Maternal Exposure to Low Level Mercury, Metabolome, and Child Cardiometabolic Risk in Multi-Ethnic Prospective Birth Cohorts

摘要 这项中美合作研究将利用来自两个良好实验室的大量数据和存档生物样本。 建立了前瞻性出生队列：一个在美国波士顿；另一个在中国上海，以检查 母亲在关键发育窗口接触汞之间的时间和剂量反应关系 （孕前和特定妊娠期）以及从出生到 21 岁的儿童心脏代谢结果。这个 这个提议有很强的科学前提。汞是一种持久且广泛的环境污染物 在世界范围内，它是一种已知的高剂量神经毒物，其在心脏代谢健康中的作用开始受到关注 认可。成人研究表明，低剂量汞暴露与心血管疾病有关 疾病、糖尿病和肥胖。一个尚未解答的关键问题是母亲产前低剂量汞是否 暴露会对发育中的胎儿产生长期影响。该提案提供了一个绝佳的机会 由于美国和中国是汞的最大排放国之一，因此中美在环境健康方面开展合作 世界。该提案重点关注宫内汞暴露对儿童长期心脏代谢的影响 考虑到汞能够穿过胎盘和良好的健康，这是新颖、重要且迫切需要的。 记录了汞的胎儿生物蓄积量。我们的初步数据显示母系脐带之间具有非常高的相关性 血汞以及母亲汞水平与儿童体重指数和血压之间的剂量反应关系。 这些发现提出了这样的假设：母亲产前低剂量接触汞会影响胎儿未来的心脏功能。 代谢健康并值得进一步研究。该提案采用了强有力的科学方法。两者都 美国和中国缺乏明确有效的策略来减少低剂量汞对健康的不利影响 曝光。我们计划评估母亲的微量营养素状况（例如叶酸）在多大程度上抵消了 根据我们的初步数据，汞暴露对儿童心脏代谢结果的不利影响。 此外，根据我们的初步数据，母体汞暴露会改变母体和胎儿 循环代谢组学概况，我们将探索母体和胎儿代谢组学以获得新的见解 机械途径。该提案为中美科学家提供了一个绝佳的平台 双方的资源和专业知识。这两个队列可以作为发现和复制队列 相互以及荟萃分析，使用类似的研究设计和结果以及协变量定义；和 相同的实验室和质量保证和控制 (QA/QC) 程序和统计方法。通过这样做， 它极大地增强了我们检验研究假设的能力，并使研究结果更具普遍性 并且有影响力。该提案具有重大的临床和公共卫生影响。它代表了一个 在阐明产前接触低剂量汞和微量营养素对儿童的作用方面迈出了重要一步 长期心脏代谢结果以及潜在机制。如果成功的话，它可以作为一个 模型来严格调查其他早期生命环境暴露。

Abstract This US-China collaborative study will leverage extensive data and archived biospecimens from two well- established prospective birth cohorts: one in Boston, US; and the other in Shanghai, China, to examine the temporal and dose-response relationships between maternal exposure to Hg at critical developmental windows (preconception and specific trimesters) and child cardio-metabolic outcomes from birth to age 21 years. This proposal has a strong scientific premise. Hg is a persistent and widespread environmental pollutant worldwide and a known neurotoxicant at high doses, and its role in cardio-metabolic health is beginning to be recognized. Studies in adults have suggested that low dose Hg exposure was associated with cardiovascular diseases, diabetes, and obesity. A critical unanswered question is whether maternal prenatal low dose Hg exposure can have a long-lasting impact on the developing fetus. This proposal presents a prime opportunity for a US-China collaboration on environmental health since US and China are among the top emitters of Hg in the world. This proposal focuses on the effect of in-utero Hg exposure on child’s long-term cardio-metabolic health, which is novel, important, and critically needed, given Hg’s ability to cross the placenta and the well- documented fetal bioaccumulation of Hg. Our preliminary data showed a very high correlation of maternal-cord blood Hg and a dose-response relationship between maternal Hg levels and child BMI and blood pressure. These findings raise the hypothesis that maternal low dose prenatal exposure to Hg affects fetal future cardio- metabolic health and warrant further investigation. This proposal uses vigorous scientific methods. Both the US and China lack clear and effective strategies to reduce the adverse health effects of low dose Hg exposure. We plan to evaluate to what extent maternal micronutrient status (e.g., folate) counteracts the adverse effects of Hg exposure on child cardio-metabolic outcomes based on our preliminary data. Furthermore, motivated by our preliminary data that maternal Hg exposure can alter both maternal and fetal circulating metabolomic profile, we will explore maternal and fetal metabolome to gain novel insight to mechanistic pathways. This proposal provides an exceptional platform for US-China scientists to leverage resources and expertise on both sides. The two cohorts can serve as a discovery and replication cohort for each other as well as meta-analysis, using a similar study design and outcome and covariate definitions; and same laboratory and quality assurance and control (QA/QC) procedures and statistical methods. By doing so, it greatly enhances our ability to test the study hypotheses and make the study findings far more generalizable and impactful. This proposal has significant clinical and public health implications. It represents a significant step forward in elucidating the roles of prenatal exposure to low dose Hg and micronutrients in child long-term cardio-metabolic outcomes, as well as the potential mechanisms. If successful, it can serve as a model to rigorously investigate other early life environmental exposures.