Published online before print January 8, 2004 Proc. Natl. Acad. Sci. USA
Benson T. Akingbemi *, Renshan Ge *, Gary R. Klinefelter , Barry R. Zirkin , and Matthew P. Hardy * *Center for Biomedical Research, Population Council, New York, NY 10021; Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711; and Division of Reproductive Biology, Department of Biochemistry and Molecular Biology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205
Edited by R. Michael Roberts, University of Missouri, Columbia, MO, and approved November 14, 2003 (received for review September 16, 2003)
The possibility that exposures to environmental agents are associated with reproductive disorders in human populations has generated much public interest recently. Phthalate esters are used most commonly as plasticizers in the food and construction industry, and di-(2-ethylhexyl) phthalate (DEHP) is the most abundant phthalate in the environment. Daily human exposure to DEHP in the U.S. is significant, and occupational and clinical exposures from DEHP-plasticized medical devices, e.g., blood bags, hemodialysis tubing, and nasogastric feeding tubes, increase body burden levels. We investigated the effects of chronic exposures to low environmentally relevant DEHP levels on testicular function. Our data show that prolonged exposures to this agent induced high levels of the gonadotropin luteinizing hormone and increased the serum concentrations of sex hormones [testosterone and 17ß-estradiol (E2)] by >50%. Increased proliferative activity in Leydig cells was evidenced by enhanced expression of cell cycle proteins, as determined by RT-PCR. The numbers of Leydig cells in the testis of DEHP-treated rats were 40-60% higher than in control rats, indicating induction of Leydig cell hyperplasia. DEHP-induced elevations in serum testosterone and E2 levels suggest the possibility of multiple crosstalks between androgen, estrogen, and steroid hormone receptors, whereas the presence of estrogen receptors in nonreproductive tissues, e.g., cardiovascular system and bones, implies that the increases in serum E2 levels have implications beyond reproduction, including systemic physiology. Analysis of the effects of phthalate exposures on gonadotropin and steroid hormone levels should form part of overall risk assessment in human populations.
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To whom correspondence should be addressed.
E-mail: m-hardy@popcbr.rockefeller.edu
www.pnas.org/cgi/doi/10.1073/pnas.0305977101
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