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.

关于代谢综合征(METS)性别差异的机械性研究目前还不够充分 解释和预防某些METS症状在女性中的发病率高于男性，以及 男性高脂血症等其他症状的患病率高于女性。大都会队描述了一种 一系列危险因素，如腹部肥胖、高血压、糖耐量异常/高血糖、 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 习惯是诱发METS症状的关键因素之一。然而，暴露在环境中 持久性有机污染物(POP)等化学品，通常由社会经济地位和 教育程度，越来越多地被认为是导致METS后果的其他关键因素。 先前的研究表明，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，多氯联苯与糖尿病、肥胖症有关 和非酒精性脂肪性肝病，这是METS发展的标志。此外，使用In- 体外模型和饮食诱导的肥胖小鼠模型，我们以前已经证明了肝脏是 对持久性有机污染物，包括多氯联苯的主要毒性靶器官和毒性机理(S)是 主要是通过激活肝脏受体导致代谢紊乱。长期以来，肝脏一直是 被确立为性二态器官，因此在以下方面处理持久性有机污染物毒性是重要的 生物差异或性别。此外，有机氯农药等持久性有机污染物是干扰内分泌的化学物质，具有 与雄激素或雌激素受体相互作用的能力，并可能促进男性和 女人。然而，大多数流行病学研究表明，持久性有机污染物暴露与肝脏之间的联系 毒性/代谢性疾病，包括糖尿病，主要集中在以男性为主的农业工人或 对性别进行了调整；但持久性有机污染物的暴露发生在男性和女性身上，因此他们的健康风险可能不同。 如今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，而血清水平可能 因性别和性别而异。因此，有必要审查持久性有机污染物的暴露情况，如基于 环境-性-基因相互作用，以更好地解决这种差异。