IRS insecticides for malaria control and child neurodevelopment in South Africa

描述（由申请人提供）：每年有2.5亿人感染疟疾，导致88万人死亡，主要是五岁以下的非洲儿童。许多疟疾流行的国家使用室内滞留喷洒，即在住宅内墙喷洒二氯二苯三氯乙烷（DDT）或拟除虫菊酯类杀虫剂，以控制疟疾。对长期、高剂量接触滴滴涕的意外后果的关注引起了大量的国际辩论。例如，《关于持久性有机污染物的斯德哥尔摩公约》旨在禁止滴滴涕，而世界卫生组织和美国国际开发署则促进和/或资助室内滞留喷洒，包括滴滴涕。 DDT和拟除虫菊酯是昆虫和动物的神经毒物。主要在接触程度低至中等的西方人口中进行的人体研究表明，产前接触滴滴涕及其分解产物DDE可能对儿童的神经发育产生不利影响。滴滴涕/E接触还与对甲状腺功能、妊娠期和出生体重的不利影响以及全球DNA甲基化的变化有关，这可能是损害神经发育的途径。虽然几乎没有关于拟除虫菊酯对人类健康影响的研究，但对啮齿动物的研究表明，拟除虫菊酯对神经发育的不利影响既有单独的影响，也有与滴滴涕协同作用的影响。没有研究评估了人类接触滴滴涕和/或拟除虫菊酯对IRS背景下神经发育的影响。我们建议通过研究接触IRS杀虫剂和神经发育之间的关系以及出生队列研究中可能的介质来解决这些重要的知识空白。我们的目标是招募750名南非农村的母亲，并跟踪他们的孩子24个月，前瞻性地评估暴露和神经发育。我们利用一个自然实验，其中海拔梯度影响蚊子的生存，并通过扩展，使用IRS，但喷洒和未喷洒的村庄在其他方面是相似的，例如，人口统计。我们提议的研究将是第一个：1）评估在室内滞留喷洒杀虫剂处理的家庭中孕妇和婴儿接触室内滞留喷洒杀虫剂的水平和决定因素; 2）研究非常高的滴滴涕/E和拟除虫菊酯接触对人类神经发育的影响; 3）评估替代室内滞留喷洒杀虫剂的相对和协同健康影响;评估贫穷、营养不良和健康状况不佳是否会加剧这些暴露对健康的影响。我们将介绍两种对环境健康科学具有更广泛影响的技术：使用PBPK模型来量化子宫内，母乳和婴儿出生后环境暴露的相对贡献，以及使用最先进的表观遗传学方法来确定环境暴露是否可以改变胎儿组织中的DNA甲基化。 本研究旨在提供数据，以评估不同疟疾控制方法的风险/效益，并制定适当的干预措施，以减少孕妇和儿童的接触。

DESCRIPTION (provided by applicant): Every year, 250 million people are infected with malaria, resulting in 880,000 deaths, primarily to African children under age five. Many malaria-endemic countries use Indoor Residual Spraying (IRS), the application of dichlorodiphenyl trichloroethane (DDT) or pyrethroid insecticides to interior walls of homes, to control malaria. Concerns regarding the unintended consequences of chronic, high-level DDT exposure have resulted in considerable international debate. For example, the Stockholm Convention on Persistent Organic Pollutants aims to ban DDT, while the World Health Organization and the U.S. Agency for International Development promote and/or fund IRS, including with DDT. DDT and pyrethroids are neurotoxicants in insects and animals. Human studies, primarily conducted in Western populations with low to moderate levels of exposure, suggest that prenatal exposure to DDT and its breakdown product, DDE, may adversely affect children's neurodevelopment. DDT/E exposure has also been related to adverse effects on thyroid function, gestational duration and birth weight, and changes in global DNA methylation, which could serve as pathways for compromised neurodevelopment. Although there is virtually no research in humans on the health effects of pyrethroids, research in rodents has shown detrimental effects on neurodevelopment both independently and synergistically with DDT. No study has evaluated the impact of human exposure to DDT and/or pyrethroids on neurodevelopment in the context of IRS We propose to address these important knowledge gaps by examining relationships between exposure to IRS insecticides and neurodevelopment, and possible mediators in a birth cohort study. We aim to enroll 750 rural South African mothers and to follow their children for 24 months, assessing exposures and neurodevelopment prospectively. We take advantage of a natural experiment where gradations in altitude impact mosquito survival and, by extension, use of IRS, but sprayed and unsprayed villages are otherwise similar, e.g, demographically. Our proposed study will be the first to: 1) assess levels and determinants of IRS insecticide exposure to pregnant women and infants in IRS-treated homes; 2) study the effects of very high DDT/E and pyrethroid exposures on human neurodevelopment; 3) assess the relative and synergistic health impacts of alternative IRS insecticides; and 4) evaluate whether poverty, malnutrition and poor health potentiate the health effects of these exposures. We will introduce two techniques with wider implications for environmental health science: the use of PBPK models to quantify the relative contributions of in utero, breast milk, and other postnatal environmental exposures in infants, and the use of state-of-the-art epigenetic methods to determine whether environmental exposures can alter DNA methylation in fetal tissue. This study aims to provide data to evaluate the risk/benefit of different methods of malaria control and for the development of appropriate interventions to reduce exposure to pregnant women and children.