Low-dose exposure to bisphenol A in combination with fructose increases expression of genes regulating angiogenesis and vascular tone in juvenile Fischer 344 rat cardiac tissue

Helén  Klint; Margareta H.  Lejonklou; Elina  Karimullina; Monika  Rönn; Lars  Lind; P. Monica  Lind; Eva  Brittebo

doi:10.1080/03009734.2016.1225870

Helén Klint Uppsala University, Department of Pharmaceutical Biosciences, SE-75124 Uppsala, Sweden
Margareta H. Lejonklou Uppsala University, Department of Medical Sciences, SE-75185 Uppsala, Sweden; http://orcid.org/0000-0002-0620-7104
Elina Karimullina University of California, Irvine, Department of Developmental and Cell Biology, Irvine, CA 92697, USA
Monika Rönn Uppsala University, Department of Medical Sciences, SE-75185 Uppsala, Sweden
Lars Lind Uppsala University, Department of Medical Sciences, SE-75185 Uppsala, Sweden
P. Monica Lind Uppsala University, Department of Medical Sciences, SE-75185 Uppsala, Sweden
Eva Brittebo Uppsala University, Department of Pharmaceutical Biosciences, SE-75124 Uppsala, Sweden http://orcid.org/0000-0002-7644-1967

DOI: https://doi.org/10.1080/03009734.2016.1225870

Keywords: Angiogenesis, bisphenol A, cardiomyocytes, cardiovascular disease, endocrine disruption, fructose, heart, vascular tone

Abstract

Objectives: Epidemiological studies report associations between exposure to the high-volume chemical and endocrine disruptor bisphenol A (BPA) and cardiovascular disorders, but there is a lack of experimental studies addressing the mechanisms of action of BPA on the cardiovascular system. In the present study, effects on markers for cardiovascular function of exposure to BPA and fructose in vivo in rat cardiac tissues, and of BPA exposure in human cardiomyocytes in vitro, were investigated.

Materials: Juvenile female Fischer 344 rats were exposed to 5, 50, and 500 μg BPA/kg bodyweight/day in their drinking water from 5 to 15 weeks of age, in combination with 5% fructose. Further, cultured human cardiomyocytes were exposed to 10 nM BPA to 1 × 10⁴ nM BPA for six hours. Expression of markers for cardiovascular function and BPA target receptors was investigated using qRT-PCR.

Results: Exposure to 5 μg BPA/kg bodyweight/day plus fructose increased mRNA expression of Vegf, Vegfr2, eNos, and Ace1 in rat heart. Exposure of human cardiomyocytes to 1 × 10⁴ nM BPA increased mRNA expression of eNOS and ACE1, as well as IL-8 and NFκβ known to regulate inflammatory response.

Conclusions:. Low-dose exposure of juvenile rats to BPA and fructose induced up-regulation of expression of genes controlling angiogenesis and vascular tone in cardiac tissues. The observed effects of BPA in rat heart were in line with our present and previous studies of BPA in human endothelial cells and cardiomyocytes. These findings may aid in understanding the mechanisms of the association between BPA exposure and cardiovascular disorders reported in epidemiological studies.

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