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

Published on May 1, 2006in Mammalian Genome2.287
· DOI :10.1007/S00335-005-0183-Z
Karen A. Gould16
Estimated H-index: 16
(UNMC: University of Nebraska Medical Center),
Tracy E. Strecker9
Estimated H-index: 9
(UNMC: University of Nebraska Medical Center)
+ 3 AuthorsJames D. Shull23
Estimated H-index: 23
(UNMC: University of Nebraska Medical Center)
Sources
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.
📖 Papers frequently viewed together
20044.01Genetics
13 Authors (Karen A. Gould, ..., James D. Shull)
78 Citations
13 Citations
20 Citations
References93
Newest
#1Nikolay M. Filipov (MSU: Mississippi State University)H-Index: 25
#2Lesya M. Pinchuk (MSU: Mississippi State University)H-Index: 14
Last. Patrick L. Crittenden (MSU: Mississippi State University)H-Index: 6
view all 4 authors...
The herbicide atrazine (ATR) is a very widely used pesticide; yet the immunotoxicological potential of ATR has not been studied extensively. Our objective was to examine the effect of ATR on selected immune parameters in juvenile mice. ATR (up to 250 mg/kg) was administered by oral gavage for 14 days to one-month-old male C57BL/6 mice. One day, one week, and seven weeks after the last ATR dose, mice were sacrificed, and blood, spleens, and thymuses were collected and processed for cell counting ...
111 CitationsSource
#1Bastien Llamas (French Institute of Health and Medical Research)H-Index: 26
#2V. Contesse (University of Rouen)H-Index: 18
Last. Marie-Pierre Moisan (French Institute of Health and Medical Research)H-Index: 25
view all 6 authors...
In the present study we searched for quantitative trait loci (QTLs) that affect neuroendocrine stress responses in a 20-min restraint stress paradigm using Brown–Norway (BN) and Wistar–Kyoto–Hyperactive (WKHA) rats. These strains differed in their hypothalamic–pituitary–adrenal axis (plasma ACTH and corticosterone levels, thymus, and adrenal weights) and in their renin–angiotensin–aldosterone system reactivity (plasma renin activity, aldosterone concentration). We performed a whole-genome scan o...
13 CitationsSource
#1Max BrennerH-Index: 15
#2Hsiang-Chi MengH-Index: 3
Last. Pércio S. GulkoH-Index: 13
view all 8 authors...
Cia5 is a locus on rat chromosome 10 which regulates the severity of collagen- and pristane-induced arthritis (CIA and PIA). To refine the region toward positional identification, Cia5 subcongenic strains were generated and studied in PIA and CIA. The protective effect of the telomeric locus Cia5a was confirmed in both models. A second arthritis severity locus ( Cia5d ) was identified within the most centromeric portion of Cia5 . DA.F344(Cia5d) rats had a significantly lower median arthritis sev...
83 CitationsSource
#1Niel A. Karrow (VCU: Virginia Commonwealth University)H-Index: 26
#2J. A. McCay (VCU: Virginia Commonwealth University)H-Index: 11
Last. Kimber L. White (VCU: Virginia Commonwealth University)H-Index: 37
view all 7 authors...
Abstract Atrazine (ATZ) is used throughout North America to control annual broadleaf weeds and grasses in various crops including; corn, sorghum, and sugar cane. Unfortunately, contamination of surface and ground water has occurred as a result of ATZ's chemical and physical properties, and its widespread use throughout the U.S. Midwest. A study of ATZ's immunomodulatory properties was conducted using female B6C3F1 mice and a panel of immune assays and host resistance models designed to evaluate ...
57 CitationsSource
#1Tracy E. Strecker (UNMC: University of Nebraska Medical Center)H-Index: 9
#2Thomas J. Spady (UNMC: University of Nebraska Medical Center)H-Index: 13
Last. James D. Shull (UNMC: University of Nebraska Medical Center)H-Index: 23
view all 10 authors...
Estrogens stimulate proliferation and enhance survival of the prolactin (PRL)-producing lactotroph of the anterior pituitary gland and induce development of PRL-producing pituitary tumors in certain inbred rat strains but not others. The goal of this study was to elucidate the genetic bases of estrogen-induced pituitary tumorigenesis in reciprocal intercrosses between the genetically related ACI and Copenhagen (COP) rat strains. Following 12 weeks of treatment with the synthetic estrogen diethyl...
26 CitationsSource
#1Maurizio Cutolo (UniGe: University of Genoa)H-Index: 102
#2Robert G. Lahita (St Vincent Hospital)H-Index: 3
Abstract Sex hormones seem to play an important role as modulators and perpetuators of rheumatic disorders with autoimmune involvement, such as rheumatoid arthritis or systemic lupus erythematosus. Estrogens are implicated in the immune response as enhancers of the humoral immunity. Sex hormones can exert local actions (paracrine) in the tissues in which they are formed; an accelerated peripheral metabolic conversion of upstream androgen precursors to estrogens has been well-assessed. Local effe...
