Endocrine-disrupting chemicals affect Sertoli TM4 cell functionality through dysregulation of gap junctional intercellular communication in vitro

• Published in: Food and chemical toxicology Vol. 164; p. 113004
• Main Authors: Yawer, Affiefa, Sychrová, Eliška, Raška, Jan, Babica, Pavel, Sovadinová, Iva
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-06-2022
• Subjects: Connexins; Endocrine-disrupting chemicals; Gap junctional intercellular communication; Reproductive toxicity; Sertoli cells; Testicular tumors; Connexins; Endocrine-disrupting chemicals; Gap junctional intercellular communication; Testicular tumors; Reproductive toxicity; Sertoli cells
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2022.113004

The frequencies of adverse outcomes associated with male reproductive health, including infertility and testicular cancer, are increasing. These adverse trends are partially attributed to increased exposure to environmental agents such as endocrine-disrupting chemicals (EDCs). This study addresses effects on EDCs on adjacent prepubertal Sertoli TM4 cells, specifically on 1) testicular gap junctional intercellular communication (GJIC), one of the hallmarks of non-genotoxic carcinogenicity, 2) GJIC building blocks connexins (Cx), and 3) mitogen-activated protein kinases MAPKs. We selected eight representatives of EDCs: organochlorine chemicals such as pesticides dichlorodiphenyltrichloroethane, lindane, methoxychlor, and vinclozolin, industrial chemicals bisphenol A and 2,2′,4,4′,5,5′-hexachlorobiphenyl, and components of personal care products, triclocarban and triclosan. EDCs rapidly dysregulated GJIC in Sertoli TM4 cells mainly via MAPK p38 and/or Erk1/2 pathways by the intermediate hyper- or de-phosphorylation of Cx43 (Ser368, Ser282) and translocation of Cx43 from the plasma membrane, suggesting disturbed intracellular trafficking of Cx43 protein. Surprisingly, EDCs did not rapidly activate MAPK Erk1/2 or p38; on the contrary, TCC and TCS decreased their activity (phosphorylation). Our results indicate that EDCs might disrupt testicular homeostasis and development via testicular GJIC, junctional and non-junctional functions of Cx43 and MAPK-signaling pathways in Sertoli cells.
•Various EDCs rapidly dysregulated testicular GJIC in Sertoli TM4 cells in vitro.•EDCs rapidly induced aberrant Cx43 localization and phosphorylation pattern.•EDCs interacted with MAPK Erk1/2 and p38 signaling pathways.•EDCs might contribute to testicular cancer development via GJIC dysregulation.