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Genetic mapping of loci controlling diethylstilbestrol-induced thymic atrophy in the Brown Norway rat

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Abstract

Chronic estrogen administration can lead to thymic atrophy in rodents. In this article we report that the Brown Norway (BN) rat is sensitive to thymic atrophy induced by the estrogen diethylstilbestrol (DES). By contrast, DES does not induce significant thymic atrophy in the August × Copenhagen-Irish (ACI) strain. The sensitivity of the BN rat to DES-induced thymic atrophy appears to segregate as an incompletely dominant trait in crosses between the BN and ACI strains. In a (BN × ACI)F2 population, we find strong evidence for three major genetic determinants of sensitivity to DES-induced thymic atrophy on rat Chromosome (RNO) 10 and RNO2. Genotypes at these loci, termed Esta1, 2, and 3, do not have a significant impact on the ability of DES to induce pituitary tumorigenesis or inhibit growth of these F2 rats. These data indicate that the genetic factors that control DES-induced thymic atrophy are distinct from those that control the effects of DES on pituitary mass and body mass. The Esta intervals on RNO10 and RNO2 overlap with loci that control sensitivity to radiation-induced thymocyte apoptosis, as well as susceptibility to a variety of allergic and autoimmune pathologies, including allergic encephalitis, arthritis, and glomerulonephritis in rodents. These observations suggest that common genetic determinants may control sensitivity to estrogen-induced thymic atrophy, maintenance of thymocyte homeostasis, and immune function.

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Acknowledgments

The authors gratefully acknowledge Beverly S. Schaffer for helpful discussions and critical review of the manuscript. This work was supported by grants R01-CA68529 and R01-CA77876 from the National Institutes of Health. T.E.S. was supported in part by National Institutes of Health training grant T32-CA09476. T.E.S. and K.K.H. were supported in part by training grant DAMD17-00-1-0361 from the U.S. Army Breast Cancer Training Program. Cancer Center Support grant P30-CA36727 supported shared resources in the UNMC Eppley Cancer Center. The authors also gratefully acknowledge the support of the National Heart, Lung and Blood Institute Mammalian Genotyping Service (Contract HV48141).

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  1. Department of Genetics, Cell Biology and Anatomy, 985805, University of Nebraska Medical Center, Omaha, Nebraska, 68198-5805, USA

    Karen A. Gould, Tracy E. Strecker, Kimberly K. Hansen, Kimberly K. Bynoté & James D. Shull

  2. Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA

    Karen A. Gould, Tracy E. Strecker, Kimberly K. Hansen, Kimberly K. Bynoté, Kelli A. Peterson & James D. Shull

  3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA

    James D. Shull

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Correspondence to Karen A. Gould.

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Gould, K.A., Strecker, T.E., Hansen, K.K. et al. Genetic mapping of loci controlling diethylstilbestrol-induced thymic atrophy in the Brown Norway rat. Mamm Genome 17, 451–464 (2006). https://doi.org/10.1007/s00335-005-0183-z

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