Developmental neurotoxicity of organophosphate and novel brominated flame retardants in children

项目摘要 毒理学和流行病学研究表明，多溴联苯具有发育神经毒性 醚(PBDEs)，一组在美国和其他地方广泛使用的阻燃剂(FR)。随着逐步淘汰 自2004年以来，市场上多溴二苯醚的替代品，包括有机磷阻燃剂(OPFR) 和新型溴化阻燃剂(NBFR)，越来越多地添加到消费产品中，以满足 易燃性要求。三(1，3-二氯-2-丙基)磷酸(TDCPP)和Firemaster®550(FM 550)是 最常用的替代FR。TDCPP，也被称为“氯化三氯甲烷”，是一次OPFR 在20世纪70年代添加到儿童睡衣中，但后来因毒性问题而被移除。 在FM 550中，三苯基磷酸(TPP)和各种TPP类似物是OPFR成分，而2-乙基己基- 2，3，4，5-四溴苯甲酸酯(TBB)和2，3，4，5-二(2-乙基己基)-2，3，4，5-四溴邻苯二甲酸酯(TBPH)是NBFR FM 550中的组件。据报道，TDCPP、TPP和FM550可以改变甲状腺激素水平，减少 神经元的存活和复制，改变神经元的分化，导致异常的胚胎发生和 发展，影响神经行为，并改变基因表达水平和DNA甲基化 学习。与OPFR和NBFR的实验研究证据相比，我们的 了解它们对人类发育的神经毒性。我们建议检查发育情况 基于辛辛那提健康结局的OPFR和NBFR的神经毒性及其测量方法 环境(家庭)研究，现有出生队列410名儿童，从产前到12岁，有 产前和产后暴露评估、甲状腺激素、认知和行为测试，以及 神经成像数据。我们假设出生前和出生后暴露于OPFR和NBFR是 与：1)母体、脐带和儿童血清样本中甲状腺激素水平的改变有关；2) 儿童认知功能下降；3)儿童神经行为功能较差；4)对大脑的不利影响 12岁时通过神经成像鉴定其结构、组织和功能。拟议的研究将是 首次全面研究OPFR和NBFR对儿童的发育神经毒性。 解决大脑发育的神经内分泌、神经行为和神经成像方面的问题是非常重要的 对这次调查来说很有创意。这些发现将对科学界和政策制定者具有关键价值 评估当前使用的替代FRS对大脑发育的潜在影响。这项研究具有很高的 与美国国立卫生研究院的任务有关，以确定可能扰乱大脑的化学暴露 发展，并提供关键数据，为预防战略提供信息。

Project Summary Toxicological and epidemiologic studies have shown developmental neurotoxicity of polybrominated diphenyl ethers (PBDEs), a group of flame retardants (FRs) widely used in the U.S. and elsewhere. With the phase-out of PBDEs from the market since 2004, replacement FRs, including organophosphate flame retardants (OPFRs) and novel brominated flame retardants (NBFRs), are increasingly added to consumer products to meet flammability requirement. Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and Firemaster® 550 (FM 550) are the most commonly used replacement FRs. TDCPP, also referred to as “chlorinated tris”, is an OPFR once added to children’s sleepwear in the 1970s but later removed because of toxicity concerns. Triphenylphosphate (TPP) and various TPP analogs are OPFR components in FM 550, while 2-ethylhexyl- 2,3,4,5-tetrabromobenzoate (TBB) and bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) are NBFR components in FM 550. TDCPP, TPP and FM 550 have been reported to alter thyroid hormone levels, reduce neuronal viability and replication, alter neuronal differentiation, cause abnormal embryogenesis and development, affect neurobehavior, and change gene expression levels and DNA methylation in experimental studies. Compared with experimental study evidence of OPFRs and NBFRs, there are significant gaps in our understanding of their developmental neurotoxicity in humans. We propose to examine developmental neurotoxicity of OPFRs and NBFRs using the Cincinnati-based Health Outcomes and Measures of the Environment (HOME) Study, an existing birth cohort of 410 children from prenatal to 12 years of age, with prenatal and postnatal exposure assessment, thyroid hormones, cognitive and behavioral tests, and neuroimaging data. We hypothesize that prenatal and postnatal exposures to OPFRs and NBFRs are associated with: 1) altered thyroid hormone levels in maternal, cord, and childhood serum samples; 2) decreased child cognitive function; 3) poorer child neurobehavioral functioning; and 4) adverse impact on brain structure, organization, and function identified by neuroimaging at age 12 years. The proposed research will be the first to comprehensively study developmental neurotoxicity of both OPFRs and NBFRs in children. Addressing neuroendocrinological, neurobehavioral, and neuroimaging aspects of brain development is highly innovative for this investigation. The findings will be of critical value to scientific community and policy makers evaluating potential impact of current-use replacement FRs on developing brain. The research is highly relevant to the National Institutes of Health mission to identify potential chemical exposures that disrupt brain development and provide critical data to inform prevention strategies.