Methoxychlor and Vinclozolin Induce Rapid Changes in
Intercellular and Intracellular Signaling in Liver Progenitor
Cells

J 2016

Methoxychlor and Vinclozolin Induce Rapid Changes in Intercellular and Intracellular Signaling in Liver Progenitor Cells

BABICA, Pavel, Rimma ZURABIAN, Esha R. KUMAR, Rajus CHOPRA, Maxwell J. MIANECKI et. al.

Basic information

Original name

Methoxychlor and Vinclozolin Induce Rapid Changes in Intercellular and Intracellular Signaling in Liver Progenitor Cells

Authors

BABICA, Pavel (203 Czech Republic, guarantor, belonging to the institution), Rimma ZURABIAN (840 United States of America), Esha R. KUMAR (840 United States of America), Rajus CHOPRA (840 United States of America), Maxwell J. MIANECKI (840 United States of America), Joon-Suk PARK (410 Republic of Korea), Libor JAŠA (203 Czech Republic, belonging to the institution), James E. TROSKO (840 United States of America) and Brad L. UPHAM (840 United States of America)

Edition

Toxicological sciences, OXFORD, OXFORD UNIV PRESS, 2016, 1096-6080

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30304 Public and environmental health

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 4.081

RIV identification code

RIV/00216224:14310/16:00093526

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1093/toxsci/kfw114

UT WoS

000386475700016

Keywords in English

gap junctional intercellular communication; endocrine disruptors; mitogen-activated protein kinases; phosphatidylcholine-specific phospholipase C; epigenetic toxicity; non-genomic signaling

Abstract

V originále

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.

Links

LM2015051, research and development project

Name: Centrum pro výzkum toxických látek v prostředí (Acronym: RECETOX RI)

Investor: Ministry of Education, Youth and Sports of the CR

LO1214, research and development project

Name: Centrum pro výzkum toxických látek v prostředí (Acronym: RECETOX)

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

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. Toxicological sciences. OXFORD: OXFORD UNIV PRESS, 2016, vol. 153, No 1, p. 174-185. ISSN 1096-6080. Available from: https://dx.doi.org/10.1093/toxsci/kfw114.

@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, 2016, vol.~153, No~1, p.~174-185. ISSN~1096-6080. Available from: https://dx.doi.org/10.1093/toxsci/kfw114.

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