Elucidation of the Cellular Mechanism Underlying the Nonmonotonic Dose Response of BPA in Female Hearts

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 338-354-Physiological Impacts of Endocrine Disrupting Chemicals
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-353
Qian Liang1, Xiaoqian Gao*1, Yamei Chen1 and Hong-Sheng Wang2
1University of Cincinnati, 2Department of Pharmacology and C, Cincinnati, OH
Previously we reported that rapid exposure to BPA and E2 had stimulatory effects on myocyte mechanics and arrhythmogenesis in female hearts. The dose-response curves of both BPA and E2 were found to be inverted-U shaped. Such inverted-U, or nonmonotonic dose-responses have been described for the actions of hormones and EDCs in various in vitro and in vivo systems, and have important implications for the assessment of toxicological effects of low-dose EDCs such as BPA. In the present study we examined the cellular mechanism that underlies the nonmonotonic dose response of BPA in the female heart.

The inverted-U shaped response was maintained in the presence of the ERalpha-selective blocker MPP, suggesting that the opposing actions of ERbeta (stimulatory) and ERalpha (inhibitory) do not play a major role in defining the observed concentration response characteristics. The rapid cardiac action of BPA is mediated by alterations of Ca handling, including increases in sarcoplasmic reticulum (SR) Ca reuptake and release (Yan et al, 2011). Interestingly, the effects of BPA on these individual elements of myocyte Ca handling were monotonic rather than nonmonotonic. Over the concentration range of 10-12 to 10-6 M, BPA progressively increased Ca spark frequency (an indication of SR spontaneous Ca release) and Ca transient decline rate (an indication of SR Ca reuptake rate). BPA also progressively inhibited the L-type Ca current with monotonic dose-response characteristics. At microM concentrations, such inhibition of the L-type Ca current reduces Ca influx and likely suppresses myocyte contraction and contributes to the inhibitory phase of the inverted U-shaped dose response curves. The combined and opposing effects of progressively increased SR Ca reuptake/release and decreased Ca influx likely produce the inverted-U shaped dose responses of estrogens.

In conclusion, our results suggest that the nonmonotonic dose response of BPA in the heart is the sum of multiple monotonic effects on individual Ca handling elements.

Nothing to Disclose: QL, XG, YC, HSW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by National Institute of Health grants R01-ES017262, R21-HL084539 (HSW)