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Gestational Exposure to Ethane Dimethanesulfonate Permanently Alters Reproductive Competence in the CD-1 Mouse¹

Curriculum in Toxicology,³ University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7270 Reproductive Toxicology Division,⁴ National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711 Population Council,⁵ New York, New York 10021

Although the adult mouse Leydig cell (LC) has been considered refractory to cytotoxic destruction by ethane dimethanesulfonate (EDS), the potential consequences of exposure during reproductive development in this species are unknown. Herein pregnant CD-1 mice were treated with 160 mg/kg on Gestation Days 11–17, and reproductive development in male offspring was evaluated. Prenatal administration of EDS compromised fetal testosterone (T) levels, compared with controls. EDS-exposed pups recovered their steroidogenic capacities after birth because T production by hCG-stimulated testis parenchyma from prepubertal male offspring was unchanged. However, prepubertal testes from prenatally exposed males contained seminiferous tubules (STs) devoid of germ cells, indicating a delay in spermatogenesis. In adults, some STs in exposed males still contained incomplete germ cell associations corroborating observed reductions in epididymal sperm reserves, fertility ratios, and litter size. Morphometry revealed an EDS-induced increase in interstitial area and a concomitant decrease in ST area, but stereology revealed an unexpected decrease in the number and size of the LCs per testis in exposed males. Paradoxically, there was an increase in both serum LH and T production by adult testis parenchyma, indicating that the LCs were hyperstimulated. These data demonstrate permanent lesions in LC development and spermatogenesis caused by prenatal exposure in mice. Thus, although adult mouse LCs are insensitive to EDS, EDS appears to have direct action on fetal LCs, resulting in abnormal testis development.

¹ The investigation by D.K.T. was funded by the EPA/UNC Toxicology Research Program, Training Agreement CT 902908 and a predoctoral traineeship (National Research Service Award 5 T32 ES07126) from the National Institute of Environmental Health Sciences, National Institutes of Health, both with the Curriculum in Toxicology, University of North Carolina at Chapel Hill. The information in this document has been funded wholly (or in part) by the U.S. Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

² Correspondence: Gary Klinefelter, Reproductive Toxicology Division MD 72, NHEERL, USEPA, Research Triangle Park, NC 27711. FAX: 919 541 4017; klinefelter.gary{at}epa.gov

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