es8b04281_si_002.xlsx (373.22 kB)
Cardiovascular Effects and Molecular Mechanisms of Bisphenol A and Its Metabolite MBP in Zebrafish
dataset
posted on 2018-12-06, 00:00 authored by A. Ross Brown, Jon M. Green, John Moreman, Lina M. Gunnarsson, Sulayman Mourabit, Jonathan Ball, Matthew J. Winter, Maciej Trznadel, Ana Correia, Christian Hacker, Alexis Perry, Mark E. Wood, Malcolm J. Hetheridge, Richard A. Currie, Charles R. TylerThe 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.