AGE-RELATED ALTERATION OF LEYDIG CELL REDOX ENVIRONMENT A RISK FACTOR FOR SUSCEPT

与年龄相关的间质细胞氧化还原环境的改变是疑似风险因素

• 批准号: 8213252
• 负责人: Kassim Traore
• 金额: $ 12.86万
• 依托单位: ELIZABETH CITY STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213252
• 关键词: Acute; Adult; Affect; Aging; Androgens; Animals; Atrophic; Blood; Breathing; Cities; Collaborations; Dermal; Developed Countries; Development; Devices; Dose; Eating; Educational process of instructing; Elderly; Endocrine; Endocrine Disruptors; Enteral Nutrition; Environment; Environmental Pollutants; Environmental Pollution; Event; Exposure to; Faculty; Fertility; Food; Funding; Goals; Grant; Human; Human Milk; Hyperplasia; Hypospadias; Infant; Infant formula; Inflammation; Institution; Laboratories; Lead; Leydig Cell Tumor; Life; Litter Size; Malignant neoplasm of testis; Measurable; Medical; Mentors; Minority; Minority-Serving Institution; Morphogenesis; Mus; Organ; Oxidants; Oxidation-Reduction; Oxidative Stress; Parenteral Nutrition; Patients; Perinatal Exposure; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Plasticizers; Play; Polymers; Population; Predisposition; Procedures; Production; Public Health Schools; Publications; Radiologic Health; Rattus; Relative (related person); Reporting; Reproductive Health; Research; Research Personnel; Risk; Risk Factors; Role; Science; Seminal fluid; Serum; Staging; Steroid biosynthesis; Steroids; Students; System; Testosterone; Time; Toxic effect; Training; Transfusion; Universities; Urine; age related; environmental agent; environmental change; environmental chemical; exposed human population; improved; intravenous drip; leydig interstitial cell; male; mature animal; mono-(2-ethylhexyl)phthalate; neonatal exposure; neonate; phthalates; programs; reproductive; sex; stressor; success; young adult

DESCRIPTION (provided by applicant): It is becoming increasingly evident that defining cellular environmental changes that represent risk factor for susceptibility to environment stressors is critical to improving the way we study potential environmental chemicals and pharmaceutical drugs. The goal of this project is to determine whether alteration of the Leydig cell redox environment during aging represents a risk factor for susceptibility to di-(2-ethylhexyl phthalate (DEHP)-induced inhibition of steroidogenesis. Exposure to DEHP, a well-known endocrine disruptor, can lead to reproductive health issues including hypospadias, testicular cancer, and poor semen quality. During development, androgen plays a critical role in programming sex organ morphogenesis and function. At all developmental stages, the presence of androgens in sufficient amounts is a critical determinant of the male phenotype. Consequently, environmental chemicals that alter endocrine function pose potential risks to the reproductive health of humans and animals. DEHP is a commonly used plasticizer that is loosely held between the interstices of the polymer matrix and thus it and its metabolites are ubiquitous contaminants of the environment. Human exposures to DEHP occur via food, inhalation, dermal contact and medical procedures (e.g. IV drip bags), which result in measurable levels of DEHP and metabolites in blood, urine, semen and breast milk. Exposure to mono-(2-ethylhexyl) phthalate (MEHP), the active metabolite of DEHP, was shown to inhibit LH-stimulated steroid formation by both purified adult rat Leydig cells and MA-10 mouse tumor Leydig cells. Interestingly, fetal exposures to DEHP have been shown to result in reduced litter size, and, later in life, Leydig cell hyperplasia, testicular atrophy, reduced serum levels of seru testosterone, and reduced fertility. Although the levels of human exposure to DEHP may not themselves result in high enough serum levels to cause harm, there are factors that may potentiate their effects. For example, changes in the cellular oxidant system that accompany aging, low grade inflammation and/or pre-exposure to other environmental agents may increase susceptibility to subsequent non-toxic doses of DEHP. The goals of this proposal are to determine whether: i) an age-related altered redox environment increases Leydig cell susceptibility to DEHP; ii) low doses of DEHP administered continuously, or second DEHP "hits" at later times, affect testosterone production in ways that single low doses do not; and iii) whether external influences such as modest inflammation might increase the susceptibility of Leydig cells to low doses of DEHP. The long term goal of this project is to enable me become an established and highly productive investigator capable of competing for and attracting R01 grant support to Elizabeth City State University (ECSU), a minority serving institution. It is expected that my involvement with the mentor's institution, The Johns Hopkins University, Bloomberg School of Public Health (JHSPH) will be a significant step in establishing a broader collaboration between JHSPH and ECSU to bring bright young minority students to pursue further training in biomedical science at JHSPH. In addition, the success of my laboratory will attract other faculty at ECSU to seek funding to develop their research and teaching capacities at ECSU. Publications that will rise from the proposed project could lead to a paradigm shift in how potential environmental chemicals and pharmaceutical drugs are evaluated. PUBLIC HEALTH RELEVANCE: The elderly continue to represent the fastest-growing segment of the population in many industrialized countries. This unprecedented event is occurring at a time of increasing exposures to environmental pollutants and pharmaceutical drugs. Therefore, it is increasingly important to understand whether older adults respond differently to environmental chemicals and pharmaceutical drugs than younger adults. The major goal of this project is to determine whether alteration of Leydig cell redox environment during aging represents a risk factor for susceptibility to environmental contaminant di-(2-ethylhexyl) phthalate (DEHP) - induced acute oxidative stress and thus the inhibition of steroidogenesis. The results of the proposed studies may bring about a paradigm shift in how potential environmental chemicals and pharmaceutical drugs are evaluated.

