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

描述(由申请人提供)：越来越明显的是，确定细胞环境变化是环境应激源易感性的风险因素，对于改善我们研究潜在环境化学品和药物的方式至关重要。该项目的目的是确定在衰老过程中间质细胞氧化还原环境的改变是否是邻苯二甲酸二(2-乙基己基)酯(DEHP)抑制类固醇生成的易感性的危险因素。暴露在DEHP中，一种众所周知的内分泌干扰物，可能会导致生殖健康问题，包括尿道下裂、睾丸癌和糟糕的精液质量。在发育过程中，雄激素在编程性器官的形态发生和功能方面起着关键作用。在所有发育阶段，足够数量的雄激素的存在是男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和动物的生殖健康构成潜在风险。DEHP是一种常用的增塑剂，它松散地固定在聚合物基质的间隙之间，因此它和它的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(例如静脉滴注袋)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。DEHP的活性代谢产物邻苯二甲酸单(2-乙基己基)酯(MEHP)可抑制黄体生成素刺激的成年大鼠间质细胞和MA-10小鼠肿瘤间质细胞的类固醇生成。有趣的是，胎儿暴露于DEHP会导致产仔数减少，在晚年会出现间质细胞增生、睾丸萎缩、血清睾酮水平降低以及生育力下降。尽管人类接触DEHP的水平本身可能不会导致血清水平高到足以造成伤害，但有一些因素可能会增强它们的影响。例如，伴随着衰老、低度炎症和/或预先暴露于其他环境制剂的细胞氧化系统的变化，可能会增加随后无毒剂量DEHP的易感性。这项建议的目的是确定：i)与年龄相关的氧化还原环境的改变是否会增加间质细胞对DEHP的敏感性；ii)持续给予低剂量的DEHP，或稍后再次注射DEHP，是否会以单一低剂量不同的方式影响睾酮的产生；以及iii)外部影响，如轻微的炎症是否可能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名成熟和高效的研究员，能够竞争并吸引对伊丽莎白城市州立大学(ECSU)的拨款支持，ECSU是一家为少数族裔服务的机构。预计我与导师的机构约翰霍普金斯大学彭博公共卫生学院(JHSPH)的参与将是在JHSPH和ECSU之间建立更广泛的合作的重要一步，以使聪明的年轻少数族裔学生在JHSPH继续接受生物医学科学方面的进一步培训。此外，我的实验室的成功将吸引ECSU的其他教员寻求资金，以发展他们在ECSU的研究和教学能力。拟议项目将产生的出版物可能会导致评估潜在环境化学品和药物的方式发生范式转变。 与公共卫生有关：在许多工业化国家，老年人仍然是人口中增长最快的部分。这一史无前例的事件发生在环境污染物和药物暴露增加的时候。因此，了解老年人对环境化学品和药物的反应是否与年轻人不同变得越来越重要。该项目的主要目的是确定在衰老过程中间质细胞氧化还原环境的改变是否是环境污染物邻苯二甲酸二(2-乙基己基)酯(DEHP)诱导的急性氧化应激的易感性的危险因素，从而抑制类固醇的生成。拟议研究的结果可能会带来潜在环境化学品和药物评估方式的范式转变。

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.