Mammary Gland Development as a Sensitive End Point after Acute Prenatal Exposure to an Atrazine Metabolite Mixture in Female Long-Evans Rats Rolondo R. Enoch,1* Jason P. Stanko,2 Sara N. Greiner,2** Geri L. Youngblood,2# Jennifer L. Rayner,3 and Suzanne E. Fenton2 1North Carolina Central University, Department of Biology, Durham, North Carolina, USA; 2U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Division, Research Triangle Park, North Carolina, USA; 3University of North Carolina, School of Public Health, Department of Environmental Sciences and Engineering, Chapel Hill, North Carolina, USA Abstract Background: Atrazine (ATR) , a widely used chlorotriazine herbicide, inhibits a number of endocrine-dependent processes, including gonadotrophin surges and mammary gland development in rats. Chlorotriazine herbicides are rapidly metabolized in plants and animals to form a group of metabolites that are detected both in the environment and in exposed animals. The extent to which these metabolites are responsible directly for the observed health effects is not understood. Objectives: Our goal was to determine if a mixture of ATR metabolites, in proportions found in the environment, might produce developmental effects in Long-Evans rats following exposure late in pregnancy. Methods: We administered an ATR metabolite mixture (AMM) containing ATR, hydroxyatrazine, diaminochlorotriazine, deethylatrazine, and deisopropylatrazine orally to pregnant Long-Evans rats at 0.09, 0.87, or 8.73 mg/kg body weight (bw) /day, on gestation days 15–19, using 0 and 100 mg ATR/kg bw/day as negative and positive controls, respectively. Results: We observed no significant effect of acute AMM exposure on body weight gain in dams during the dosing period, weight loss in pups on postnatal day (PND) 4, or pubertal timing, as is seen with ATR alone. However, as with ATR, we detected delayed mammary gland development, evaluated by whole mount analysis, as early as PND4 in all treatment groups. Conclusions: Our data suggest that acute exposure to AMM at levels as low as 0.09 mg/kg bw during late pregnancy causes persistent alterations in mammary gland development of female offspring, and that these effects do not appear to be related to bw or associated with pubertal timing. Key words: atrazine, body weight, development, mammary gland, metabolites, mixture, prenatal exposure, puberty. Environ Health Perspect 115:541–547 (2007) . doi:10.1289/ehp.9612 available via http://dx.doi.org/ [Online 18 December 2006] Address correspondence to S.E. Fenton, U.S. Environmental Protection Agency, Reproductive Toxicology Division, 2525 Hwy 54, MD-67, Research Triangle Park, NC 27713 USA. Telephone: (919) 541-5220. Fax: (919) 541-4017. E-mail: fenton.suzanne@epa.gov Current addresses: *Amgen, Thousand Oaks, CA ; **U.S. EPA, San Francisco, CA ; #Medical University of South Carolina, Charleston, SC. We thank A. Buckalew, K. McElroy (RIAs) , A. Moore, F. Poythress, A. Walden (animal care) , J. Schmid (statistics) , and M. Narotsky (mixture development advice) for their assistance. We appreciate constructive review of this manuscript by L. Birnbaum (U.S. EPA, NHEERL) and C. Eldridge (Wake Forest University) . This study was supported by U.S. EPA/NCCU (North Carolina Central University) Cooperative Research Training Grant CT829460 (R.R.E.) ; U.S. EPA, NHEERL-DESE Cooperative Training Agreement CT826513 (J.L.R.) ; and U.S. EPA/Duke University Toxicology Training Grant CT826514 (S.N.G) . The U.S. EPA has funded the studies in this document. This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory (NHEERL) 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. Portions of these data were presented at the Society of Toxicology Meeting in Salt Lake City, UT, March 2003. The authors declare they have no competing financial interests. Received 14 August 2006 ; accepted 18 December 2006. The full version of this article is available for free in HTML or PDF formats. |