72 CitationsSource
#1Max BrennerH-Index: 15
#2Hsiang-Chi MengH-Index: 3
Last. Pércio S. GulkoH-Index: 13
view all 7 authors...
Objective To construct rats congenic for the chromosome 2 arthritis-regulatory quantitative trait locus Cia10, originally identified in a (DA × ACI)F2 intercross rat strain that had been assessed for collagen-induced arthritis (CIA), and to determine the effect of this congenic interval on arthritis severity, joint histologic structure, and cytokine transcription in rats with pristane-induced arthritis (PIA). Methods A 52.6-MB interval derived from the ACI (CIA- and PIA-resistant) strain and con...
85 CitationsSource
#1Karen A. GouldH-Index: 16
#2Martin Tochacek (UNMC: University of Nebraska Medical Center)H-Index: 7
Last. James D. Shull (UNMC: University of Nebraska Medical Center)H-Index: 23
view all 13 authors...
Hormonal, genetic, and environmental factors play major roles in the complex etiology of breast cancer. When treated continuously with 17β-estradiol (E2), the ACI rat exhibits a genetically conferred propensity to develop mammary cancer. The susceptibility of the ACI rat to E2-induced mammary cancer appears to segregate as an incompletely dominant trait in crosses to the resistant Copenhagen (COP) strain. In both (ACI × COP)F2 and (COP × ACI)F2 populations, we find strong evidence for a major ge...
78 CitationsSource
#1Anne E. Bygrave (Imperial College London)H-Index: 19
#2Kirsten L. Rose (Imperial College London)H-Index: 7
Last. Marina Botto (Imperial College London)H-Index: 80
view all 9 authors...
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder in which complex genetic factors play an important role. Several strains of gene-targeted mice have been reported to develop SLE, implicating the null genes in the causation of disease. However, hybrid strains between 129 and C57BL/6 mice, widely used in the generation of gene-targeted mice, develop spontaneous autoimmunity. Furthermore, the genetic background markedly influences the autoimmune phenotype of SLE in gene-targe...
249 CitationsSource
#1Magali Mas (French Institute of Health and Medical Research)H-Index: 7
#2Pierre Cavaillès (French Institute of Health and Medical Research)H-Index: 8
Last. Gilbert J. Fournié (French Institute of Health and Medical Research)H-Index: 25
view all 11 authors...
Brown Norway (BN) rats treated with aurothiopropanol-sulfonate (Atps) constitute a model of Th2-mediated immunological disorders associated with elevated IgE responses and renal IgG deposits. Using F2 offspring between Atps-susceptible BN and Atps-resistant Lewis rats, we had previously mapped three quantitative trait loci on chromosomes 9, 10, and 20 for which BN alleles increased susceptibility to Atps-induced immunological disorders (Aiid). In this study we have used congenic lines for the la...
17 CitationsSource
Cited By10
Newest
#1Kirsten L. Dennison (UW: University of Wisconsin-Madison)H-Index: 6
#2Aaron C. Chack (UW: University of Wisconsin-Madison)H-Index: 1
Last. James D. Shull (UW: University of Wisconsin-Madison)H-Index: 23
view all 5 authors...
Pituitary adenoma is a common intracranial neoplasm that is observed in approximately 10% of unselected individuals at autopsy. Prolactin-producing adenomas, i.e., prolactinomas, comprise approximately 50% of all pituitary adenomas and represent the most common class of pituitary tumor. Multiple observations suggest that estrogens may contribute to development of prolactinoma; however, direct evidence for a causal role of estrogens in prolactinoma etiology is lacking. Rat models of estrogen-indu...
1 CitationsSource
#1James D. Shull (UW: University of Wisconsin-Madison)H-Index: 23
#2Kirsten L. Dennison (UW: University of Wisconsin-Madison)H-Index: 6
Last. Amy Trentham-Dietz (UW: University of Wisconsin-Madison)H-Index: 55
view all 4 authors...
Numerous laboratory and epidemiologic studies strongly implicate endogenous and exogenous estrogens in the etiology of breast cancer. Data summarized herein suggest that the ACI rat model of 17β-estradiol (E2)-induced mammary cancer is unsurpassed among rodent models in the extent to which it faithfully reflects the etiology and biology of luminal types of breast cancer, which together constitute approximately 70% of all breast cancers. E2 drives cancer development in this model through mechanis...
