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: 8657454
• 负责人: Kassim Traore
• 金额: $ 12.98万
• 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/8657454
• 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.

描述（由申请人提供）：越来越明显的是，定义代表对环境压力易感性风险因素的细胞环境变化对于改善我们研究潜在环境化学物质和药物药物的方式至关重要。该项目的目的是确定衰老过程中Leydig细胞氧化还原环境的改变是否代表了易感性的危险因素（2-乙基苯甲酸酯（DEHP）诱导的抑制类固醇生成的抑制作用。暴露于DEHP，DEHP暴露于DEHP，一种众所周知的内分泌干扰器，可以导致良好的健康状况，包括良好的疾病，并在良好的疾病中，测试良好的质量良好，在测试中，在良好的疾病中，并且在测试中的质量良好，并在良好的状态下，并具有良好的状态。在所有发育阶段，在所有发育阶段的形态发生和功能中的作用，在足够数量的情况下，雄性表型的重要决定因素。环境的无处不在污染物。 IV滴水袋），导致血液，尿液，精液和母乳中可测量的DEHP和代谢物水平。暴露于DEHP的活性代谢产物（MEHP）邻苯二甲酸酯（MEHP）暴露于纯化的成年大鼠leydig细胞和MA-10小鼠肿瘤leydig细胞中抑制LH刺激的类固醇形成。有趣的是，已显示出对DEHP的胎儿暴露会导致垃圾的大小降低，后来在生命中，Leydig细胞增生，睾丸萎缩，血清睾丸激素的血清水平降低和生育力降低。尽管人类接触DEHP的水平本身可能不会导致足够高的血清水平造成伤害，但有些因素可能会增强其影响。例如，伴随衰老，低年级炎症和/或暴露于其他环境药物的细胞氧化剂系统的变化可能会增加对随后的无毒剂量DEHP的敏感性。该提案的目标是确定：i）与年龄相关的氧化还原环境的改变会增加Leydig细胞对DEHP的敏感性； ii）低剂量的DEHP连续给药，或者以后的第二个DEHP“命中”会影响睾丸激素的产生方式，而单个低剂量不会； iii）外部影响（例如适度的炎症）是否会增加Leydig细胞对低剂量DEHP的敏感性。该项目的长期目标是使我成为一名能够竞争并吸引R01赠款支持Elizabeth City State University（ECSU）的成熟且高产的调查员，这是一个少数服务机构。可以预期，我参与导师机构，约翰·霍普金斯大学，彭博公共卫生学院（JHSPH）将是建立JHSPH和ECSU之间更广泛合作的重要一步，以使聪明的少数族裔学生在JHSPH在生物医学科学领域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其在ECSU的研究和教学能力。从拟议项目中提出的出版物可能会导致如何评估潜在的环境化学药品和药物的范式。