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@article{1372465,
author = {Babica, Pavel and Zurabian, Rimma and Kumar, Esha R. and Chopra, Rajus and Mianecki, Maxwell J. and Park, JoonandSuk and Jaša, Libor and Trosko, James E. and Upham, Brad L.},
article_location = {OXFORD},
article_number = {1},
doi = {http://dx.doi.org/10.1093/toxsci/kfw114},
keywords = {gap junctional intercellular communication; endocrine disruptors; mitogen-activated protein kinases; phosphatidylcholine-specific phospholipase C; epigenetic toxicity; non-genomic signaling},
language = {eng},
issn = {1096-6080},
journal = {Toxicological sciences},
title = {Methoxychlor and Vinclozolin Induce Rapid Changes in Intercellular and Intracellular Signaling in Liver Progenitor Cells},
url = {https://academic.oup.com/toxsci/article-abstract/153/1/174/2223882/Methoxychlor-and-Vinclozolin-Induce-Rapid-Changes?redirectedFrom=fulltext},
volume = {153},
year = {2016}
}
TY - JOUR
ID - 1372465
AU - Babica, Pavel - Zurabian, Rimma - Kumar, Esha R. - Chopra, Rajus - Mianecki, Maxwell J. - Park, Joon-Suk - Jaša, Libor - Trosko, James E. - Upham, Brad L.
PY - 2016
TI - Methoxychlor and Vinclozolin Induce Rapid Changes in Intercellular and Intracellular Signaling in Liver Progenitor Cells
JF - Toxicological sciences
VL - 153
IS - 1
SP - 174-185
EP - 174-185
PB - OXFORD UNIV PRESS
SN - 10966080
KW - gap junctional intercellular communication
KW - endocrine disruptors
KW - mitogen-activated protein kinases
KW - phosphatidylcholine-specific phospholipase C
KW - epigenetic toxicity
KW - non-genomic signaling
UR - https://academic.oup.com/toxsci/article-abstract/153/1/174/2223882/Methoxychlor-and-Vinclozolin-Induce-Rapid-Changes?redirectedFrom=fulltext
L2 - https://academic.oup.com/toxsci/article-abstract/153/1/174/2223882/Methoxychlor-and-Vinclozolin-Induce-Rapid-Changes?redirectedFrom=fulltext
N2 - Methoxychlor (MXC) and vinclozolin (VIN) are well-recognized endocrine disrupting chemicals known to alter epigenetic regulations and transgenerational inheritance; however, non-endocrine disruption endpoints are also important. Thus, we determined the effects of MXC and VIN on the dysregulation of gap junctional intercellular communication (GJIC) and activation of mitogen-activated protein kinases (MAPKs) in WB-F344 rat liver epithelial cells. Both chemicals induced a rapid dysregulation of GJIC at non-cytotoxic doses, with 30 min EC50 values for GJIC inhibition being 10 A mu M for MXC and 126 A mu M for VIN. MXC inhibited GJIC for at least 24 h, while VIN effects were transient and GJIC recovered after 4 h. VIN induced rapid hyperphosphorylation and internalization of gap junction protein connexin43, and both chemicals also activated MAPK ERK1/2 and p38. Effects on GJIC were not prevented by MEK1/2 inhibitor, but by an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC), resveratrol, and in the case of VIN, also, by a p38 inhibitor. Estrogen (ER) and androgen receptor (AR) modulators (estradiol, ICI 182,780, HPTE, testosterone, flutamide, VIN M2) did not attenuate MXC or VIN effects on GJIC. Our data also indicate that the effects were elicited by the parental compounds of MXC and VIN. Our study provides new evidence that MXC and VIN dysregulate GJIC via mechanisms involving rapid activation of PC-PLC occurring independently of ER- or AR-dependent genomic signaling. Such alterations of rapid intercellular and intracellular signaling events involved in regulations of gene expression, tissue development, function and homeostasis, could also contribute to transgenerational epigenetic effects of endocrine disruptors.
ER -
BABICA, Pavel, Rimma ZURABIAN, Esha R. KUMAR, Rajus CHOPRA, Maxwell J. MIANECKI, Joon-Suk PARK, Libor JAŠA, James E. TROSKO and Brad L. UPHAM. Methoxychlor and Vinclozolin Induce Rapid Changes in Intercellular and Intracellular Signaling in Liver Progenitor Cells. \textit{Toxicological sciences}. OXFORD: OXFORD UNIV PRESS, vol.~153, No~1, p.~174-185. ISSN~1096-6080. doi:10.1093/toxsci/kfw114. 2016.
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