Methoxychlor and Vinclozolin Induce Rapid Changes in Intercellular and Intracellular Signaling in Liver Progenitor Cells
| Autor: | James E. Trosko, Maxwell J. Mianecki, Esha Kumar, Pavel Babica, Rimma Zurabian, Joon Suk Park, Libor Jaša, Brad L. Upham, Rajus Chopra |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Insecticides medicine.medical_specialty Cell signaling MAP Kinase Signaling System p38 mitogen-activated protein kinases Cell Communication Biology Resveratrol Toxicology p38 Mitogen-Activated Protein Kinases Cell Line 03 medical and health sciences chemistry.chemical_compound Internal medicine medicine Animals Vinclozolin Oxazoles Stem Cells Gap Junctions Rats Inbred F344 Epigenetic Changes in Liver Progenitor Cells by Methoxychlor and Vinclozolin Rats Cell biology Androgen receptor 030104 developmental biology Endocrinology Liver Methoxychlor Receptors Estrogen chemistry Receptors Androgen Connexin 43 Signal transduction Intracellular Signal Transduction |
| Zdroj: | Toxicological Sciences. 153:174-185 |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfw114 |
| Popis: | 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 µM for MXC and 126 µM 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. |
| Databáze: | OpenAIRE |
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