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Article

Structure-Dependent Effects of Phthalates on Intercellular and Intracellular Communication in Liver Oval Cells

1
RECETOX, Faculty of Science, Masaryk University, Kamenice 753/5, Pavilion A29, 625 00 Brno, Czech Republic
2
Department of Experimental Phycology and Ecotoxicology, Institute of Botany of the Czech Academy of Sciences, Lidická 25/27, 602 00 Brno, Czech Republic
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(17), 6069; https://doi.org/10.3390/ijms21176069
Received: 29 July 2020 / Revised: 17 August 2020 / Accepted: 20 August 2020 / Published: 23 August 2020
(This article belongs to the Special Issue Connexin and Pannexin Signaling in Health and Disease)
Humans are exposed to phthalates released from plastics, cosmetics, or food on a daily basis. Phthalates have low acute liver toxicity, but their chronic exposures could induce molecular and cellular effects linked to adverse health outcomes, such as liver tumor promotion or chronic liver diseases. The alternation of gap junctional intercellular communication (GJIC) and MAPK-Erk1/2 pathways in liver progenitor or oval cells can disrupt liver tissue homeostatic mechanisms and affect the development and severity of these adverse outcomes. Our study with 20 different phthalates revealed their structurally dependent effects on liver GJIC and MAPK-Erk1/2 signaling in rat liver WB-F344 cell line with characteristics of liver oval cells. The phthalates with a medium-length side chain (3–6 C) were the most potent dysregulators of GJIC and activators of MAPK-Erk1/2. The effects occurred rapidly, suggesting the activation of non-genomic (non-transcriptional) mechanisms directly by the parental compounds. Short-chain phthalates (1–2 C) did not dysregulate GJIC even after longer exposures and did not activate MAPK-Erk1/2. Longer chain (≥7 C) phthalates, such as DEHP or DINP, moderately activated MAPK-Erk1/2, but inhibited GJIC only after prolonged exposures (>12 h), suggesting that GJIC dysregulation occurs via genomic mechanisms, or (bio)transformation. Overall, medium-chain phthalates rapidly affected the key tissue homeostatic mechanisms in the liver oval cell population via non-genomic pathways, which might contribute to the development of chronic liver toxicity and diseases. View Full-Text
Keywords: gap junctional intercellular communication; gap junctions; hepatotoxicity; MAP-kinases Erk1/2 activation; non-genomic mechanism; oval cells; phthalates; progenitor cells gap junctional intercellular communication; gap junctions; hepatotoxicity; MAP-kinases Erk1/2 activation; non-genomic mechanism; oval cells; phthalates; progenitor cells
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MDPI and ACS Style

Čtveráčková, L.; Jančula, D.; Raška, J.; Babica, P.; Sovadinová, I. Structure-Dependent Effects of Phthalates on Intercellular and Intracellular Communication in Liver Oval Cells. Int. J. Mol. Sci. 2020, 21, 6069. https://doi.org/10.3390/ijms21176069

AMA Style

Čtveráčková L, Jančula D, Raška J, Babica P, Sovadinová I. Structure-Dependent Effects of Phthalates on Intercellular and Intracellular Communication in Liver Oval Cells. International Journal of Molecular Sciences. 2020; 21(17):6069. https://doi.org/10.3390/ijms21176069

Chicago/Turabian Style

Čtveráčková, Lucie, Daniel Jančula, Jan Raška, Pavel Babica, and Iva Sovadinová. 2020. "Structure-Dependent Effects of Phthalates on Intercellular and Intracellular Communication in Liver Oval Cells" International Journal of Molecular Sciences 21, no. 17: 6069. https://doi.org/10.3390/ijms21176069

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