Serum testosterone levels decrease with age in both human and rat males. Using a rat model, we found that this age-related decrease results from the reduced ability of Leydig cells to produce testosterone. Our objective is to determine what causes Leydig cells to become hypofunctional with respect to steroidogenesis with age. We found that after the aged Leydig cells are eliminated by an injection of ethane dimethanesulfonate, a "young" population of Leydig cells is restored in the aged rat testis. This suggests that there may be a biological "clock" in these cells to control their own aging, instead of extrinsic factors in the testis to influence their aging (i.e. steroidogenically hypofunctional). In the following experiments we found that Leydig cells aging process can be delayed significantly by keeping the cells functional quiescence. These both observations are very consistent with the current hypothesis that accumulation of free radical damages of DNA, proteins and/or lipids are involved in cell aging process.

Recently, we have made several very important discoveries that not only help forward our understanding of age-related reduction in Leydig cell steroidogenesis, but also help us to understand general aging as well. First, we found that old Leydig cells reduced their ability to response to a very important pituitary hormone, LH. This reduction does not result from reductions in LH receptor, G protein nor adenylyl cyclase, but instead, it may be related to the reactive oxygen species mediated damages of cell membrane lipids. This suggests that in the aging process not all damages in the cell influences the cell function equally. The damage of key process may do more harm to cell than other relative unimportant components. The damage of LH receptor-cAMP cascade, a key process in Leydig cells, may result in changes in the down stream sterodogenic machinery, ultimately, causing these cells to become ‘steroidogenic hypofunctional’. In consistent with this hypothesis, we also have found that age-related reduction in steroidogenesis of Leydig cells can not be reversed by LH, but can be reversed by dibutyryl cAMP, an agent that can by-pass the defective LH receptor-adenylyl cyclase cascade in the old cell membrane.

The second line of research focuses on stem Leydig cell differentiation in vitro. In collaboration with Dr. Renshan Ge (Population Council, New York), we have found that the peritubular cells of adult rat testis can be induced to differentiate into testosterone producing Leydig cells in vitro. These cells may be the sought-after adult stem Leydig cells because they are pluropotent. They can be induced to differentiate not only into Leydig cells, but also into other cell types, such as adipose and osteogenic cells.

Biochemistry and molecular biology, reproductive biology, aging, stem cell, Leydig cell, testosterone, steroidogenesis

Honors

Invited Speaker, XIV North American Testis Workshop (Baltimore), 1997

Awards

Student Merit Award 19th Annual Meeting of American Society of Andrology, 1994

Chen H, Pechenino AS, Liu J, Beattie MC, Brown TR, Zirkin BR. Effect of Glutathione Depletion on Leydig Cell Steroidogenesis in Young and Old Brown Norway Rats. Endocrinology. 149(5):2612-9, 2008.

Rosenberg BG, Chen H, Folmer J, Liu J, Papadopoulos V, Zirkin BR. Gestational Exposure to Atrazine: Effects on the Postnatal Development of Male Offspring. Journal of Andrology. 29(3):304-11, 2008.

Midzak AS, Liu J, Zirkin BR, Chen H. Effect of Myxothiazol on Leydig Cell Steroidogenesis: Inhibition of LH-Mediated Testosterone Synthesis But Stimulation of Basal Steroidogenesis. Endocrinology 148(6): 2583-90, 2007.

Chen H, Luo L, Liu J, Zirkin BR. Cyclooxygenases in rat Leydig cells: effects of LH and aging. Endocrinology 148(2): 735-742, 2007.

Luo L, Chen H, Trush MA, Show MD, Anway MD, Zirkin BR. Aging and the Brown Norway Rat Leydig Cell Antioxidant Defense System. Journal of Andrology 27:240-247, 2006.

Chen H, Luo L, Liu J, Brown T, Zirkin BR. Aging and caloric restriction: effects on Leydig cell steroidogenesis. Experimental Gerontology 40(6): 498-505, 2005.

Chen H, Liu J, Luo L, Baig MU, Kim JM, Zirkin BR. Vitamin E, aging and Leydig cell steroidogenesis. Experimental Gerontology 40(8-9): 728-36, 2005.

Chen H. Gene expression by the anterior pituitary gland: effects of age and caloric restriction. Molecular and Cellular Endocrinology 222(1-2): 21-31, 2004.

Chen H, Liu J, Luo L, Zirkin BR. Dibutyryl cyclic adenosine monophosphate restores the ability of aged Leydig cells to produce testosterone at the high levels characteristic of young cells. Endocrinology 145(10): 4441-6, 2004.

Chen H, Zirkin BR. Long-term suppression of Leydig cell steroidogenesis prevents Leydig cell aging. Proceedings of the National Academy of Sciences 96(26): 14877-14881, 1999.

Chen H, Huhtaniemi I, Zirkin BR. Depletion and repopulation of Leydig cells in the testes of aging Brown Norway rats. Endocrinology 137(8): 3447-3452, 1996.