From the Cover: Lifelong Exposure of C57bl/6n Male Mice to Bisphenol A or Bisphenol S Reduces Recovery From a Myocardial Infarction

Abstract

Bisphenol A (BPA) leaches from plastics to contaminate foodstuffs. Analogs, such as bisphenol S (BPS), are now used increasingly in manufacturing. Greater BPA exposure has been correlated with exacerbation of cardiovascular disease, including myocardial infarction (MI). To test the hypothesis that bisphenol exposure impairs cardiac healing, we exposed C57bl/6n mice to water containing 25ng/ml BPA or BPS from conception and surgically induced an MI in adult male progeny. Increased early death and cardiac dilation, and reduced cardiac function were found post-MI in BPA- and BPS-exposed mice. Flow cytometry revealed increased monocyte and macrophage infiltration that correlated with increased chemokine C-C motif ligand-2 expression in the infarct. In vitro BPA and BPS addition increased matrix metalloproteinase-9 (MMP) protein and secreted activity in RAW264.7 macrophage cells suggesting that invivo increases in MMP2 and MMP9 in exposed infarcts were myeloid-derived. Bone marrow-derived monocytes isolated from exposed mice had greater expression of pro-inflammatory polarization markers when chemokine stimulated indicating an enhanced susceptibility to develop a pro-inflammatory monocyte population. Chronic BPA exposure of estrogen receptor beta (ERβ) deficient mice did not worsen early death, cardiac structure/function, or expression of myeloid markers after an MI. In contrast, BPS exposure of ERβ-deficient mice resulted in greater death and expression of myeloid markers. We conclude that lifelong exposure to BPA or BPS augmented the monocyte/macrophage inflammatory response and adverse remodeling from an MI thereby reducing the ability to survive and successfully recover, and that the adverse effect of BPA, but not BPS, is downstream of ERβ signaling.

Bisphenol A induces coronary endothelial cell necroptosis by activating RIP3/CamKII dependent pathway

“…The presence of CCR2 + macrophages, together with reduced myocardial vascularization, may be indicative of defective reparative processes. In agreement with our results, chronic administration of BPA or its substitute, Bisphenol S (BPS), can reduce active cardiac remodeling in response to myocardial infarction, increasing metalloproteinase (MMP) expression in male mice 12 . Moreover, the exposure of resting monocytes to BPA increased polarization to activated macrophages 64 .…”

“…Recently, it has been reported that a life long exposure to BPA in rodents produces arrhythmogenic effects 11 . Moreover, it has been demonstrated that acute or chronic exposure to BPA, impaired functional recovery after myocardial infarction due to a reduced ability to induce macrophage polarization from proinflammatory to a reparative state 12,13 . Indeed, there is an increasing concern about BPA higher bioaccumulation in developing organisms and special vulnerable populations such cell cultures.…”

BPA Alters Estrogen Receptor Expression in the Heart After Viral Infection Activating Cardiac Mast Cells and T Cells Leading to Perimyocarditis and Fibrosis

“…BPA preferentially binds ERβ over ERα but the metabolized forms of BPA, such as BPA glucuronide, do not bind the ERs (28). Epidemiological and animal data indicate that increased exposure to BPA worsens cardiovascular diseases including hypertension (31–33), atherosclerosis (34–36), myocardial infarct (37), arrhythmias (13, 14), and DCM (38). To our knowledge, no one has examined the role of BPA on myocarditis.…”

Bisphenol S rapidly depresses heart function through estrogen receptor-β and decreases phospholamban phosphorylation in a sex-dependent manner

“…13 who suggested a conflict of interest in the form of chemical industry funding. In mouse models of myocardial infarctions several studies found chronic BPA exposure worsened outcomes 14–16 . Furthermore, laboratory animal studies consistently show acute 5,17 and life-long 18,19 exposure of BPA at doses within the ranges seen in human populations has pro-arrhythmic effects.…”

“…A study examining individuals from the United States and 7 Asian countries detected BPS in 81% of urine samples with an average concentration of 2.6 nM, suggesting widespread exposure 23 . Of significant concern is the finding that acute BPS exposure shows a similar pro-arrhythmic effect 21 and impairment of post-myocardial infarction recovery 14 as BPA. Chronic exposure of BPS to zebrafish larvae induce developmental deformities in a number of organs including the heart 24,25 .…”