Toxicology

Nonylphenol Alters Connexin 43 Levels and Connexin 43 Phosphorylation Via an Inhibition of the P38-MAP Kinase Pathway

Abstract
Endocrine disrupting chemicals are exogenous compounds that mimic or inhibit the action of estrogens or other hormones. Nonylphenol, an environmental contaminant distributed along the St. Lawrence River, has been reported to act as a weak estrogen. Previous studies from our lab have shown that rats who were fed fish taken from nonylphenol contaminated sites have altered spermatogenesis and decreased sperm count. The mechanism responsible for this effect is unknown. Gap junctional intercellular communication (GJIC) in the testis is critical for coordinating spermatogenesis. The objectives of the study were to determine the effects of nonylphenol on gap junctional intercellular communication (GJIC) and connexin 43 (Cx43) in a murine Sertoli cell line (TM4). Cells were exposed for 24h to different concentrations (1 to 50 µM) of either nonylphenol or 17-estradiol. GJIC was determined using a microinjection approach in which Lucifer Yellow was injected directly into a single cell, and GJIC was assessed 3 min post-injection. Nonylphenol exposure decreased GJIC between adjacent cells by almost 80% relative to controls. A significant concentration-dependent reduction in GJIC was observed at nonylphenol concentrations between 1-50 µM. Cx43 immunofluorescent staining was reduced at both 10 and 50µM doses of nonylphenol. Cx43 phosphorylation, as determined by Western blots, was reduced at both 10 and 50 µM concentrations, which may explain, at least in part, the inhibition of GJIC. In contrast, no effect on GJIC or Cx43 protein was observed in cells exposed to 17-estradiol at these concentrations. Cx43 has been reported to be phosphorylated via the p38-MAPK pathway. P38-MAPK activity was assessed in both control and nonylphenol-exposed cells. A dose dependent decrease in p38-MAPK activity was observed in nonylphenol- exposed Sertoli cells. Protein kinase C (PKC) activity was also measured and was not influenced by nonylphenol. These results suggest that nonylphenol inhibits GJIC between Sertoli cells and that this is modulated via non-estrogenic pathways.

Key words: Environment • Testis • Toxicology • Sertoli cells • Signal transduction

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