Docosahexaenoic acid protects against lipopolysaccharide-induced fetal growth restriction via inducing the ubiquitination and degradation of NF-B p65 in placental trophoblasts

Lipopolysaccharide (LPS) could induce adverse birth outcomes by evoking inflammation. We investigated the effect and mechanism of docosahexaenoic acid (DHA) on LPS-induced placental inflammation and fetal growth restriction (FGR). In vivo, pregnant CD-1 mice were divided into four groups: Ctrl, DHA, LPS and DHA+LPS group. We found that DHA pretreatment reduced the incidence of FGR induced by LPS and activated the expression of peroxisome proliferators-activated receptor gamma (PPAR gamma) in placental tissue. Moreover, the LPS-induced increase of mRNA levels of Tnf-alpha, Il-6, Il-1 beta, Mip-2 and Kc in placental tissue was significantly attenuated by DHA pretreatment. A similar effect of DHA was observed in serum of pregnant mice and amniotic fluid. In contrast, the levels of the IL-10 were significantly increased after DHA pretreatment. In vitro, we clarified that DHA antagonized the activation of the NF-kappa B signaling pathway induced by LPS, which was dependent on PPAR gamma. Subsequently, CHX (translation inhibitor) was used to indicated that PPAR gamma significantly increased the degradation rate of p65, an effect that was inhibited by MG132 (proteasome inhibitor) treatment. Finally, it was confirmed that the activation of PPAR gamma could significantly promote the ubiquitination and degradation of p65. Our results suggested that DHA alleviated LPS-induced inflammatory responses and FGR by activating PPAR gamma expression, leading to p65 ubiquitination and degradation. (c) 2023 Published by Elsevier Inc.