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A Mixture of the "Antiandrogens" Linuron and Butyl Benzyl Phthalate Alters Sexual Differentiation of the Male Rat in a Cumulative Fashion¹

Deparment of Zoology,⁴ North Carolina State University, Raleigh, North Carolina 27695 U.S. Environmental Protection Agency,⁵ National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Division, Endocrinology Branch, Research Triangle Park, North Carolina 27711

Prenatal exposure to environmental chemicals that interfere with the androgen signaling pathway can cause permanent adverse effects on reproductive development in male rats. The objectives of this study were to 1) determine whether a documented antiandrogen butyl benzyl phthalate (BBP) and/or linuron (an androgen receptor antagonist) would decrease fetal testosterone (T) production, 2) describe reproductive developmental effects of linuron and BBP in the male, 3) examine the potential cumulative effects of linuron and BBP, and 4) investigate whether treatment-induced changes to neonatal anogenital distance (AGD) and juvenile areola number were predictive of adult reproductive alterations. Pregnant rats were treated with either corn oil, 75 mg/kg/day of linuron, 500 mg/kg/day of BBP, or a combination of 75 mg/kg/day linuron and 500 mg/kg/day BBP from gestational Day 14 to 18. A cohort of fetuses was removed to assess male testicular T and progesterone production, testicular T concentrations, and whole-body T concentrations. Male offspring from the remaining litters were assessed for AGD and number of areolae and then examined for alterations as young adults. Prenatal exposure to either linuron or BBP or BBP + linuron decreased T production and caused alterations to androgen-organized tissues in a dose-additive manner. Furthermore, treatment-related changes to neonatal AGD and infant areolae significantly correlated with adult AGD, nipple retention, reproductive malformations, and reproductive organ and tissue weights. In general, consideration of the dose-response curves for the antiandrogenic effects suggests that these responses were dose additive rather than synergistic responses. Taken together, these data provide additional evidence of cumulative effects of antiandrogen mixtures on male reproductive development.

¹ Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and has been approved for publication. Approval does not necessarily reflect the views and policies of the agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use. A.K.H. was on a NCSU/EPA Cooperative Training program.

² Correspondence: L. Earl Gray, Jr., U.S. EPA, NHEERL, RTD (MD-72), RTP, NC 27711. FAX: 919 541 4017; gray.earl{at}epamail.epa.gov

³ Current address: Department of Develop & Reprod Toxicology, Merck Research Lab, WP 45-119, West Point, PA 19486. FAX: 215 652 7758; louise_saldutti{at}merck.com