Effects of Flame Retardants on Brain Function and Attentional Deficits in School-age Children - Brain Imaging, Neurobehavioral, and Gut Microbiome Studies in a Longitudinal Birth Cohort

总结 被诊断患有注意力缺陷多动障碍（ADHD）的儿童人数稳步上升， ADHD的可预防原因在很大程度上仍然未知。产前接触环境化学品， 包括多溴联苯醚（PBDEs）等阻燃剂， ADHD，但他们在ADHD因果关系中的作用是有争议的。由于担心可能的毒性， 制造商已经用更新的化学品取代多溴二苯醚，如卤化的非多溴二苯醚化合物， 这还没有在人类研究中进行过调查，因此可能更具威胁性。美国环保署 《儿童与环境》报告指出，阻燃剂与多动症之间可能存在联系， 关键的研究空白，如果不及时解决，可能会使数百万儿童不必要地接触到 可能产生长期不良影响的化学品。我们将通过以下方式解决这一紧迫的优先事项： 使用最先进的脑成像进行行为评估-即，基于任务的功能性磁共振成像（fMRI），休息- 国家功能磁共振成像和扩散磁共振成像，以确定阻燃剂对功能和组织的影响， (i.e.,连接）的儿童的大脑。这种方法提供了一个显着的优势，比以前的研究， 阻燃剂，只使用行为ADHD评估或临床诊断，可能没有 检测临床前变化，低估影响，并提供了缺乏神经生物学的理解。我们 把重点放在怀孕作为一个关键的接触窗口，因为有毒物质最有可能影响发育中的大脑。 然而，我们也将建立在新的证据表明，肠道微生物群-一个可能的生物学 阻燃剂目标-调节儿童时期的注意力和冲动。因此，我们也将探讨 是否暴露于阻燃剂之间的6-9岁，当多动症最常见的表现， 通过改变儿童的肠道微生物组对大脑功能和表型产生不利影响。为此，我们将 利用现有的盖斯特出生队列，专门用于研究阻燃剂的神经毒性， 孩子盖斯特拥有广泛的产前和儿童期暴露数据和神经心理学评估， 6-7年当建议的MRI技术可行时，我们将在8-9岁时重新评估儿童（n=500） 并且可以对注意力/冲动进行更精确的测试。在目标1中，我们将确定 产前接触多溴二苯醚阻燃剂与脑功能的MRI异常有关， 连接和ADHD行为和诊断。在目标2中，我们将确定产前暴露是否 卤化非PBDE阻燃剂与脑功能的MRI异常有关， 连接和ADHD行为和诊断。在探索性目标3中，我们将探讨 在儿童时期的血液和粪便中检测到的多溴联苯醚及其替代品的含量与MRI有关， 通过肠道微生物组的改变进行大脑测量、神经行为和ADHD诊断。我们的结果将 帮助识别有害化学物质的影响，保护美国和全球数百万儿童。

SUMMARY The number of children diagnosed with attention deficit hyperactivity disorder (ADHD) has risen steadily, yet preventable causes of ADHD remain largely unknown. Prenatal exposures to environmental chemicals, including flame retardants such as polybrominated diphenyl ethers (PBDEs), have been increasingly linked to ADHD, but their role in ADHD causation is controversial. Due to concerns about possible toxicity, manufacturers have substituted PBDEs with newer chemicals, such as halogenated non-PBDE compounds, that have not yet been investigated in human studies and thus could be even more threatening. The EPA Report on Children and the Environment identified the possible link between flame retardants and ADHD as a critical research gap that, if not promptly addressed, could keep millions of children needlessly exposed to chemicals with possible long-lasting adverse effects. We will address this urgent priority by combining behavioral assessments with state-of-the-art brain imaging—i.e., task-based functional MRI (fMRI), resting- state fMRI, and diffusion MRI—to identify the influences of flame retardants on the functioning and organization (i.e., connectivity) of children’s brains. This approach provides a significant advantage over previous studies of flame retardants, which used only behavioral ADHD assessments or clinical diagnosis and may have failed to detect preclinical alterations, underestimated effects, and provided scant neurobiological understanding. We focus on pregnancy as a critical exposure window when toxicants are most likely to affect the developing brain. However, we will also build upon new evidence demonstrating that the gut microbiome—a possible biological target of flame retardants—modulates attention and impulsivity during childhood. Hence, we will also explore whether exposures to flame retardants between 6-9 years of age—when ADHD most commonly presents— adversely affect brain function and phenotypes by altering the child’s gut microbiome. To do so, we will leverage the existing GESTE birth cohort, designed specifically to investigate flame retardant neurotoxicity in children. GESTE has extensive prenatal and childhood exposure data and neuropsychological assessments at 6-7 years. We will reevaluate children (n=500) at 8-9 years, when the proposed MRI techniques are feasible and more accurate testing for attention/impulsivity can be conducted. In Aim 1, we will determine whether prenatal exposure to PBDE flame retardants is associated with MRI abnormalities in brain function and connectivity and with ADHD behaviors and diagnosis. In Aim 2, we will determine whether prenatal exposure to halogenated non-PBDE flame retardants is associated with MRI abnormalities in brain function and connectivity and with ADHD behaviors and diagnosis. In Exploratory Aim 3, we will explore whether the levels of PBDEs and their substitutes, measured in both blood and stools during childhood, are associated with MRI brain measures, neurobehaviors and ADHD diagnosis via alterations of the gut microbiome. Our results will help identify adverse chemical effects and protect millions of children in the U.S. and worldwide.