title: Cellular mechanism of the nonmonotonic dose response of bisphenol A in rat cardiac myocytes.
abstract: BACKGROUND
  The need for mechanistic understanding of nonmonotonic dose responses has been identified as one of the major data gaps in the study of bisphenol A (BPA). Previously we reported that acute exposure to BPA promotes arrhythmogenesis in female hearts through alteration of myocyte Ca(2+) handling, and that the dose response of BPA was inverted U-shaped.
  
  
  OBJECTIVE
  We sought to define the cellular mechanism underlying the nonmonotonic dose response of BPA in the heart.
  
  
  METHODS
  We examined rapid effects of BPA in female rat ventricular myocytes using video-edge detection, confocal and conventional fluorescence imaging, and patch clamp.
  
  
  RESULTS
  The rapid effects of BPA in cardiac myocytes, as measured by multiple end points, including development of arrhythmic activities, myocyte mechanics, and Ca(2+) transient, were characterized by nonmonotonic dose responses. Interestingly, the effects of BPA on individual processes of myocyte Ca(2+) handling were monotonic. Over the concentration range of 10(-12) to 10(-6) M, BPA progressively increased sarcoplasmic reticulum (SR) Ca(2+) release and Ca(2+) reuptake and inhibited the L-type Ca(2+) current (I(CaL)). These effects on myocyte Ca(2+) handling were mediated by estrogen receptor (ER) β signaling. The nonmonotonic dose responses of BPA can be accounted for by the combined effects of progressively increased SR Ca(2+) reuptake/release and decreased Ca(2+) influx through I(CaL).
  
  
  CONCLUSIONS
  The rapid effects of BPA on female rat cardiac myocytes are characterized by nonmonotonic dose responses as measured by multiple end points. The nonmonotonic dose response was produced by ERβ-mediated monotonic effects on multiple cellular Ca(2+) handling processes. This represents a distinct mechanism underlying the nonmonotonicity of BPA's actions.
authors.affiliation: Department of Cardiology, Second Affiliated Hospital of Nanchang University, Nanchang, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Liang
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Gao
authors.forename: Yamei
authors.initials: Y
authors.lastname: Chen
authors.forename: Kui
authors.initials: K
authors.lastname: Hong
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000633:toxicity*; D020013:Calcium Signaling / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010636:Phenols / Q000633:toxicity*; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D047629:Estrogen Receptor beta; D010636:Phenols; C006780:bisphenol A; D000098826:Bisphenol A Compounds