Parental lifetime occupational exposures and risk of autism spectrum disorder in offspring

项目摘要/摘要 自闭症谱系障碍(ASD)可能是环境侮辱引发的遗传风险的后果。 通过识别可改变的危险因素来预防自闭症已获得更多的公众健康 利息。类钙毒物可以积聚在骨骼中，亲脂化合物可以积聚在脂肪中。 在职业接触之后。随着骨骼和脂肪的新陈代谢，这两种物质都可以释放到血液中。 在怀孕期间，亲脂化合物可以很容易地通过母乳转移给婴儿。也有 男性通过父亲职业暴露导致胚胎畸形的途径。 尽管之前对父母职业和子女自闭症的研究使用了暴露估计，但据报道 在怀孕和出生时或前后，父母的职业暴露与神经发育有关 需要跨越几年并持续到婴儿期和幼儿期的数据收集。在这项研究中， 我将利用丹麦国家患者登记处(DNRP)的基于人口的监测数据来确定所有 丹麦1995年至2018年的ASD病例和10例性别和出生年份匹配的对照组。这些数据将是 链接到医疗出生登记处记录，以及丹麦中央人口的父母记录 登记。从出生后16岁到6个月的父母职业历史将从 丹麦养恤基金，将使用工作暴露矩阵(JEM)估计职业暴露 由北欧职业癌症研究中心为丹麦开发。然后我会调查终生的、产前的和 出生后父母职业评估持久性化学物质积累和ASD风险的影响 在后代中进行诊断。我还将确定父母接触每种毒物的潜在病因学窗口。 使用来自前面提到的种群子集的质量受控的全基因组数据 伦德贝克综合精神病学研究基金会(IPSYCH)队列研究，我将计算 ASD的遗传风险描述然后测试父母职业暴露是否与ASD多基因相互作用 与ASD诊断相关的风险评分。从丹麦就业分类模块获得的数据将是 与上述JEM结合使用以估计特定时间的父母职业暴露， 我将使用回归分析来研究基因与环境的相互作用。这项建议是建立在我的 以前在环境暴露和自闭症方面的博士研究，以及以前的博士后研究 使用丹麦登记数据的累积职业暴露。我召集了一位杰出的导师 团队，以获得最高水平的训练。这是使用丰富数据源的独特机会 世界级导师团队的指导将使我能够将我的专业知识扩展到包括基因 流行病学、基因-环境相互作用分析和围产期流行病学。拟议的研究 培训将为我提供过渡到环境问题独立研究人员所需的技能 风险和神经后果。

Project Summary / Abstract Autism spectrum disorder (ASD) may be the consequence of genetic risk triggered by environmental insult. The prevention of ASD through the identification of modifiable risk factors has garnered increased public health interest. Calcium-mimicking toxicants can accumulate in bone and lipophilic compounds can accumulate in fat after occupational exposures. Both of these can be released into the blood stream as bone and fat metabolize during pregnancy, and lipophilic compounds can be easily transferred to infants via breastmilk. There are also suggested pathways of male-mediated embryonic malformations via paternal occupational exposures. Although previous studies of parental occupation and ASD in offspring have used exposure estimates reported at or around the time of pregnancy and birth, linking parental occupational exposures to neurodevelopment requires data collection that spans several years and continues into infancy and early childhood. For this study, I will utilize population-based surveillance data from the Danish National Patient Registry (DNRP) to identify all ASD cases in Denmark from 1995 to 2018 and ten sex and birth-year matched controls. These data will be linked to Medical Birth Registry records, along with parental records from the Danish Central Population Register. Parental occupation history from the age of 16 to 6 months post-childbirth will be obtained from the Danish Pension Fund, and occupational exposures will be estimated using job exposure matrices (JEMs) developed by the Nordic Occupational Cancer Study for Denmark. I will then investigate lifetime, prenatal, and postnatal parental occupation to evaluate the impact of accumulation of persistent chemicals and risk of ASD diagnosis in offspring. I will also identify potential etiologic windows of parental exposure for each toxicant. Using quality-controlled genome-wide data from a subset of the previously mentioned population via the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) cohort study, I will compute genetic risk profiles for ASD then test whether parental occupational exposures interact with ASD polygenic risk scores in relation to ASD diagnosis. Data obtained from Danish Employment Classification Module will be used in conjunction with the aforementioned JEMs to estimate time-specific parental occupational exposures, and I will use regression analyses to investigate gene-environment interaction. This proposal builds on my previous doctoral research in environmental exposures and ASD as well as previous postdoctoral research on cumulative occupational exposures using Danish registry data. I have assembled an exceptional mentoring team in order to acquire the highest level of training. This unique opportunity to use rich data sources with guidance by a world-class team of mentors will enable me to expand my expertise to include genetic epidemiology, analysis of gene-environment interaction, and perinatal epidemiology. The proposed research and training will provide me with the skills needed to transition to an independent researcher of environmental risk and neurological outcomes.