue for such research, since RSFC has been shown to initially develop in utero and has been associated with both youth BP and toxicant exposure during childhood. The goal of this R21 is to examine associations between prenatal exposure to three common toxicants (tobacco smoke, lead, and mercury) and fetal RSFC at 35-weeks gestation, and the longitudinal consequences of these associations for child BP. We will first establish prenatal exposure to lead, mercury, and/or cotinine as predictor(s) of RSFC in the developing fetal brain. We will next evaluate fetal RSFC as a predictor of BP at age 3. We will then examine whether fetal RSFC mediates associations between child BP and prenatal toxicant exposure. We will thus be able to meaningfully evaluate whether and how prenatal toxicant exposures affect functional neurocircuitry of the developing fetal brain, and the long-term behavioral consequences of those associations. Such work would constitute a substantial advance in our understanding of not only the long-term effects of prenatal toxicant exposure, but also the origins of child BP.