Estrogenic Mechanisms and Cardiac Responses Following Early Life Exposure to Bisphenol A (BPA) and Its Metabolite 4-Methyl-2,4-bis(p-hydroxyphenyl)pent-1-ene (MBP) in Zebrafish

Abstract

Environmental exposure to Bisphenol A (BPA) has been associated with a range of adverse health effects, including on the cardiovascular system in humans. Lack of agreement on its mechanism(s) of action likely stem from comparisons between in vivo and in vitro test systems and potential multiple effects pathways. In rodents, in vivo, metabolic activation of BPA produces 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), which is reported to be up to 1000 times more potent as an estrogen than BPA. We investigated the estrogenic effects and estrogen receptor signaling pathway(s) of BPA and MBP following early life exposure using a transgenic, estrogen responsive (ERE-TG) zebrafish and a targeted morpholino approach to knockdown the three fish estrogen receptor (ER) subtypes. The functional consequences of BPA exposure on the cardiovascular system of zebrafish larvae were also examined. The heart atrioventricular valves and the bulbus arteriosus were primary target tissues for both BPA and MBP in the ERE-TG zebrafish, and MBP was approximately 1000-fold more potent than BPA as an estrogen in these tissues. Estrogen receptor knockdown with morpholinos indicated that the estrogenic responses in the heart for both BPA and MBP were mediated via an estrogen receptor 1 (esr1) dependent pathway. At the highest BPA concentration tested (2500 μg/L), alterations in the atrial:ventricular beat ratio indicated a functional impact on the heart of 5 days post fertilization (dpf) larvae, and there was also a significantly reduced heart rate in these larvae at 14 dpf. Our findings indicate that some of the reported adverse effects on heart function associated with BPA exposure (in mammals) may act through an estrogenic mechanism, but that fish are unlikely to be susceptible to adverse effects on heart development for environmentally relevant exposures.

Transforming Waste Poly(Ethylene Terephthalate) into Nitrogen Doped Carbon Nanotubes and Its Utility in Oxygen Reduction Reaction and Bisphenol-A Removal from Contaminated Water

“…An EDC is a chemical that imitates biological activity of natural hormones and occupies the hormone receptors, and because its weak estrogen-like effect interfere with the metabolic processes of natural hormones especially in females thereby posing a considerable risk to reproductivity in humans. Besides due to the biochemical activity of liver, BPA is converted to 4-methyl-2,4-bis(4-hydroxyphenyl) pent-1-ene (MBP) which has 1000-fold stronger binding affinity to endocrine receptors compared to BPA [ 43 ]. Though many techniques like adsorption, ion-exchange, membrane, oxidation, etc.…”

Repeated Exposure to 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), an Active Metabolite of Bisphenol A, Aggressively Stimulates Breast Cancer Cell Growth in an Estrogen Receptor β (ERβ)–Dependent Manner

“…that the estrogenic activity of MBP was approximately 500fold more potent than that of BPA in in vivo experiments performed in ovariectomized Wistar rats (Okuda et al, 2010). In addition, potent estrogenic effects were observed in experiments on medaka (Oryzias latipes) and zebrafish, in which MBP exhibited approximately 250-fold and 1000-fold stronger estrogenic activity than did BPA (Ishibashi et al, 2005;Moreman et al, 2018). As mentioned above, MBP is thought to be a key candidate for resolving the difference of in vitro and in vivo effects of BPA.…”

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

“…39 Furthermore, 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 ( vtg1 , vtg2 ) gene and protein expression in medaka ( Oryzias latipes ) (×250–400); 42,43 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 BPA and its analogues and metabolites.…”

“…45 Spatial and temporal resolution of key molecular events in TG zebrafish can facilitate the detection of chemical effects throughout the body in vivo, in real time 45−49 and can help establish causal links with subsequent adverse effects on biological development and/or function. 39,44 Here we exploit TG(ERE:GFP)Casper zebrafish to study the effects of BPA and its highly estrogenic metabolite MBP on cardiovascular (CV) development and function, building on previous work using this model, which highlighted the heart, and heart valves in particular, as being key targets for these compounds. 39,44,47,48…”