Evaluating mechanisms of sex differences in environmentally-induced metabolic diseases

评估环境引起的代谢疾病中性别差异的机制

• 批准号: 10818773
• 负责人: Banrida Wahlang
• 金额: $ 6.98万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818773
• 关键词: Address; Agricultural Workers; Androgen Receptor; Authorization documentation; Biological; Cardiovascular system; Development; Diabetes Mellitus; Dyslipidemias; Educational Status; Endocrine Disruptors; Energy Intake; Environment; Environmental Health; Estrogen Receptors; Exposure to; Food Contamination; Future; Gender; Glucose Intolerance; Grant; Habits; Health; Health Care Costs; Hepatic; Hepatotoxicity; High Prevalence; Human; Hyperglycemia; Hyperlipidemia; Hypertension; Ingestion; Knowledge; Liver; Metabolic; Metabolic Diseases; Metabolic syndrome; Morbidity - disease rate; Obesity; Organ; Outcome; Polychlorinated Biphenyls; Population; Predisposition; Reporting; Risk; Risk Factors; Serum; Sex Differences; Socioeconomic Status; Symptoms; Therapeutic; Toxic effect; Water; Woman; abdominal fat; authority; design; diet-induced obesity; environmental chemical; epidemiology study; gene interaction; in vitro Model; in vivo Model; men; mouse model; non-alcoholic fatty liver disease; organochlorine pesticide; persistent organic pollutants; prevent; receptor; sedentary lifestyle; sex; sex disparity; sexual dimorphism

Mechanistic studies pertaining to sex-based differences in metabolic syndrome (MetS) are currently insufficient to explain and prevent the higher prevalence of certain MetS symptoms in women versus men and higher prevalence of other symptoms such as hyperlipidemia in men versus women. MetS describes a constellation of risk factors, such as abdominal adiposity, hypertension, glucose intolerance/hyperglycemia, and dyslipidemia, leading to diabetes and cardiovascular morbidity. High-caloric intake and sedentary lifestyle habits are among key players shown to induce symptoms of MetS. However, exposures to environmental chemicals such as persistent organic pollutants (POPs), often dictated by socio-economic status and education levels, have been increasingly identified as additional key players leading to MetS consequences. Previous studies showed that exposures to POPs, such as organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs), in in-vivo models and human studies were associated with diabetes, obesity and non-alcoholic fatty liver disease, which are hallmarks for MetS development. Furthermore, using in- vitro models and diet-induced obesity mouse models, we had previously demonstrated that the liver was the predominant target organ of toxicity to POPs, including PCBs, and mechanism(s) of toxicity were primarily through activation of hepatic receptors leading to metabolic disruption. The liver has long been established as a sexually dimorphic organ and it is therefore important to address POPs toxicity in term of biological differences or sex. Additionally, POPs such as OCPs are endocrine disrupting chemicals, having the ability to interact with androgen or estrogen receptors, and potentially promoting variable effects in men and women. However, most epidemiologic studies demonstrating associations between POPs exposure with liver toxicity/metabolic diseases including diabetes either focused on agricultural workers who were mostly men or adjusted for sex; but POPs exposures occur in both men and women and thus their health risks may vary. POPs exposures today is primarily through ingestion of contaminated food and water, and serum levels can vary depending on sex and gender. Hence, it is relevant to examine exposures to POPs such as OCPs based on ‘environment-sex-gene’ interactions to better address such discrepancies.

代谢综合征（MetS）性别差异的机制研究目前尚不充分 解释和预防女性中某些MetS症状的患病率高于男性， 其他症状如高脂血症在男性中的患病率高于女性。MetS描述了一个 一系列风险因素，如腹部肥胖、高血压、葡萄糖耐受不良/高血糖症， 和血脂异常，导致糖尿病和心血管疾病。高热量摄入和久坐不动的生活方式 习惯是引起代谢综合征症状的关键因素之一。然而，暴露于环境 化学品，如持久性有机污染物（POP），往往取决于社会经济地位， 教育水平，已越来越多地被确定为额外的关键球员导致MetS的后果。 以往的研究表明，接触持久性有机污染物，如有机氯农药（OCPs）和 在体内模型和人体研究中，多氯联苯（PCBs）与糖尿病、肥胖症 和非酒精性脂肪性肝病，这是代谢综合征发展的标志。此外，在- 体外模型和饮食诱导的肥胖小鼠模型，我们以前已经证明， 持久性有机污染物（包括多氯联苯）的主要毒性靶器官及其毒性机制如下 主要通过激活肝受体导致代谢破坏。肝脏长期以来 因此，必须从以下方面解决持久性有机污染物的毒性问题： 生理差异或性别。此外，持久性有机污染物，如有机氯农药，是内分泌干扰化学品， 与雄激素或雌激素受体相互作用的能力，并可能促进男性的可变效应， 妇女然而，大多数流行病学研究表明， 包括糖尿病在内的毒性/代谢疾病要么集中在以男性为主的农业工人身上， 根据性别调整;但男性和女性都会接触持久性有机污染物，因此其健康风险可能有所不同。 今天，持久性有机污染物的暴露主要是通过摄入受污染的食物和水，血清水平可以 因性别而异。因此，有必要审查对持久性有机污染物的接触情况， 研究“环境-性别-基因”的相互作用，以更好地解决这种差异。