Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances
Akingbemi,Benson T.; Ge,Renshan; Klinefelter,Gary R.; Zirkin,Barry R.; Hardy,Matthew P.
Proceedings of the National Academy of Sciences of the United States of America 101(3): 775-780
Publication date: 2004
The possibility that exposures to environmental agents are associatedwith reproductive disorders in human populations has generatedmuch public interest recently. Phthalate esters are used mostcommonly as plasticizers in the food and construction industry,and di-(2-ethylhexyl) phthalate (DEHP) is the most abundantphthalate in the environment. Daily human exposure to DEHP inthe U.S. is significant, and occupational and clinical exposuresfrom DEHP-plasticized medical devices, e.g., blood bags, hemodialysistubing, and nasogastric feeding tubes, increase body burdenlevels. We investigated the effects of chronic exposures tolow environmentally relevant DEHP levels on testicular function.Our data show that prolonged exposures to this agent inducedhigh levels of the gonadotropin luteinizing hormone and increasedthe serum concentrations of sex hormones [testosterone and 17ß-estradiol(E2)] by >50%. Increased proliferative activity in Leydigcells was evidenced by enhanced expression of cell cycle proteins,as determined by RT-PCR. The numbers of Leydig cells in thetestis of DEHP-treated rats were 40-60% higher than incontrol rats, indicating induction of Leydig cell hyperplasia.DEHP-induced elevations in serum testosterone and E2 levelssuggest the possibility of multiple crosstalks between androgen,estrogen, and steroid hormone receptors, whereas the presenceof estrogen receptors in nonreproductive tissues, e.g., cardiovascularsystem and bones, implies that the increases in serum E2 levelshave implications beyond reproduction, including systemic physiology.Analysis of the effects of phthalate exposures on gonadotropinand steroid hormone levels should form part of overall riskassessment in human populations.