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Michele La Merrill,¹ Bittu S. Kuruvilla,¹ Daniel Pomp,¹ Linda S. Birnbaum,^2,* and David W. Threadgill^1,3

¹Department of Genetics, Curriculum in Toxicology, Center for Environmental Health and Susceptibility, Clinical Nutrition Research Unit, Lineberger Cancer Center and Carolina Genome Sciences Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; ²Experimental Toxicology Division, U.S. Environmental Protection Agency, Office of Research and Development/National Health and Environmental Effects Research Laboratory, Research Triangle Park, North Carolina, USA; ³Department of Genetics, North Carolina State University, Raleigh, North Carolina, USA

Abstract
Background: Increased fat intake is associated with obesity and may make obese individuals uniquely susceptible to the effects of lipophilic aryl hydrocarbon receptor (AHR) ligands.

Objectives: We investigated the consequences of high-fat diet (HFD) and AHR ligands on body composition, mammary development, and hepatic P450 expression.

Methods: Pregnant C57BL/6J (B6) and DBA/2J (D2) dams, respectively expressing high- or low-responsive AHR, were dosed at mid-gestation with TCDD. At parturition, mice were placed on an HFD or a low-fat diet (LFD) . Body fat of progeny was measured before dosing with 7,12-dimethylbenz[a]anthracene (DMBA) . Fasting blood glucose was measured, and liver and mammary glands were analyzed.

Results: Maternal TCDD exposure resulted in reduced litter size in D2 mice and, on HFD, reduced postpartum survival in B6 mice. In D2 mice, HFD increased body mass and fat in offspring, induced precocious mammary gland development, and increased AHR expression compared with mice given an LFD. Maternal TCDD exposure increased hepatic Cyp1a1 and Cyp1b1 expression in offspring on both diets, but DMBA depressed Cyp1b1 expression only in mice fed an HFD. In D2 progeny, TCDD exposure decreased mammary terminal end bud size, and DMBA exposure decreased the number of terminal end buds. Only in D2 progeny fed HFD did perinatal TCDD increase blood glucose and the size of mammary fat pads, while decreasing both branch elongation and the number of terminal end buds.

Conclusions: We conclude that despite having a low-responsive AHR, D2 progeny fed a diet similar to that consumed by most people are susceptible to TCDD and DMBA exposure effects blood glucose levels, mammary differentiation, and hepatic Cyp1 expression.

Key words: aryl hydrocarbon receptor, fetal loss, gene–environment interactions, mouse, obesity, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) . Environ Health Perspect 117:1414–1419 (2009) . doi:10.1289/ehp.0800530 available via http://dx.doi.org/ [Online 18 May 2009]

Address correspondence to D. Threadgill, Department of Genetics, CB#7614, North Carolina State University, Raleigh, NC 27695 USA. Telephone: (919) 515-2292. Fax: (919) 515-3355. E-mail: Threadgill@ncsu.edu

*Current address: National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

We thank K. Hua of the Animal Metabolism Phenotyping Core for assistance with the dual-energy X-ray absorptiometry, C. Wiesen of the Odum Institute for assistance with statistical analysis, and S. Fenton and M. DeVito of the U.S. Environmental Protection Agency (EPA) for discussion and comments on the manuscript.

This work was supported by research grants from the National Institutes of Health (U01CA105417, U01CA134240, P30CA016086, T32ES007126, P30ES010126, R01DK56350, and P30DK056350) and the U.S. Department of Defense (BC050873) .

This document has been reviewed in accordance with U.S. EPA policy and approved for publication. Approval does not signify that the content necessarily reflects the view and policies of the agency, nor does mention of the trade names or commercial products constitutes endorsement or recommendation for use.

The authors declare they have no competing financial interests.

Received 30 December 2008 ; accepted 14 May 2009.

This error has been corrected in the HTML version of this article.

An erratum is posted online at http://www.ehponline.org/docs/2009/117-10/errata2.html.