14 CitationsSource
#1D. Joseph Jerry (Baystate Medical Center)H-Index: 26
#2James D. Shull (UW: University of Wisconsin-Madison)H-Index: 23
Last. Amy Trentham-Dietz (UW: University of Wisconsin-Madison)H-Index: 55
view all 10 authors...
Breast cancer risk is intimately intertwined with exposure to estrogens. While more than 160 breast cancer risk loci have been identified in humans, genetic interactions with estrogen exposure remain to be established. Strains of rodents exhibit striking differences in their responses to endogenous ovarian estrogens (primarily 17β-estradiol). Similar genetic variation has been observed for synthetic estrogen agonists (ethinyl estradiol) and environmental chemicals that mimic the actions of estro...
10 CitationsSource
#1Rachel Frawley (UM: Maastricht University)
#2Dori Germolec (Centre for Health Protection)
Last. Henk van Loveren (NIH: National Institutes of Health)
view all 3 authors...
Source
#1Scott G. Kurz (UNMC: University of Nebraska Medical Center)H-Index: 9
#2Kirsten L. Dennison (UW: University of Wisconsin-Madison)H-Index: 6
Last. James D. Shull (UNMC: University of Nebraska Medical Center)H-Index: 23
view all 8 authors...
Estrogens control many aspects of pituitary gland biology, including regulation of lactotroph homeostasis and synthesis and secretion of prolactin. In rat models, these actions are strain specific and heritable, and multiple quantitative trait loci (QTL) have been mapped that impact the responsiveness of the lactotroph to estrogens. One such QTL, Ept7, was mapped to RNO7 in female progeny generated in an intercross between BN rats, in which the lactotroph population is insensitive to estrogens, ...
9 CitationsSource
#1Claude Szpirer (ULB: Université libre de Bruxelles)H-Index: 53
#2Göran Levan (University of Gothenburg)H-Index: 33
The rat has been used for a long time as the model of choice in several biomedical disciplines. Numerous inbred strains have been isolated, displaying a wide range of phenotypes and providing many models of human traits and common diseases. Unlike the mouse, the rat was neglected by geneticists. However, most traits and diseases studied in the rat are complex, polygenic, and their analysis requires genetic approaches. Rat genome mapping and genomics were considerably developed in the last two de...
3 CitationsSource
#1Leon Earl Gray (RTP: Research Triangle Park)H-Index: 46
#2Bryce C. Ryan (University of Redlands)H-Index: 9
Last. Kevin M. Crofton (RTP: Research Triangle Park)H-Index: 74
view all 4 authors...
12 CitationsSource
#1Leon Earl GrayH-Index: 46
#2Bryce C. RyanH-Index: 9
Last. Kevin M. CroftonH-Index: 74
view all 4 authors...
That the developmental effects of the potent environment estrogen ethinyl estradiol (EE2) address important agency research needs and that EE2 is not just a ‘‘positive control.’’ Why the Long Evans (LE) rat and several other rat strains are excellent animal models for the study of the potential adverse effects of xenoestrogens. Why the argument that LE rats and other rat strains are ‘‘insensitive strains’’ is not consistent with (a) the pharmacological and toxicological data showing that humans ...
1 Citations
#1Scott G. Kurz (UNMC: University of Nebraska Medical Center)H-Index: 9
#2Kimberly K. Hansen (UNMC: University of Nebraska Medical Center)H-Index: 2
Last. James D. Shull (UNMC: University of Nebraska Medical Center)H-Index: 23
view all 9 authors...
Ept1, Ept2, Ept6, and Ept9 are quantitative trait loci mapped in crosses between the ACI and Copenhagen (COP) rat strains as genetic determinants of responsiveness of the pituitary gland to estrogens. We have developed four congenic rat strains, each of which carries, on the genetic background of the ACI rat strain, alleles from the COP rat strain that span one of these quantitative trait loci. Relative to the female ACI rats, female ACI.COP-Ept1 rats exhibited reduced responsiveness to 17β-estr...
19 CitationsSource
#1James D. Shull (UNMC: University of Nebraska Medical Center)H-Index: 23
#2Cynthia M. Lachel (UNMC: University of Nebraska Medical Center)H-Index: 13
Last. Karen A. Gould (UNMC: University of Nebraska Medical Center)H-Index: 16
view all 7 authors...
Estrogens are important regulators of growth and development and contribute to the etiology of several types of cancer. Different inbred rat strains exhibit marked, cell-type-specific differences in responsiveness to estrogens as well as differences in susceptibility to estrogen-induced tumorigenesis. Regulation of pituitary lactotroph homeostasis is one estrogen-regulated response that differs dramatically between different inbred rat strains. In this article we demonstrate that the growth resp...
15 CitationsSource