title: Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A.
abstract: Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24h following administration of the last of five daily oral doses of 250mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats.
authors.affiliation: Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States. Electronic address: sander10@mail.nih.gov.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Sanders
authors.affiliation: Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States.
authors.forename: Sherry J
authors.initials: SJ
authors.lastname: Coulter
authors.affiliation: Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Knudsen
authors.affiliation: National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States.
authors.forename: June K
authors.initials: JK
authors.lastname: Dunnick
authors.affiliation: National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States.
authors.forename: Grace E
authors.initials: GE
authors.lastname: Kissling
authors.affiliation: Laboratory of Toxicology and Toxicokinetics, National Cancer Institute at the National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Birnbaum
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000235:genetics; D047629:Estrogen Receptor beta / Q000235:genetics; D004967:Estrogens / Q000097:blood / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006706:Homeostasis / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011075:Polybrominated Biphenyls / Q000633:toxicity*; D017208:Rats, Wistar; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D004785:Environmental Pollutants; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D011075:Polybrominated Biphenyls; C020806:tetrabromobisphenol A
keywords: Estrogen homeostasis; Gene expression; Rats; TBBPA; Tetrabromobisphenol A; Uterine toxicity