Abstract
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.
Highlights
(45%) are estrogenic, that is, estrogen receptor (ER) and/or estrogen-related receptor (ERR) agonists.[6−8] Estrogens play a fundamental role in the formation and function of numerous organs and systems[9] and imbalances are known to increase risks of cancers and disorders of reproductive, nervous, metabolic, immune, and cardiovascular systems in various animal models and humans.[10−14] linking cause and effect remains a major challenge in chemical risk/safety assessment
Environmental Science & Technology gene and protein expression in medaka (Oryzias latipes) (×250−400);[42,43] Estrogen Response Element (ERE) activation in zebrafish (Danio rerio) (×1000) via esr1.44 These findings indicate an urgent need for more integrative test systems capable of evaluating multiple effect levels, linking key molecular events and adverse outcomes for chemicals like Bisphenol A (BPA) and its analogues and metabolites
Mean measured bioconcentration factors for BPA were 5 day BCFwhole body = 2.5 and 3.8 for 100 and 1000 μg/L BPA exposures, respectively, corresponding with whole body concentrations of ∼250 and ∼3700 ng/g, which are equivalent to ×2.5 and ×37 maximum human maternal-fetal-placental unit concentrations of 105 ng/g
Summary
Over 1400 chemicals have been identified as potential endocrine disrupting chemicals (EDCs)[1] with potential to “alter function(s) of the endocrine system and cause adverse health effects in an intact organism, or its progeny, or (sub)populations”.2−5 Over 100 of these chemicals are regarded internationally as priority EDCs and almost half (45%) are estrogenic, that is, estrogen receptor (ER) and/or estrogen-related receptor (ERR) agonists.[6−8] Estrogens play a fundamental role in the formation and function of numerous organs and systems[9] and imbalances are known to increase risks of cancers and disorders of reproductive, nervous, metabolic, immune, and cardiovascular systems in various animal models and humans.[10−14] linking cause and effect remains a major challenge in chemical risk/safety assessment. Bisphenol A (BPA) is associated with the above disorders and is one of the world’s highest production volume chemicals,[15] to which humans are continually exposed via plastic and other products.[16−23] Reported BPA-effect mechanisms include agonism of nuclear ERs,[24] ERRs,[25,26] membrane ERs,[27,28] epigenetic modulation of estrogen response elements (EREs)[29,30] and weak agonism of androgen and thyroid (T3). The reactive BPA metabolite 4-methyl-2,4-bis(p-hydroxyphenyl)pent-1-ene (MBP) has been shown to be far more potent than the parent BPA in terms of: estrogen receptor binding and activation in vitro (×10−1000);[40] stimulation of uterine growth in rats (×500);[41] elevated estrogen receptor (esr1) and vitellogenin
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