Chronic Exposure to Bisphenol A Reduces Successful Cardiac Remodeling After an Experimental Myocardial Infarction in Male C57bl/6n Mice.

Estrogenic compounds such as bisphenol A (BPA) leach from plastics into food and beverage containers. Increased BPA exposure has been correlated with increased cardiovascular disease. To test the hypothesis that increased BPA exposure reduces cardiovascular remodeling, we chronically exposed C57bl/6n male mice to BPA and performed a myocardial infarction (MI). We measured cardiac function, as well as myeloid and cardiac fibroblast accumulation and activity. We found increased early death as well as increased cardiac dilation and reduced cardiac function in surviving BPA-exposed mice. Matrix metalloproteinase-2 (MMP2) protein and activity were increased 1.5-fold in BPA-exposed heart. BPA-exposed mice had similar neutrophil infiltration; however, monocyte and macrophage (MΦ) infiltration into the ischemic area was 5-fold greater than VEH mice potentially due to a 2-fold increase in monocyte chemoattractant protein-1. Monocyte and MΦ exposure to BPA in vitro in primary bone marrow cultures or in isolated peritoneal MΦ increased polarization to an activated MΦ, increased MMP2 and MMP9 expression 2-fold and activity 3-fold, and increased uptake of microspheres 3-fold. Cardiac fibroblasts (CF) differentiate to α-smooth muscle actin (αSMA) expressing myofibroblasts, migrate to the ischemic area and secrete collagen to strengthen the scar. Collagen and αSMA expression were reduced 50% in BPA-exposed hearts. Chronic in vivo or continuous in vitro BPA exposure ablated transforming growth factor beta-mediated differentiation of CF, reduced αSMA expression 50% and reduced migration 40% yet increased secreted MMP2 activity 2-fold. We conclude that chronic BPA exposure reduces the ability to successfully remodel after an MI by increasing MΦ-based inflammation and reducing myofibroblast repair function.

Sex-specific cardiovascular responses to control or high fat diet feeding in C57bl/6 mice chronically exposed to bisphenol A.

The increased pericardial fat which often accompanies overall obesity is thought to alter cardiac structure/function and increase the risk for atrial fibrillation. We hypothesized that chronic exposure to bisphenol A (BPA) would induce pericardial fat, cardiac hypertrophy or arrhythmia. C57bl/6n dams were exposed to BPA (25 ng/ml drinking water) beginning on gestation day 11 and progeny continued on 2.5 ng BPA/ml drinking water. The progeny of control dams (VEH) and dams treated with diethylstilbestrol (DES, 1 µg/kg/day, gestation days 11â¿¿14) had tap water. After weaning progeny were fed either a control (CD) or high fat diet (HFD) for 3 months. Pericardial fat was present in CD-BPA and CD-DES and not CD-VEH mice, and was increased in all HFD mice. Catecholamine challenge revealed no differences in males, but BPA-exposed females had longer P-wave and QRS complex duration. Only CD-BPA and CD-DES females developed cardiac hypertrophy which was independent of increased blood pressure. Calcium homeostasis protein expression changes in HFD-BPA and HFD-DES mice predict reduced SERCA2 activity in males and increased SERCA2 activity in females. Thus, chronic BPA exposure induced pericardial fat in the absence of HFD, and female-specific changes in cardiac hypertrophy development and cardiac electrical conduction after a catecholamine challenge.

Metabolic response to chronic bisphenol A exposure in C57bl/6n mice.

Fetal/neonatal exposure to the endocrine disruptor bisphenol A (BPA) has induced obesity and increased glucose intolerance. We hypothesized that chronic BPA exposure would worsen the obesity and glucose intolerance induced by a high fat diet (HFD). The drinking water of C57bl/6n dams was treated with vehicle (VEH) or BPA (25 ng/ml) from gestation day 11.5 to postnatal day 21. Another group was treated with oral diethylstilbestrol (DES, 1 µg/kg/day) during gestation. Progeny were treated with VEH (VEH and DES groups) or BPA (2.5 ng/ml) in the drinking water and fed either a control diet (CD) or HFD from weaning until euthanasia at 4 months of age. CD-fed mice were similar in size; however HFD-BPA males and HFD-DES mice were smaller than HFD-VEH mice. No CD-fed mice were glucose intolerant. All HFD-fed mice were glucose intolerant. Cholesterol and triglyceride were increased in HFD-VEH mice and HFD-BPA males. Total fat weight and adipocyte area were similar in HFD-VEH and HFD-BPA mice and reduced in HFD-DES mice. HFD-BPA females increased perirenal and reduced gonadal fat weights. Reduced leptin and increased IL-6 in CD-BPA and CD-DES mice were not found in their HFD-cohorts. Adiponectin levels were similar. Thus, although chronic BPA exposure did not increase body size or increase glucose intolerance, it induced an adipokine imbalance in CD-fed mice and sex-specifically altered the lipid response and adipose deposition when fed the HFD.

Lifelong exposure to bisphenol a alters cardiac structure/function, protein expression, and DNA methylation in adult mice.

Bisphenol A (BPA) is an estrogenizing endocrine disruptor compound of concern. Our objective was to test whether lifelong BPA would impact cardiac structure/function, calcium homeostasis protein expression, and the DNA methylation of cardiac genes. We delivered 0.5 and 5.0 µg/kg/day BPA lifelong from gestation day 11 or 200 µg/kg/day from gestation day 11 to postnatal day 21 via the drinking water to C57bl/6n mice. BPA 5.0 males and females had increased body weight, body mass index, body surface area, and adiposity. Echocardiography identified concentric remodeling in all BPA-treated males. Systolic and diastolic cardiac functions were essentially similar, but lifelong BPA enhanced male and reduced female sex-specific differences in velocity of circumferential shortening and ascending aorta velocity time integral. Diastolic blood pressure was increased in all BPA females. The calcium homeostasis proteins sarcoendoplasmic reticulum ATPase 2a (SERCA2a), sodium calcium exchanger-1, phospholamban (PLB), phospho-PLB, and calsequestrin 2 are important for contraction and relaxation. Changes in their expression suggest increased calcium mobility in males and reduced calcium mobility in females supporting the cardiac function changes. DNA methyltransferase 3a expression was increased in all BPA males and BPA 0.5 females and reduced in BPA 200 females. Global DNA methylation was increased in BPA 0.5 males and reduced in BPA 0.5 females. BPA induced sex-specific altered DNA methylation in specific CpG pairs in the calsequestrin 2 CpG island. These results suggest that continual exposure to BPA impacts cardiac structure/function, protein expression, and epigenetic DNA methylation marks in males and females.