Resveratrol ameliorates toxic effects of cadmium on placental development in mouse placenta and human trophoblast cells

Background Cadmium (Cd) is a common heavy metal pollutant. Prenatal exposure to Cd results in adverse effects on fetal development. Placental apoptosis, inflammation, and epigenetic disruption have been implicated in Cd-induced placental toxicity. Resveratrol (Res) is a naturally occurring polyphenol with anti-apoptotic, anti-inflammatory, and epigenetic regulatory activities. In present study, the effects of Res on placental toxicity induced by Cd were evaluated. Methods Pregnant CD-1 mice were fed with base diet containing 0.2% Res started on gestational day 0 (GD0), and intraperitoneally injected with 4.5 mg/kg CdCl2 or saline once on GD9. JEG-3 cells were treated with 20 mu M Res for 24 hr in the absence or presence of 20 mu M CdCl2 for the second 12 hr. The fetal outcomes, the apoptosis in placenta and JEG-3 cells, the expression of inflammatory cytokines and chemokines including tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein-2 (MIP-2) and chemokine (C-X-C motif) ligand 1 (KC), and expression of endoplasmic reticulum (ER) stress markers were evaluated. The expression and activities of DNA methyltransferase (DNMT), and the activation of Akt signaling pathway were detected. Results Cd exposure resulted in decreased fetal weight and crown-rump length while Res ameliorated these outcomes. Res suppressed Cd-induced apoptosis in placenta and JEG-3 cells, and decreased Cd-induced expression of TNF-alpha, IFN-gamma, MCP-1, MIP-2, and KC in placenta. Cd greatly increased ER stress in placenta in mice, which was partially ameliorated by Res treatment. Res decreased Cd-induced upregulation of DNMT activity and suppressed Cd-induced expression of DNMT3B. Res restored estradiol secretion, enhances activity and protein levels of SIRT1 and inhibited Cd-induced activation of Akt signaling pathway. Conclusion Res ameliorated Cd-induced placental toxicity and regulated DNMT3 expression and PI3K/Akt pathway activation.

Automated summary

The study revealed that resveratrol (Res) alleviated cadmium (Cd)-induced placental toxicity, regulated DNMT3 expression, and suppressed PI3K/Akt signaling pathway activation.