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.
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.
|Zhou, Liang; Beattie, Matthew C; Lin, Chieh-Yin et al. (2013) Oxidative stress and phthalate-induced down-regulation of steroidogenesis in MA-10 Leydig cells. Reprod Toxicol 42:95-101|