No abstract

Bisphenol A (BPA), a typical environmental endocrine-disrupting chemical, induces epigenetic inheritance. Whether histone acetylation plays a role in these effects of BPA is largely unknown. Here, we investigated histone acetylation in male rats after long-term exposure to a ‘safe’ dose of BPA. Twenty adult male rats received either BPA (50 μg/kg·bw/day) or a vehicle diet for 35 weeks. Decreased protein lysine-acetylation levels at approximately ~17 kDa and ~25 kDa, as well as decreased histone acetylation of H3K9, H3K27 and H4K12, were detected by Western blot analysis of testes from the treated rats compared with controls. Additionally, increased protein expression of deacetylase Sirt1 and reduced binding of Sirt1, together with increased binding of estrogen receptor β (ERβ) to caveolin-1 (Cav-1), a structural protein component of caveolar membranes, were detected in treated rats compared with controls. Moreover, decreased acetylation of Cav-1 was observed in the treated rats for the first time. Our study showed that long-term exposure to a ‘safe’ dose of BPA reduces histone acetylation in the male reproductive system, which may be related to the phenotypic paternal-to-offspring transmission observed in our previous study. The evidence also suggested that these epigenetic effects may be meditated by Sirt1 via competition with ERβ for binding to Cav-1.

Resveratrol (RES), a dietary polyphenol compound, has been shown to possess health benefits due to its anti-inflammatory, antioxidative, and antiatherosclerosis properties. Tryptophan metabolite-derived indoxyl sulfate (IS) is identified as one of the uremic toxins and physiological endogenous ligand/activator of aryl hydrocarbon receptor (AHR), associated with atherosclerosis in chronic kidney disease (CKD) patients. Studies have shown that a high serum level of IS causes deleterious effects on health primarily by inducing oxidative stress and endothelial dysfunction. However, the precise mechanisms are still unclear. Here, we investigated the underlying mechanism of IS effect on endothelial permeability and the role of RES on IS-induced endothelial hyperpermeability via the AHR/Src-dependent pathway. Bovine aorta endothelial cells (BAECs) were cultured and incubated with IS in the presence or absence of RES, and transendothelial electrical resistance (TEER) and permeability of cells were measured. Alongside, AHR, Src kinase, and Vascular Endothelial Cadherin (VE-Cadherin) activation were examined. Our data showed that IS reduced TEER of cells resulting in increased permeability. VE-Cadherin, a vital regulator of endothelial permeability, was also significantly activated in response to IS, which appeared to be associated with changes of endothelial permeability and AHR/Src kinase. Interestingly, in this setting, RES reversed the effect of IS and inhibited the increased activation of Src induced by IS-activated AHR and modulated VE-Cadherin and permeability. CH223191, an inhibitor of AHR, significantly inhibits IS-induced endothelial hyperpermeability. Further analysis with treatment of PP2, an inhibitor of Src abolishing Src activation, suggests downstream factors. All our data indicated that IS upregulated the AHR/Src kinase pathway, and increased endothelial permeability and phosphorylation of VE-Cadherin may be represented and provide new strategies for addressing protective properties of RES against Src kinase involved in AHR-mediated endothelial hyperpermeability. The findings may be crucial for managing diseases in which endothelial permeability is compromised, and the dietary polyphenols are involved.