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In Utero Exposure to Di-(2-ethylhexyl) Phthalate Exerts Both Short-Term and Long-Lasting Suppressive Effects on Testosterone Production in the Rat¹

Department of Biochemistry and Molecular and Cellular Biology,³ Georgetown University Medical Center, Washington, District of Columbia 20057 The Research Institute of the McGill University Health Centre and Department of Medicine,⁴ McGill University, Montreal, Quebec, Canada H3G 1A4 Division of Reproductive Biology,⁵ Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205

ABSTRACT

We examined the effects of fetal exposure to a wide range of di-(2-ethylhexyl) phthalate (DEHP) doses on fetal, neonatal, and adult testosterone production. Pregnant rats were administered DEHP from Gestational Day (GD) 14 to the day of parturition (Postnatal Day 0). Exposure to between 234 and 1250 mg/kg/day of DEHP resulted in increases in the absolute volumes of Leydig cells per adult testis. Despite this, adult serum testosterone levels were reduced significantly compared to those of controls at all DEHP doses. Organ cultures of testes from GD20 rats exposed in utero to DEHP showed dose-dependent reductions in basal testosterone production. Surprisingly, however, no significant effect of DEHP was found on hCG-induced testosterone production by GD20 testes, suggesting that the inhibition of basal steroidogenesis resulted from the alteration of molecular events upstream of the steroidogenic enzymes. Reduced fetal and adult testosterone production in response to in utero DEHP exposure appeared to be unrelated to changes in testosterone metabolism. In view of the DEHP-induced reductions in adult testosterone levels, a decrease in the expression of steroidogenesis-related genes was anticipated. Surprisingly, however, significant increases were seen in the expression of Cyp11a1, Cy17a1, Star, and Tspo transcripts, suggesting that decreased testosterone production after birth could not be explained by decreases in steroidogenic enzymes as seen at GD20. These changes may reflect an increased number of Leydig cells in adult testes exposed in utero to DEHP rather than increased gene expression in individual Leydig cells, but this remains uncertain. Taken together, these results demonstrate that in utero DEHP exposure exerts both short-term and long-lasting effects on testicular steroidogenesis that might involve distinct molecular targets in fetal and adult Leydig cells.

endocrine disruptors, Leydig cells, phthalates, testosterone, toxicology

¹Supported by a grant (ES 013495 to V.P.) from the National Institute of Environmental Health Sciences, National Institutes of Health.

Correspondence: ²V. Papadopoulos, The Research Institute of the McGill University Health Centre, 2155 Guy Street, 5th Floor, Montreal, Quebec H3H 2R9, Canada. FAX: 514 934 8439; e-mail: vassilios.papadopoulos{at}mcgill.ca

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				H. Lin, Q.-Q. Lian, G.-X. Hu, Y. Jin, Y. Zhang, D. O. Hardy, G.-R. Chen, Z.-Q. Lu, C. M. Sottas, M. P. Hardy, et al. In Utero and Lactational Exposures to Diethylhexyl-Phthalate Affect Two Populations of Leydig Cells in Male Long-Evans Rats Biol Reprod, May 1, 2009; 80(5): 882 - 888. [Abstract] [Full Text] [PDF]