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

摘要 这项美国和中国的合作研究将利用来自两口井的大量数据和存档的生物标本- 建立了预期出生队列：一个在美国波士顿；另一个在上海，中国，以检查 关键发育窗口期母亲汞暴露的时间和剂量-反应关系 (先入为主和特定三个月)和从出生到21岁的儿童心脏代谢结果。这 建议有很强的科学性前提。汞是一种持久性强、分布广泛的环境污染物。 在世界范围内，它是一种已知的高剂量神经毒剂，它在心脏代谢健康中的作用开始 被认可了。对成年人的研究表明，低剂量汞暴露与心血管疾病有关 疾病、糖尿病和肥胖症。一个关键的悬而未决的问题是，孕妇产前低剂量汞 暴露在空气中可能会对发育中的胎儿产生长期影响。这项提议提供了一个绝佳的机会 对于美国和中国在环境健康方面的合作，因为美国和中国是#年汞排放量最大的国家之一 整个世界。这项建议侧重于宫内汞暴露对儿童长期心脏代谢的影响 健康，这是新的，重要的，和迫切需要的，考虑到汞跨越胎盘和井口的能力- 有记录的胎儿汞的生物蓄积。我们的初步数据显示，母体脐带高度相关 母体汞水平与儿童体重指数和血压之间的剂量-反应关系。 这些发现提出了一种假设，即孕妇产前低剂量汞暴露会影响胎儿未来的心脏功能。 新陈代谢健康状况，需要进一步调查。这项提议使用了强有力的科学方法。两者都有 美国和中国缺乏明确有效的战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，在我们初步数据的推动下，母亲接触汞可以改变母亲和胎儿 循环代谢谱，我们将探索母体和胎儿代谢组，以获得新的见解 机械化的道路。这一提议为美国-中国科学家提供了一个特殊的平台来利用 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 使用相似的研究设计、结果和协变量定义进行相互以及荟萃分析；以及 相同的实验室和质量保证与控制程序和统计方法。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 也很有影响力。这项建议具有重大的临床和公共卫生影响。它代表着一种 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取得了重大进展 长期的心脏代谢结果，以及潜在的机制。如果成功，它可以作为一种 模型，以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.