Methylmercury Exposure Through Rice Ingestion, Gut Microbes, and Offspring Development

 描述(申请人提供)：汞是一种已知的神经毒素；甲基汞是最有效的形式之一，因为它能够跨越血脑和胎盘屏障。与毒性较低的无机汞不同，膳食中约95%的甲基汞被吸收到血液中，进入肝脏门脉循环。甲基汞的生物半衰期较长(45-70天)，归因于广泛的肠-肝循环，当肠道微生物群将甲基汞去甲基化并从粪便中排泄时，这种循环会中断。因此，肠道微生物功能通过其在人体新陈代谢和甲基汞的消除中的作用而对解毒很重要。相反，来自人类研究的证据表明，并不是所有肠道中的甲基汞都是去甲基化的，而元老(从人类粪便中分离出来)对无机汞的甲基化也是可能的。无机汞(或甲基汞)暴露引起肠道微生物群落的变化；然而，数据仅限于涉及猴子、甲壳类动物和蚯蚓的研究。需要进行人体研究，以建立肠道微生物区系、膳食甲基汞摄入量和组织中甲基汞累积之间的双向联系。为了解决这一知识差距，我们将利用我们在中国进行的预期出生和儿童队列研究，调查产前/出生后甲基汞暴露与儿童粪便中肠道微生物群评估的相关性。具体目标如下：目的1.用贝利婴幼儿发育量表评估出生前和出生后大米摄入甲基汞暴露对儿童神经发育的影响。目的2.利用16S rRNA基因图谱，评估儿童粪便中肠道微生物区系(门、纲、目、科、属)的相对丰度和多样性，调查肠道微生物与甲基汞暴露(产前/出生后)和其他混杂因素之间的关系。目的3.确定甲基汞代谢和暴露的可变性是否与通过量化儿童粪便样本中的汞抗性基因(MERA和merB)进行微生物解毒相对应。这项研究的结果将澄清我们对肠道微生物促进儿童甲基汞代谢和暴露的可变性，潜在影响后代发育的机制的理解。

 DESCRIPTION (provided by applicant): Mercury is a known neurotoxin; methylmercury is one of the most potent forms due to its ability to cross both the blood-brain and placental barriers. Unlike less toxic inorganic mercury, about 95% of dietary methylmercury is absorbed into the bloodstream, entering the hepatic portal circulation. The long, biological half-time of methylmercury (45-70 days) is attributed to extensive enterohepatic recycling, which is interrupted when methylmercury is demethylated by gut microbiota and excreted in feces. Thus gut microbial function is important to detoxification via its role in human metabolism and elimination of methylmercury. Conversely, evidence from human studies indicates not all methylmercury in the gut is demethylated, while inorganic Hg methylation by an archeon (isolated from human feces) is also possible. Inorganic mercury (or methylmercury) exposure induced changes in gut microbe communities; however data were limited to studies involving monkeys, crustaceans, and earthworms. Human studies are needed to establish bi-directional associations between gut microbiota, dietary methylmercury intake, and accumulation of methylmercury in tissues. To address this knowledge gap, we will leverage our prospective birth and child cohort study in China, to investigate associations between prenatal/postnatal methylmercury exposure and gut microbiota assessed in children's stools. The following includes the specific aims: Aim 1. Establish the impacts of prenatal and postnatal methylmercury exposure through rice ingestion on children's neurodevelopment, evaluated using the Bayley Scales of Infant Development. Aim 2. Assess the relative taxonomic abundance and diversity of gut microbiota (phylum, class, order, family, and genus levels) in children's stool samples using 16S rRNA gene profiling, to investigate associations between gut microbes, methylmercury exposure (prenatal/postnatal), and other confounders. Aim 3. Establish whether variability in methylmercury metabolism and exposure corresponds to microbial detoxification via mercury resistance genes (merA and merB) quantified in children's stool samples. Results from this study will clarify our understanding of the mechanisms by which gut microbes contribute to variability in children's methylmercury metabolism and exposure, potentially impacting offspring development.