描述（由申请人提供）：越来越明显的是，定义细胞环境变化对环境压力易感性的风险因素对于改善我们研究潜在环境化学物质和药物的方式至关重要。该项目的目的是确定衰老过程中间质细胞氧化还原环境的改变是否代表对邻苯二甲酸二（2-乙基己基酯）诱导的类固醇生成抑制易感性的危险因素。DEHP是一种众所周知的内分泌干扰物，它会导致生殖健康问题，包括尿道下裂、睾丸癌和精液质量差。在发育过程中，雄激素在性器官的形态发生和功能调控中起着至关重要的作用。在所有发育阶段，雄激素的存在是雄性表型的关键决定因素。因此，改变内分泌功能的环境化学品对人类和动物的生殖健康构成潜在风险。DEHP是一种常用的增塑剂，松散地保持在聚合物基质的间隙之间，因此它及其代谢物是无处不在的环境污染物。人类通过食物、吸入、皮肤接触和医疗程序（如静脉滴注袋）接触DEHP，导致血液、尿液、精液和母乳中DEHP和代谢物的可测量水平。暴露于邻苯二甲酸单-（2-乙基己基）酯（MEHP）， DEHP的活性代谢物，被证明可以抑制纯化的成年大鼠间质细胞和MA-10小鼠肿瘤间质细胞lh刺激的类固醇形成。有趣的是，胎儿暴露于DEHP已被证明会导致产仔数减少，并且在以后的生活中，间质细胞增生，睾丸萎缩，血清睾酮水平降低，生育能力降低。虽然人类接触DEHP的水平本身可能不会导致足够高的血清水平造成伤害，但有一些因素可能会增强其影响。例如，伴随衰老、低度炎症和/或预先暴露于其他环境因素的细胞氧化系统的变化可能会增加对随后无毒剂量DEHP的易感性。本提案的目的是确定：i)年龄相关的氧化还原环境改变是否会增加间质细胞对DEHP的易感性；ii)连续注射低剂量DEHP，或在晚些时候注射第二次DEHP，会以单次低剂量不会的方式影响睾丸激素的产生；iii)轻度炎症等外部影响是否会增加间质细胞对低剂量DEHP的敏感性。这个项目的长期目标是使我成为一个成熟的和高生产力的研究者能够竞争和吸引R01资助支持伊丽莎白城市州立大学（ECSU），一个少数民族服务机构。预计我与导师所在机构约翰霍普金斯大学彭博公共卫生学院（JHSPH）的合作将是建立JHSPH与ECSU之间更广泛合作的重要一步，以吸引聪明的年轻少数民族学生在JHSPH接受进一步的生物医学科学培训。此外，我的实验室的成功将吸引ECSU的其他教师寻求资金来发展他们在ECSU的研究和教学能力。拟议项目将产生的出版物可能导致如何评估潜在的环境化学品和药物的范式转变。