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Robert W. Moore,^1,2 Thomas A. Rudy,¹ Tien-Min Lin,¹ Kinarm Ko,³ and Richard E. Peterson^1,2,3

¹School of Pharmacy, ²Environmental Toxicology Center, and ³Endocrinology-Reproductive Physiology Program, University of Wisconsin, Madison, Wisconsin, USA

Abstract

Several members of the phthalate ester family have antiandrogenic properties, yet little is known about how exposure to these ubiquitous environmental contaminants early in development may affect sexual development. We conducted experiments to determine effects of in utero and lactational exposure to the most prevalent phthalate ester, di(2-ethylhexyl) phthalate (DEHP) , on male reproductive system development and sexual behavior. Sprague-Dawley rats were dosed with corn oil or DEHP (0, 375, 750, or 1,500 mg/kg/day, per os) from gestation day 3 through postnatal day (PND) 21. Dose-related effects on male offspring included reduced anogenital distance, areola and nipple retention, undescended testes, and permanently incomplete preputial separation. Testis, epididymis, glans penis, ventral prostate, dorsolateral prostate, anterior prostate, and seminal vesicle weights were reduced at PND 21, 63, and/or 105-112. Additional dose-related effects included a high incidence of anterior prostate agenesis, a lower incidence of partial or complete ventral prostate agenesis, occasional dorsolateral prostate and seminal vesicle agenesis, reduced sperm counts, and testicular, epididymal, and penile malformations. Many DEHP-exposed males were sexually inactive in the presence of receptive control females, but sexual inactivity did not correlate with abnormal male reproductive organs. These results suggest that in utero and lactational DEHP exposure also inhibited sexually dimorphic central nervous system development. No major abnormalities were found in any of eight control litters, but DEHP caused severe male reproductive system toxicity in five of eight litters at 375 mg/kg/day, seven of eight litters at 750 mg/kg/day, and five of five litters at 1,500 mg/kg/day. These results demonstrate that the male reproductive system is far more sensitive to DEHP early in development than when animals are exposed as juveniles or adults. The effects of DEHP on male reproductive organs and sexual behaviors and the lack of significant effects on time to vaginal opening and first estrus in their littermates demonstrate that DEHP (and/or its metabolites) affects development of the male reproductive system primarily by acting as an antiandrogen. The pattern of effects of in utero and lactational DEHP exposure differed from patterns caused by other phthalate esters, and the preponderance of anterior prostate agenesis appears to be unique among all chemicals. These results suggest that DEHP acts partly by mechanisms distinct from those of other antiandrogens. Key words: antiandrogens, di(2-ethylhexyl) phthalate, in utero exposure, lactational exposure, male reproductive system development, masculine sexual behaviors, reproductive organ agenesis. Environ Health Perspect 109:229-237 (2001) . [Online 28 February 2001]

http://ehpnet1.niehs.nih.gov/docs/2001/109p229-237moore/ abstract.html

Address correspondence to R.W. Moore, School of Pharmacy, University of Wisconsin, 425 N. Charter Street, Madison, WI 53706 USA. Telephone: (608) 265-2531. Fax: (608) 265-3316. E-mail: rwmoore@pharmacy.wisc.edu

We thank O. Li for sperm analyses.

This research was supported by NIH grants ES 06806 and ES 01332 and by the University of Wisconsin EHS Center for Developmental and Molecular Toxicology.

This article is contribution 331 from the Environmental Toxicology Center, University of Wisconsin, Madison.

Received 15 August 2000 ; accepted 13 October 2000.