Consequences of prenatal toxicant exposure on fetal brain function

 描述（由申请人提供）：数十年的研究已经强调了产前暴露于常见环境毒物（即，烟草烟雾、铅和汞）对以后健康结果的影响。胎儿和婴儿对这种暴露特别敏感，这既是因为发育的早期中断可能产生长期影响，也是因为许多神经毒物很容易穿过胎盘和胎儿血脑屏障。因此，毫不奇怪，出生在污染物水平高的地区的儿童（例如， 贫困的城市社区）遭受许多不良健康结果的显著更高比率，包括儿童行为问题（BP），如攻击性、反社会行为和多动。虽然现在很少有人会质疑产前污染物暴露的行为后遗症，但驱动这些影响的机制尚不清楚。胎儿期静息状态功能连接（RSFC）改变的研究代表了此类研究的一个特别有前途的途径，因为RSFC已被证明最初在子宫内发育，并与青年BP和儿童期毒物暴露有关。这个R21的目的是检查产前暴露于三种常见毒物（烟草烟雾，铅和汞）和胎儿RSFC在35周妊娠，和这些协会的纵向后果儿童BP之间的关联。我们将首先建立产前暴露于铅，汞，和/或可替宁作为预测（S）的RSFC在发育中的胎儿大脑。我们接下来将评估胎儿RSFC作为3岁时BP的预测因子。然后，我们将研究胎儿RSFC是否介导儿童BP和产前毒物暴露之间的关联。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性神经回路，以及这些协会的长期行为后果。这项工作将使我们不仅对产前毒物暴露的长期影响，而且对儿童BP的起源的理解取得重大进展。

 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.