Effects of bisphenol A on gap junctions in HaCaT cells as mediated by the estrogen receptor pathway

Abstract

Bisphenol A (BPA) is widely used as the raw material for the production of plastics and paper products. People can be exposed to BPA through dermal contact, particularly for cashiers in contact with thermal paper every day. BPA is a known endocrine disruptor that has been shown to be carcinogenic. Many tumors show weak gap junctional intercellular communication (GJIC) function. The aim of this study was to investigate the effects and possible mechanisms of BPA's action on GJIC of human HaCaT skin cells. The results showed that BPA increased cell proliferation rates, prolonged GJIC photobleaching fluorescence recovery times and reduced overall fluorescence recovery rates at 0.01, 0.1 and 1 μm. BPA downregulated connexin (Cx)26 mRNA level at 0.1 μm. Estrogen receptor (ER) antagonist ICI 182 780 at 5 nm partially blocked the above effects of BPA indicating involvement of the ER pathway with BPA exposure. However, BPA did not influence Cx43 mRNA and protein levels. Our immunofluorescence data showed that Cx26 was expressed in the cytoplasm and plasma membrane, and was involved in the formation of gap junctions between adjacent cells, while Cx43 was expressed only in the cytoplasm. Therefore, our data indicate that Cx26 gap junctions may be involved in the GJIC inhibition caused by BPA. In conclusion, our results indicate that BPA can promote human skin cell proliferation, inhibit skin cell GJIC function but not formation and downregulate Cx26 mRNA levels partially through the ER pathway. We hypothesize that BPA can exhibit carcinogenicity by inhibiting GJIC.

Pregnant Women and Endocrine Disruptors: Role of P2X7 Receptor and Mitochondrial Alterations in Placental Cell Disorders

“…Skin, in addition to its main protective function, can also be classified as an endocrine organ endowed with local steroidogenic activities [47,48]. HaCaT keratinocytes possess different steroid receptors [49][50][51] and metabolize progesterone to deoxycorticosterone, cortisone, aldosterone and cortisol [47]. On the contrary, pulmonary epithelial cells do not possess any hormonal receptors and are not able to produce hormones.…”

The Neurochemical Characterization of Parasympathetic Nerve Fibers in the Porcine Uterine Wall Under Physiological Conditions and After Exposure to Bisphenol A (BPA)

“…It is present in many everyday objects, including paints, bottles, containers, thermal paper, household products, and many other things (Mikołajewska et al 2015 ). With regard to its chemical structure, BPA is similar to estrogen, resulting in the possibility of it having an impact on estrogen receptors (Zhang et al 2018 ). This possibility makes this substance possibly have an adverse effect on living organisms and is classified as an endocrine disruptor.…”

Brain Disorders and Chemical Pollutants: A Gap Junction Link?

“…BPA (0.01-1 µM for 48 h) significantly inhibits GJIC between human skin HaCaT cells and significantly downregulates Cx26 mRNA expression (0.1 µM BPA) partially through the ER pathway. In contrast, BPA does not influence Cx43 mRNA, Cx26 and Cx43 protein expression levels and Cx locations in HaCaT cells [319]. Interestingly, an analysis of the Cx43 structure showed the presence of a docking 'pocket' in Cx43-based connexon for estradiol-17b and BPA.…”

“…Another potential mechanism of action is an inhibition of GJIC by physically blocking the GJ channel pore [309][310][311]. Changes in the Cx gene expression, endocytosis and degradation were also observed in response to several pollutants [312][313][314][315][316][317][318][319][320][321]. The last potential mechanisms of action are through non-classical estrogen receptors (ERs) [322,323] or through a toxic action on the aryl hydrocarbon receptor (AhR) [312].…”