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Changes in mRNA and protein expression in the renal cortex of male and female F344 rats treated with bromate

  • Inorganic Compounds
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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.

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Acknowledgments

We thank Dr. James Bruckner for use of his lab facilities to conduct many of the in vivo studies. We also thank Dr. Robert Arnold for use of his microscope for the immunohistochemistry studies. This work was supported by the Georgia Cancer Coalition and Joseph Cotruvo & Associates LLC with grants from the Water Research Foundation Project #4042–International Ozone Assoc., Environment Agency of Abu Dhabi, Veolia Water, Metropolitan Water District of Southern Calif., Los Angeles Department of Water and Power, Singapore Public Utilities Bureau, National Water Research Institute, Walkerton Clean Water Centre, Calleguas Municipal Water District, Long Beach Water Department, and in-kind contributions of the participants. We gratefully acknowledge and thank the Water Research Foundation and all of the sponsors for their financial, technical, and administrative assistance in funding the project through which this information was discovered.

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Authors and Affiliations

  1. Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, 30602, USA

    Narendrababu Kolisetty, Srinivasa Muralidhara & Brian S. Cummings

  2. School of Medicine, University of Utah, Salt Lake City, UT, 84132, USA

    Don A. Delker

  3. MoBull Consulting, Richland, WA, 99352, USA

    Richard J. Bull

  4. Joseph Cotruvo and Associates, LLC, Washington, DC, 20016, USA

    Joseph A. Cotruvo

  5. National Center for Toxicological Research, FDA, Jefferson, AR, 72079, USA

    Jeff W. Fisher

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  1. Narendrababu Kolisetty
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  2. Don A. Delker
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  7. Brian S. Cummings
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Correspondence to Brian S. Cummings.

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Disclaimer: This document has been reviewed in accordance with United States Food and Drug Administration (FDA) policy and approved for publication. Approval does not signify that the contents necessarily reflect the position or opinions of the FDA nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the FDA.

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Kolisetty, N., Delker, D.A., Muralidhara, S. et al. Changes in mRNA and protein expression in the renal cortex of male and female F344 rats treated with bromate. Arch Toxicol 87, 1911–1925 (2013). https://doi.org/10.1007/s00204-013-1052-2

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  • DOI: https://doi.org/10.1007/s00204-013-1052-2

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