| Abstrakt: |
Pediatric intensive care and cardiac surgery patients are subjected to high concentrations of bisphenol-a (BPA), a chemical used in plastic medical products. Due to health concerns, structural analogues are being explored as replacements for BPA. This study aimed to compare the effects of BPA, BPS (bisphenol-s) and BPF (bisphenol-f) using the comprehensive in vitro proarrhythmia assay (CiPA) and in silico modeling. Whole-cell voltage clamp recordings were performed on cell lines transfected with Nav1.5, hERG, or Cav1.2 to generate cardiac currents (fast and late sodium, potassium, calcium). Currents were evoked and recorded before and after exposure to BPA, BPS or BPF. Current amplitude after chemical treatment was divided by the stable current amplitude in controls to calculate fractional block; the latter was plotted against concentration to generate a half-maximal inhibitory concentration (IC50). In silico modeling was performed using simulated human ventricular action potentials using the computed IC50. L-type calcium current was the most sensitive with an IC50of 30.8 ?M (BPA), 76 ?M (BPF) and 333 ?M (BPS). Of the two sodium currents tested, late sodium was more sensitive with IC50of 23.6 ?M (BPA), 100 ?M (BPF) and 369 ?M (BPS), whereas fast sodium inhibition was observed at 55.3 ?M (BPA), 232 ?M (BPF) and 1090 ?M (BPS). hERG inhibition was observed at IC50of 127 ?M (BPA), 209 ?M (BPA) and 633 ?M (BPS). In silico modeling revealed an 8-60% decrease in dV/dt after BPA exposure (10-100 ?M), and modest 11% increase in action potential duration (100 ?M). No difference in action potential morphology was observed with BPS or BPF. Results demonstrate that BPA analogues are safer alternatives given the minimal effects on ion channel currents. Although the inhibitory effects of BPA on calcium and hERG channels only partly explain our previously published data, which included slowed atrioventricular conduction, prolonged effective refractory period and decreased inotropy beginning at low nanomolar BPA concentrations. Additional testing is needed to quantify the risk of plastic exposure to vulnerable populations, including pediatric cardiology and cardiac surgery patients, since myocardial immaturity and perioperative injury may exacerbate such effects. |
