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.

与代谢综合征（METS）基于性别的差异有关的机械研究目前不足 解释和防止女性与男性中某些METS症状的较高患病率以及 其他症状的患病率较高，例如男性与女性的高脂血症。大都会描述 危险因素的星座，例如腹部肥胖，高血压，葡萄糖intlerance/高血糖， 和血脂异常，导致糖尿病和心血管发病率。高热量摄入和久坐的生活方式 习惯是显示出大都会症状的主要参与者。但是，暴露于环境 诸如持续的有机污染物（POP）之类的化学物质，通常由社会经济地位和 教育水平已被越来越被确定为导致大都会后果的其他关键参与者。 先前的研究表明，对流行音乐的暴露，例如有机氯农药（OCP）和 多氯化双苯基（PCB），体内模型和人类研究与糖尿病，肥胖有关 和非酒精性脂肪肝病，这是Mets发育的标志。此外，使用 体外模型和饮食引起的肥胖小鼠模型，我们以前证明了肝脏是 对POP的毒性的主要目标器官，包括PCB和毒性机制是 首先，通过激活肝素受体导致代谢破坏。肝脏长期以来一直是 以性二态器官的形式建立 生物学差异或性别。此外，诸如OCP之类的流行音乐正在破坏化学物质，具有 能够与雄激素或雌激素受体相互作用，并有可能促进男性和 女性。但是，大多数流行病学研究表明POP与肝脏之间的关联 包括糖尿病在内的毒性/代谢性疾病，要么主要是男性或 为性调整；但是男性和女人都会发生POP暴露，因此其健康风险可能会有所不同。 如今，流行音乐的暴露主要是通过摄入受污染的食物和水，血清水平可以 因性别和性别而异。因此，检查对基于OCPS的POP的暴露是重要的 关于“环境性别 - 基因”的互动，以更好地解决此类差异。