Abstract
Controversy exists about the human health risk of environmental exposure to bisphenol A (BPA). Telomerase activity is emerging both as biomarker and contributing factor for age-related diseases. The effects of BPA exposure at 1–1000 nM on telomerase, DNA integrity and cell proliferation were investigated in PBMC from human donors. Telomerase activity was determined by TRAP-ELISA assay and mRNA expression by qRT-PCR. Mechanistic studies were carried out on the ER/GPR30-ERK pathway using specific inhibitors/antagonists, the comet assay to quantify DNA damage and flow cytometry for cell proliferation. 24 h BPA exposure inhibited telomerase in a non-monotonic pattern with a peak inhibition of 32% at 1 nM (p ≤ 0.01). A significant telomerase inhibition was evident at 1 h after exposure with a minimum at 6 h. Elevated levels of DNA damage frequency and decrease in cell proliferation were evident upon long-term exposure. The results further demonstrate that BPA triggered rapidly an ER/GPR30-ERK transduction pathway that leads to decreased telomerase activity in human PBMC. This is the first study to demonstrate adverse impact of BPA at levels of current human exposure on telomerase in normal cells, mediated by ER/GPR30-ERK. The results suggest a potentially harmful influence of BPA on immune cells and should be addressed in future studies.
Highlights
® of bisphenol A (BPA) was evaluated in comparison to E2 using the Estrogen receptor (ER)-CALUX reporter gene assay
Significance of difference was calculated relative to the respective control, *p < 0.05; **p < 0.01. (D) Activated peripheral blood mononuclear cells (PBMC) were analysed for full length hTERT mRNA expression after 6 h and 24 h exposure to 1 nM BPA using qRT-PCR
The present in vitro study provides important evidence that BPA is hormonally active on telomerase which was used as key readout for the effects of low-dose BPA exposure on human PBMC
Summary
® of BPA was evaluated in comparison to E2 using the ER-CALUX reporter gene assay. The maximum response of E2 was set to 100%. In human peripheral blood mononuclear cells (PBMC), results with estrogen are more inconsistent: at supra-physiological concentrations, estradiol increased telomerase mRNA expression and activity via ERα in one study[24]. The results show a significant decrease in telomerase activity in activated primary human PBMC upon low-dose (1–10 nM) BPA exposure. This occurs by activation of ERK1/2 through ER/GPR30.
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