Metabolic Health Risk Among Mid-Life Women: The Roles of Toxicants, Inflammation, and Epigenetics

项目总结/摘要 在女性中，代谢综合征（MetS）的发病率在中年时增加， 促进内脏脂肪堆积和更高的循环炎症标志物。生活方式是好的- 心脏代谢疾病的风险因素，但对短期的潜在风险知之甚少。 改变健康行为，以减少炎症和代谢综合征在更年期/更年期，当妇女更多 可能会寻求医疗保健。邻苯二甲酸酯和苯酚，发现2类内分泌干扰化学品（EDCs） 在食品、塑料和个人护理产品中， 横截面研究。炎症是一种可能的途径，将这些EDC暴露与 代谢综合征在中年的发展和进展，但关于毒物的文献很少考虑健康 行为作为混杂因素或效果修饰符。因此，评价毒物和其他物质之间的相互作用， 生活方式因素--包括饮食、睡眠和体力活动--是理解EDC作用的关键差距 暴露对中年女性炎症和代谢综合征发展的影响。后生 改变也可以作为EDC-代谢关系的生物标志物，因为这些EDC具有潜在的 影响表观基因组;即不改变DNA序列本身的基因表达的可遗传改变。 妊娠期暴露对后代表观基因组的影响是众所周知的，但其他生命过程时期 通过表观遗传机制-包括衰老-可能易受有毒物质影响的研究较少。 墨西哥环境毒物早期暴露（ELEMENT）队列具有独特的定位， 考虑到随访时间以及对毒物和饮食、睡眠和睡眠的重复测量，解决这些研究差距 体力活动。在600名自怀孕以来一直接受随访的女性中，我们将 利用2008年成年期的存档数据和生物标本，以及新收集的2个中年期的数据 访问超过3年（2019-20，2022-24）。具体目标是：1）确定接触酚类的作用， 邻苯二甲酸酯对中年MetS的发展和进展的影响; 2）调查 炎症机制是暴露于苯酚和邻苯二甲酸酯之间的关联的基础， 在2次中年访视中代谢结果的变化; 3）发现将苯酚和 邻苯二甲酸酯暴露于MetS的前瞻性研究和使用表观遗传学方法在中年的进展。大都会 流行率在世界范围内急剧增加--了解女性暴露于EDCs的影响 每天对中年心脏代谢风险的研究以及这些途径的确切性质将提供关键的新信息 知识，以帮助预防和管理代谢综合征的妇女，因为他们的年龄。

PROJECT SUMMARY / ABSTRACT Among women, incidence of metabolic syndrome (MetS) increases in midlife, when hormonal changes promote visceral fat accumulation and higher circulating inflammatory markers. Lifestyle behaviors are well- established risk factors for cardiometabolic disease, but less is known about the potential for short-term changes in health behaviors to reduce inflammation and MetS during peri-/menopause, when women are more likely to seek health care. Phthalates and phenols, 2 classes of endocrine disrupting chemicals (EDCs) found in foods, plastics and personal care products, have been linked to higher MetS among women primarily in cross-sectional studies. Inflammation is one plausible pathway connecting these EDC exposures to the development and progression of MetS in midlife but literature on toxicants infrequently accounts for health behaviors as confounders or effect modifiers. Thus, evaluating the interaction between toxicants and other lifestyle factors--including diet, sleep, and physical activity--is a critical gap in understanding the role of EDC exposures on changes in inflammation and MetS development among women in mid-life. Epigenetic alterations may also serve as biomarkers of EDC-metabolic relationships, since these EDCs have the potential to affect the epigenome; i.e. heritable alterations to gene expression that do not alter the DNA sequence itself. The influence of gestational exposures on the offspring epigenome is well-known, but other life course periods potentially vulnerable to effects of toxicants through epigenetic mechanisms—including aging--are less studied. The Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort is uniquely positioned to address these research gaps, given length of follow up and repeated measures of toxicants and diet, sleep and physical activity. Among 600 women followed since pregnancy who now span peri-/menopausal ages, we will leverage archived data and biospecimens from adulthood in 2008, and newly collected data from 2 mid-life visits over 3 years (2019-20, 2022-24). Specific Aims are to: 1) Ascertain the role of exposure to phenols and phthalates in adulthood on the development and progression of MetS in mid-life; 2) Investigate the inflammatory mechanisms that underlie associations between exposure to phenols and phthalates and changes in metabolic outcomes over 2 mid-life visits; 3) Uncover other biological pathways that link phenol and phthalate exposures prospectively to MetS and progression in midlife using an epigenetics approach. MetS prevalence is increasing dramatically worldwide--understanding the impact of EDCs that women are exposed to daily on midlife cardiometabolic risk and the exact nature of these pathways will provide critical new knowledge to aid in prevention and management of MetS in women as they age.