Modulation of rat Leydig cell steroidogenic function by di(2-ethylhexyl) phthalate
Akingbemi,Benson T.; Youker,Robert T.; Sottas,Chantal M.; Ge,Renshan; Katz,Emily; Klinefelter,Gary R.; Zirkin,Barry R.; Hardy,Matthew P.
Biology of Reproduction 65(4): 1252-1259
Publication date: 2001
Exposure of rodents to phthalates is associated with developmentaland reproductive anomalies, and there is concern that thesecompounds may be causing adverse effects on human reproductivehealth. Testosterone (T), secreted almost exclusively by Leydigcells in the testis, is the primary steroid hormone that maintainsmale fertility. Leydig cell T biosynthesis is regulated by thepituitary gonadotropin LH. Herein, experiments were conductedto investigate the ability of di(2-ethylhexyl)phthalate (DEHP)to affect Leydig cell androgen biosynthesis. Pregnant dams weregavaged with 100 mg kg day DEHP from Gestation Days 12to 21. Serum T and LH levels were significantly reduced in maleoffspring, compared to control, at 21 and 35 days of age. However,these inhibitory effects were no longer apparent at 90 days.In a second set of experiments, prepubertal rats, from 21 or35 days of age, were gavaged with 0, 1, 10, 100, or 200 mgkg day DEHP for 14 days. This exposure paradigm affectedLeydig cell steroidogenesis. For example, exposure of rats to200 mg kg day DEHP caused a 77% decrease in the activityof the steroidogenic enzyme 17ß-hydroxysteroid dehydrogenase,and reduced Leydig cell T production to 50% of control. Paradoxically,extending the period of DEHP exposure to 28 days (PostnatalDays 21-48) resulted in significant increases in Leydigcell T production capacity and in serum LH levels. The no-observed-effect-leveland lowest-observed-effect-level were determined to be 1 mgkg day and 10 mg kg day, respectively. In contrastto observations in prepubertal rats, exposure of young adultrats by gavage to 0, 1, 10, 100, or 200 mg kg day DEHPfor 28 days (Postnatal Days 62-89) induced no detectablechanges in androgen biosynthesis. In conclusion, data from thisstudy show that DEHP effects on Leydig cell steroidogenesisare influenced by the stage of development at exposure and mayoccur through modulation of T-biosynthetic enzyme activity andserum LH levels.