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Genetic mapping of Eutr1, a locus controlling E2-induced pyometritis in the Brown Norway rat, to RNO5

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Abstract

In certain rat strains, chronic estrogen administration can lead to pyometritis, an inflammation of the uterus accompanied by infection and the accumulation of intraluminal pus. In this article, we report that the Brown Norway (BN) rat is highly susceptible to pyometritis induced by 17β-estradiol (E2). The susceptibility of the BN rat to E2-induced pyometritis appears to segregate as a recessive trait in crosses to the resistant August × Copenhagen Irish (ACI) strain. In a (BN × ACI)F2 population, we find strong evidence for a major genetic determinant of susceptibility to E2-induced pyometritis on rat chromosome 5 (RNO5). Our data are most consistent with a model in which the BN allele of this locus, designated Eutr1 (Estrogen-induced uterine response 1), acts in an incompletely dominant manner to control E2-induced pyometritis. Furthermore, we have confirmed the contribution of Eutr1 to E2-induced uterine pyometritis using an RNO5 congenic rat strain. In addition to Eutr1, we obtained evidence suggestive of linkage for five additional loci on RNO2, 4, 11, 17, and X that control susceptibility to E2-induced pyometritis in the (BN × ACI)F2 population.

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References

  • Amory JH, Adams KM, Lin MT, Hansen JA, Eschenbach DA, et al. (2004) Adverse outcomes after preterm labor are associated with tumor necrosis factor-alpha polymorphism -863, but not -308, in mother-infant pairs. Am J Obstet Gynecol 191: 1362–1367

    Article  PubMed  CAS  Google Scholar 

  • Armstrong DT (1968) Hormonal cohtrol of uterine lumen fluid retention in the rat. Am J Physiol 214: 764–771

    PubMed  CAS  Google Scholar 

  • Bagchi IC, Li Q, Cheon YP (2001) Role of steroid hormone-regulated genes in implantation. Ann N Y Acad Sci 943: 68–76

    PubMed  CAS  Google Scholar 

  • Burrows H (1935) Leucocytic invasion as an accompaniment of epithelial metaplasia. J Pathol Bacteriol 41: 43–49

    Google Scholar 

  • Churchill GA, Doerge RW (1994) Empirical threshold values for quantitative trait mapping. Genetics 138: 963–971

    PubMed  CAS  Google Scholar 

  • Doerge RW (2002) Mapping and analysis of quantitative trait loci in experimental populations. Nat Rev Genet 3: 43–52

    Article  PubMed  CAS  Google Scholar 

  • Elovitz MA, Mrinalini C (2004) Animal models of preterm birth. Trends Endocrinol Metab 15: 479–487

    PubMed  CAS  Google Scholar 

  • Everett JW (1939) Spontaneous persistent estrus in a strain of albino rats. Endocrinology 25: 123–127

    Article  Google Scholar 

  • Falconer DS, Mackay TR (1996) Introduction to Quantitative Genetics. (Harlow, UK: Longman Group, Ltd.)

    Google Scholar 

  • Gould KA, Dietrich WF, Borenstein N, Lander ES, Dove WF (1996) Mom1 is a semi-dominant odifier of intestinal adenoma size and multiplicity in Min/+ mice. Genetics 144: 1769–1776

    PubMed  CAS  Google Scholar 

  • Gould KA, Tochacek M, Schaffer BS, Reindl TM, Murrin CR, et al. (2004) Genetic determination of susceptibility to estrogen-induced mammary cancer in the ACI rat: mapping of Emca1 and Emca2 to chromosomes 5 and 18. Genetics 168: 2113–2125

    Article  PubMed  CAS  Google Scholar 

  • Griffith JS, Jensen SM, Lunceford JK, Kahn MW, Zheng Y, et al. (1997) Evidence for the genetic control of estradiol-regulated responses. Implications for variation in normal and pathological hormone-dependent phenotypes. Am J Pathol 150: 2223–2230

    PubMed  CAS  Google Scholar 

  • Holtzman S, Stone JP, Shellabarger CJ (1979) Synergism of diethylstilbestrol and radiation in mammary carcinogenesis in female F344 rats. J Natl Cancer Inst 63: 1071–1074

