Ryanodine receptor type 2: A molecular target for dichlorodiphenyltrichloroethane- And dichlorodiphenyldichloroethylene-mediated cardiotoxicity

Kim M. Truong, Wei Feng, Isaac N. Pessah

Research output: Contribution to journalArticlepeer-review

Abstract

Dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyl-dichloroethylene (DDE) are ubiquitously found in the environment and linked to cardiovascular diseases-with a majority of the work focused on hypertension. Studies investigating whether DDx can interact with molecular targets on cardiac tissue to directly affect cardiac function are lacking. Therefore, we investigated whether o,p0-DDT, p,p0-DDT, o,p0-DDE, or p,p0-DDE (DDx, collectively) can directly alter the function of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) by assessing their effect(s) on hiPSC-CMs Ca dynamics. DDx (0.1-10 mM) affected hiPSC-CMs synchronous Ca oscillation frequency in a concentration-dependent manner, with p,p0-DDT and p,p0-DDE also decreasing Ca stores. HEK-RyR2 cells cultured under antibiotic selection to induce expression of wild-type mouse ryanodine receptor type 2 (RyR2) are used to further investigate whether DDx alters hiPSC-CMs Ca dynamics through engagement with RyR2, a protein critical for cardiac muscle excitation-contraction coupling (ECC). Acute treatment with 10 mM DDx failed to induce Ca release in HEK293-RyR2, whereas pretreatment with DDx (0.1-10 mM) for 12- or 24-h significantly decreased sarcoplasmic reticulum Ca stores in HEK-RyR2 cells challenged with caffeine (1 mM), an RyR agonist. [3H]ryanodine-binding analysis using murine cardiac RyR2 homogenates further confirmed that all DDx isomers (10 mM) can directly engage with RyR2 to favor an open (leaky) confirmation, whereas only the DDT isomers (10 mM) modestly (10%) inhibited SERCA2a activity. The data demonstrate that DDx increases heart rate and depletes Ca stores in human cardiomyocytes through a mechanism that impairs RyR2 function and Ca dynamics. Impact Statement: DDT/DDE interactions with RyR2 alter cardiomyocyte Ca dynamics that may contribute to adverse cardiovascular outcomes associated with exposures.

Original languageEnglish (US)
Pages (from-to)159-172
Number of pages14
JournalToxicological Sciences
Volume178
Issue number1
DOIs
StatePublished - Nov 1 2020

Keywords

  • Cardiovascular disease
  • DDE
  • DDT
  • Human iPSC-derived cardiomyocytes
  • Organochlorines
  • Ryanodine receptor

ASJC Scopus subject areas

  • Toxicology

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