Cardiovascular Effects and Molecular Mechanisms of Bisphenol A and Its Metabolite MBP in Zebrafish

• Published in: Environmental science & technology Vol. 53; no. 1; pp. 463 - 474
• Main Authors: Brown, A. Ross, Green, Jon M, Moreman, John, Gunnarsson, Lina M, Mourabit, Sulayman, Ball, Jonathan, Winter, Matthew J, Trznadel, Maciej, Correia, Ana, Hacker, Christian, Perry, Alexis, Wood, Mark E, Hetheridge, Malcolm J, Currie, Richard A, Tyler, Charles R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02.01.2019
• Subjects: Animal models; Animals; Aortic valve; Benzhydryl Compounds; Biomarkers; Bisphenol A; Blood flow; Cardiovascular disease; Cardiovascular diseases; Cardiovascular system; Chemicals; Child; Children; Collagen; Computer simulation; Curvature; Embryos; Environmental science; Estrogens; Exposure; Extracellular matrix; Fetuses; Fluorescence; Heart; Heart valves; Histopathology; Humans; Metabolites; Molecular modelling; Organic chemistry; Phenols; Rheumatic heart disease; Structural integrity; Ventricle; Wildlife; Xenoestrogens; Zebrafish
• ISSN: 0013-936X; 1520-5851
• DOI: 10.1021/acs.est.8b04281

The plastic monomer bisphenol A (BPA) is one of the highest production volume chemicals in the world and is frequently detected in wildlife and humans, particularly children. BPA has been associated with numerous adverse health outcomes relating to its estrogenic and other hormonal properties, but direct causal links are unclear in humans and animal models. Here we simulated measured (1×) and predicted worst-case (10× ) maximum fetal exposures for BPA, or equivalent concentrations of its metabolite MBP, using fluorescent reporter embryo-larval zebrafish, capable of quantifying Estrogen Response Element (ERE) activation throughout the body. Heart valves were primary sites for ERE activation by BPA and MBP, and transcriptomic analysis of microdissected heart tissues showed that both chemicals targeted several molecular pathways constituting biomarkers for calcific aortic valve disease (CAVD), including extra-cellular matrix (ECM) alteration. ECM collagen deficiency and impact on heart valve structural integrity were confirmed by histopathology for high-level MBP exposure, and structural defects (abnormal curvature) of the atrio-ventricular valves corresponded with impaired cardiovascular function (reduced ventricular beat rate and blood flow). Our results are the first to demonstrate plausible mechanistic links between ERE activation in the heart valves by BPA’s reactive metabolite MBP and the development of valvular-cardiovascular disease states.