    PubMed  CAS  Google Scholar 

  • Homeister JW, Thall AD, Petryniak B, Maly P, Rogers CE, et al. (2001) The alpha(1,3)fucosyltransferases FucT-IV and FucT-VII exert collaborative control over selectin-dependent leukocyte recruitment and lymphocyte homing. Immunity 15: 115–126

    Article  PubMed  CAS  Google Scholar 

  • Jishage K, Arita M, Igarashi K, Iwata T, Watanabe M, et al. (2001) Alpha-tocopherol transfer protein is important for the normal development of placental labyrinthine trophoblasts in mice. J Biol Chem 276: 1669–1672

    Article  PubMed  CAS  Google Scholar 

  • Kaempf-Rotzoll DE, Igarashi K, Aoki J, Jishage K, Suzuki H, et al. (2002) Alpha-tocopherol transfer protein is specifically localized at the implantation site of pregnant mouse uterus. Biol Reprod 67: 599–604

    PubMed  CAS  Google Scholar 

  • Kaushic C, Frauendorf E, Rossoll RM, Richardson JM, Wira CR (1998) Influence of the estrous cycle on the presence and distribution of immune cells in the rat reproductive tract. Am J Reprod Immunol 39: 209–216

    PubMed  CAS  Google Scholar 

  • Larsen B, Galask RP (1980) Vaginal microbial flora: practical and theoretic relevance. Obstet Gynecol 55: 100S–113S

    PubMed  CAS  Google Scholar 

  • Larsen B, Galask RP (1984) Influence of estrogen and normal flora on vaginal candidiasis in the rat. J Reprod Med 29: 863–868

    PubMed  CAS  Google Scholar 

  • Larsen B, Markovetz AJ, Galask RP (1976a) The bacterial flora of the female rat genital tract. Proc Soc Exp Biol Med 151: 571–574

    CAS  Google Scholar 

  • Larsen B, Markovetz AJ, Galask RP (1976b) Quantitative alterations in the genital microflora of female rats in relation to the estrous cycle. J Infect Dis 134: 486–489

    CAS  Google Scholar 

  • Larsen B, Markovetz AJ, Galask RP (1977) Role of estrogen in controlling the genital microflora of female rats. Appl Environ Microbiol 34: 534–540

    PubMed  CAS  Google Scholar 

  • Lee YH, Howe RS, Sha SJ, Teuscher C, Sheehan DM, et al. (1989) Estrogen regulation of an eosinophil chemotactic factor in the immature rat uterus. Endocrinology 125: 3022–3028

    PubMed  CAS  Google Scholar 

  • Locksmith G, Duff P (2001) Infection, antibiotics, and preterm delivery. Semin Perinatol 25: 295–309

    PubMed  CAS  Google Scholar 

  • Macones GA, Parry S, Elkousy M, clothier B, Ural SH, et al. (2004) A polymorphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of gene-environment interaction in the etiology of spontaneous preterm birth. Am J Obstet Gynecol 190: 1504–1508; discussion 1503A

    Article  PubMed  CAS  Google Scholar 

  • Manly KF, Cudmore RH Jr, Meer JM (2001) MapManager QTX, cross-platform software for genetic mapping. Mamm Genome 12: 930–932

    Article  PubMed  CAS  Google Scholar 

  • Martens MG, Faro S, Hammill HA, Smith D, riddle G, et al. (1990) Ampicillin/sulbactam versus clindamycin in the treatment of postpartum endomyometritis. South Med J 83: 408–413

    PubMed  CAS  Google Scholar 

  • Martens MG, Faro S, Maccato M, Riddle G, Hammill HA (1991) Susceptibility of female pelvic pathogens to oral antibiotic agents in patients who develop postpartum endometritis. Am J Obstet Gynecol 164: 1383–1386

    PubMed  CAS  Google Scholar 

  • Mcmaster MT, Newton RC, Dey SK, Andrews GK (1992) Activation and distribution of inflammatory cells in the mouse uterus during the preimplantation period. J Immunol 148: 1699–1705

