Nutritional modulation of fetal susceptibility to lower birth weight in relation to inorganic arsenic (iAs) exposure

项目摘要 NIH Ruth L.Kirschstein NRSA个人博士前奖学金(F31-多样性)申请旨在 促进环境科学系博士前学生Jeliyah Clark的培训 北卡罗来纳大学教堂山分校的工程学专业。克拉克女士打算成为一名独立的学术调查员，并将 接受她的赞助商丽贝卡·弗莱博士和卡门·马西特博士的指导，他们是环境健康领域的领导者； 咨询委员会，流行病学、毒理学和 分别是：营养学；以及导师，流行病学专家尚特尔·马丁博士。考虑到广泛的无机物 砷(IAS)对饮用水的污染，拟议的研究将评估对胎儿的营养修改 与IAS相关的出生体重下降易感性。在怀孕期间暴露于IAS是一个主要的公众 健康问题，因为IAS是一种强有力的发育毒物，有几项研究将产前暴露于 较低的出生体重。IAS还与促进氧化应激的转录失调有关， 炎症和其他发育相关的信号在胎儿细胞中，代表了潜在的生物学 机制。值得注意的是，IAS的代谢依赖于叶酸和其他组成一碳的B族维生素 新陈代谢途径，补充维生素B已被证明可以降低IAS的毒性。然而，国际会计准则- 营养物质的相互作用与胎儿发育的关系仍未得到充分研究，这是低氧的关键障碍。 预防出生体重。这项研究的中心假设是，母亲的饮食改变了胎儿的易感性。 与IAS相关的出生体重下降有关。在目标1中，克拉克女士将确定负面联系是否 IAS暴露与婴儿体重之间的关系受母体血清中OCM因子浓度的影响。在目标2中， 她将评估OCM因素是否减弱了IAS暴露和表达之间的正相关 促进脐带血氧化应激失衡和炎症的基因。拟议的研究将 利用来自现有怀孕队列的数据，即暴露于砷(熊)队列的生物标记物(N=200)。 将使用嵌套线性回归模型的似然比检验来评估 脐带血IAS暴露与出生体重(AIM 1)和基因表达的关系 碳代谢因素。此外，从复制妊娠队列中收集的数据将用于 验证AIM 1中的发现。这项研究是创新的，因为很少有研究评估维生素B作为决定因素 母体IAS甲基化效率还整合了出生体重和多组学评估，这可能预示着 在分子水平上降低IAS的毒性。这项研究将产生重大影响，因为它探索了产妇 饮食作为对IAS相关性低出生体重的预防性干预，并可能为食品强化政策提供参考 和对孕妇的饮食建议，改善临床实践。

PROJECT ABSTRACT This NIH Ruth L. Kirschstein NRSA Individual Predoctoral Fellowship (F31-Diversity) application seeks to promote the training of Jeliyah Clark, a pre-doctoral student in the Department of Environmental Sciences and Engineering at UNC Chapel Hill. Ms. Clark intends to become an independent academic investigator and will receive guidance from her sponsors, Drs. Rebecca Fry and Carmen Marsit, leaders in environmental health; advisory committee, Drs. Alex Keil, Julia Rager, and Mirek Styblo, experts in epidemiology, toxicology, and nutrition, respectively; and mentor, Dr. Chantel Martin, expert in epidemiology. Given widespread inorganic arsenic (iAs) contamination of drinking water, the proposed research will assess nutritional modification of fetal susceptibility to iAs-associated decreases in birth weight. Exposure to iAs during pregnancy is a major public health concern because iAs is a potent developmental toxicant, with several studies linking prenatal exposure to lower birth weight. iAs is also associated with transcriptional dysregulation promoting oxidative stress, inflammation, and other development-related signaling in fetal cells, representing a potential biological mechanism. Notably, iAs metabolism is dependent on folate and other B vitamins comprising the one-carbon metabolism pathway, and B vitamin supplementation has been shown to reduce iAs toxicity. However, iAs- nutrient interactions remain understudied in relation to fetal development, representing a critical barrier to low birth weight prevention. The central hypothesis of this research is that maternal diet modifies fetal susceptibility to iAs-associated decreases in birth weight. In Aim 1, Ms. Clark will determine whether the negative association between iAs exposure and infant BW is modified by maternal serum concentrations of OCM factors. In Aim 2, she will assess whether OCM factors attenuate the positive association between iAs exposure and expression of genes promoting oxidative stress imbalance and inflammation in cord blood. The proposed research will leverage data from an existing pregnancy cohort, the Biomarkers of Exposure to Arsenic (BEAR) cohort (N=200). Likelihood ratio tests of nested linear regression models will be employed to evaluate effect modification of the association between iAs exposure and birth weight (Aim 1) and gene expression in cord blood (Aim 2) by one- carbon metabolism factors. Additionally, data collected from a replication pregnancy cohort will be utilized to validate findings in Aim 1. This research is innovative, as few studies evaluating B vitamins as determinants of maternal iAs methylation efficiency also integrate birth weight and multi-omics assessments that may portend decreased iAs toxicity at the molecular level. The research will have a significant impact, as it explores maternal diet as a preventative intervention for iAs-associated lower birth weight and may inform food fortification policy and dietary recommendations for pregnant women, improving clinical practice.