title: Changes in mRNA and protein expression in the renal cortex of male and female F344 rats treated with bromate.
abstract: Bromate (BrO3(-)), a by-product of ozonation of drinking water, induces nephrotoxicity in male rats at much lower doses than in female rats. This difference appears to be related to the development of α-2u-globulin nephropathy in males. To determine sex-dependent changes in mRNA and protein expression in the renal cortex attributable to α-2u-globulin nephropathy, we performed microarray and immunohistochemical analyses in proximal renal tubules of male and female F344 rats treated with KBrO3 for 28 days. Particular attention was paid to molecular biomarkers of renal tubular injury. Microarray analysis of male and female rats treated with BrO3(-) at low doses (125 mg/L KBrO3) displayed marked sex-dependent changes in renal gene expression. The greatest differences were seen in genes encoding for cellular differentiation, apoptosis, ion transport, and cell proliferation. Differences by sex were especially prominent for the cell cycle checkpoint gene p21, the renal injury protein Kim-1, and the kidney injury and cancer biomarker protein osteopontin. Dose-related nephrotoxicity, assessed by hematoxylin and eosin staining, was greater in males compared to female rats, as was cellular proliferation, assessed by bromodeoxyuridine staining. The fraction of proximal renal cells with elevated 8-oxodeoxyguanosine (8-OH-dG) was only increased at the high dose and did not differ by sex. Dose-dependent increases in the expression of osteopontin were detected immunohistochemically only in male rats and were localized in proximal tubule cells. Similarly, BrO3(-) treatment increased clusterin and Kim-1 staining in the proximal tubules; however, staining for these proteins did not differ appreciably between males and females. These data demonstrate both qualitative and quantitative differences in the response of male versus female kidneys to BrO3(-)-treatment. These sex-dependent effects likely contribute to renal carcinogenesis of BrO3(-) in the male rat.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Narendrababu
authors.initials: N
authors.lastname: Kolisetty
authors.affiliation: School of Medicine, University of Utah, Salt Lake City, UT, 84132, USA.
authors.forename: Don A
authors.initials: DA
authors.lastname: Delker
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, 30602, USA.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Muralidhara
authors.affiliation: MoBull Consulting, Richland, WA, 99352, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bull
authors.affiliation: Joseph Cotruvo and Associates, LLC, Washington, DC, 20016, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Cotruvo
authors.affiliation: National Center for Toxicological Research, FDA, Jefferson, AR, 72079, USA.
authors.forename: Jeff W
authors.initials: JW
authors.lastname: Fisher
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, 30602, USA. bsc@rx.uga.edu.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Cummings
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001959:Bromates / Q000633:toxicity*; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D051152:Clusterin / Q000096:biosynthesis / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D046228:Microarray Analysis; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis / Q000235:genetics; D053495:Osteopontin / Q000096:biosynthesis / Q000235:genetics; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D001959:Bromates; D015815:Cell Adhesion Molecules; D051152:Clusterin; D003849:Deoxyguanosine; D015689:Oncogene Protein p21(ras); D053495:Osteopontin; D012333:RNA, Messenger; C110936:Havcr1 protein, rat