    PubMed  CAS  Google Scholar 

  • Mikamo H, Kawazoe K, Izumi K, Watanabe K, Ueno K, et al. (1998) Studies on the pathogenicity of anaerobes, especially Prevotella bivia, in a rat pyometra model. Infect Dis Obstet Gynecol 6: 61–65

    PubMed  CAS  Google Scholar 

  • Moore S, Ide M, Randhawa M, Walker JJ, Reid JG, et al. (2004) An investigation into the association among preterm birth, cytokine gene polymorphisms and periodontal disease. BJOG 111: 125–132

    PubMed  CAS  Google Scholar 

  • Pandey J, Gould KA, McComb RD, Shull JD (2005) Localization of Eutr2, a locus controling susceptibility to DES-induced uterine inflammation and pyometritis, to proximal RNO5 using a congenic rat strain. Mamm Genome 16: XXX–XXX

    PubMed  CAS  Google Scholar 

  • Perez MC, Furth EE, Matzumura PD, Lyttle CR (1996) Role of eosinophils in uterine responses to estrogen. Biol Reprod 54: 249–254

    Article  PubMed  CAS  Google Scholar 

  • Romero R, Chaiworapongsa T, Kuivaniemi H, Tromp G (2004) Bacterial vaginosis, the inflammatory response and the risk of preterm birth: a role for genetic epidemiology in the prevention of preterm birth. Am J Obstet Gynecol 190: 1509–1519

    PubMed  Google Scholar 

  • Roper RJ, Griffith JS, Lyttle CR, Doerge RW, Mcnabb AW, et al. (1999) Interacting quantitative trait loci control phenotypic variation in murine estradiol-regulated responses. Endocrinology 140: 556–561

    Article  PubMed  CAS  Google Scholar 

  • Sandholm M, Vasenius H, Kivisto AK (1975) Pathogenesis of canine pyometra. J Am Vet Med Assoc 167: 1006–1010

    PubMed  CAS  Google Scholar 

  • Schock BC, Van Der Vliet A, Corbacho AM, Leonard SW, Finkelstein E, et al. (2004) Enhanced inflammatory responses in alpha-tocopherol transfer protein null mice. Arch Biochem Biophys 423: 162–169

    Article  PubMed  CAS  Google Scholar 

  • Shull JD, Spady TD, Snyder MC, Johansson SL, Pennington KL (1997) Ovary-intact, but not ovariectomized female ACI rats treated with 17beta-estradiol rapidly develop mammary carcinoma. Carcinogenesis 18: 1595–1601

    Article  PubMed  CAS  Google Scholar 

  • Shull JD, Pennington KL, Reindl TM, Snyder MC, Strecker TE, et al. (2001) Susceptibility to estrogen-induced mammary cancer segregates as an incompletely dominant phenotype in reciprocal crosses between the ACI and Copenhagen rat strains. Endocrinology 142: 5124–5130

    Article  PubMed  CAS  Google Scholar 

  • Spady TJ, Pennington KL, Mccomb RD, Birt DF, Shull JD (1999a) Estrogen-induced pituitary tumor development in the ACI rat not inhibited by dietary energy restriction. Mol Carcinog 26: 239–253

    Article  CAS  Google Scholar 

  • Spady TJ, Pennington KL, Mccomb RD, Shull JD (1999b) Genetic bases of estrogen-induced pituitary growth in an intercross between the ACI and Copenhagen rat strains: dominant mendelian inheritance of the ACI phenotype. Endocrinology 140, 2828–2835

    Article  CAS  Google Scholar 

  • Stone JP, Holtzman S, Shellabarger CJ (1979) Neoplastic responses and correlated plasma prolactin levels in diethylstilbestrol-treated ACI and Sprague-Dawley rats. Cancer Res 39, 773–778

    PubMed  CAS  Google Scholar 

  • Strecker TE, Spady TJ, Schaffer BS, Gould KA, Kaufman AE, et al. (2005) Genetic bases of estrogen-induced pituitary tumorigenesis: identification of genetic loci determining estrogen-induced pituitary growth in reciprocal crosses between the ACI and Copenhagen rat strains. Genetics 169: 2189–2197

    Article  PubMed  CAS  Google Scholar 

  • Tchernitchin A, Roorijck J, Tchernitchin X, Vandenhende J, Galand F (1974) Dramatic early increase in uterine eosinophils after oestrogen administration. Nature 248: 142–143

    Article  PubMed  CAS  Google Scholar 

  • Tchernitchin A, Tchernitchin X, Galand P (1975) Correlation of estrogen-induced uterine eosinophilia with other parameters of estrogen stimulation, produced with estradiol-17beta and estriol. Experientia 31: 993–994

    PubMed  CAS  Google Scholar 

  • Terzidou V, Bennett PR (2002) Preterm labour. Curr Opin Obstet Gynecol 14: 105–113

    Article  PubMed  Google Scholar 

  • Teuscher C, Butterfield RJ, Ma RZ, Zachary JF, Doerge RW, et al. (1999) Sequence polymorphisms in the chemokines Scya1 (TCA-3), Scya2 (monocyte chemoattractant protein (MCP)-1), and Scya12 (MCP-5) are candidates for eae7, a locus controlling susceptibility to monophasic remitting/nonrelapsing experimental allergic encephalomyelitis. J Immunol 163: 2262–2266

    PubMed  CAS  Google Scholar 

  • Visscher PM, Thompson R, Haley CS (1996) Confidence intervals in QTL mapping by bootstrapping. Genetics 143: 1013–1020

    PubMed  CAS  Google Scholar 

  • Wakeland E, Morel L, Achey K, Yui M, Longmate J (1997) Speed congenics: a classic technique in the fast lane (relatively speaking). Immunol Today 18: 472–477

    Article  PubMed  CAS  Google Scholar 

  • Zeng ZB (1993) Theoretical basis for separation of multiple linked gene effects in mapping quantitative trait loci. Proc Natl Acad Sci U S A 90: 10972–10976

    PubMed  CAS  Google Scholar 

  • Zeng ZB (1994) Precision mapping of quantitative trait loci. Genetics 136, 1457–1468

    PubMed  CAS  Google Scholar 

  • Zondek B (1937) The effect of long-continued large doses of follicle hormone upon the uterus of the rat. Am J Obstet Gynecol 33: 979–988

    Google Scholar 

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Acknowledgments

The authors gratefully acknowledge members of the Shull Laboratory, particularly Linda Buckles for her helpful discussions and critical review of the manuscript, and Kimberly Bynoté, Tracy Strecker, MacMcLaughlin, and Scott Kurz for technical assistance. This work was supported by grants R01-CA68529 (JDS) and R01-CA77876 (JDS) from the National Institutes of Health and DAMD 17-98-1-8217 (JDS) from the U.S. Army Breast Cancer Research Program. MT and BSS were supported in part by training grant DAMD 17-00-1-0361 from the U.S. Army Breast Cancer Training Program. BSS was supported in part by DAMD 17-03-1-0477 from the U.S. Army Breast Cancer Training Program. Cancer Center Support grant P30-CA36727 supported shared resources in the UNMC Eppley Cancer Center.

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Authors and Affiliations

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

    Karen A. Gould, Cynthia M. Lachel, Karen L. Pennington, Beverly S. Schaffer & James D. Shull

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

    Karen A. Gould, Cynthia M. Lachel, Clare R. Murrin, Lisa A. Flood, Karen L. Pennington, Beverly S. Schaffer, Martin Tochacek & James D. Shull

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

    Rodney D. McComb & James D. Shull

  4. Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA

    Jane L. Meza

  5. Department of Biological Sciences, Oakland University, Rochester, Michigan, 48309, USA

    Jyotsna Pandey & Douglas L. Wendell

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  1. Karen A. Gould
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Correspondence to Karen A. Gould.

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Gould, K.A., Pandey, J., Lachel, C.M. et al. Genetic mapping of Eutr1, a locus controlling E2-induced pyometritis in the Brown Norway rat, to RNO5. Mamm Genome 16, 854–864 (2005). https://doi.org/10.1007/s00335-005-0070-7

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