Abstract:
Nicotine is developmentally toxic. Prenatal nicotine exposure (PNE) affects the development of multiple fetal organs and causes susceptibility to a variety of diseases in offspring. In this study, we aimed to investigate the effect of PNE on cartilage development and osteoarthritis susceptibility in female offspring rats. Wistar rats were orally gavaged with nicotine on days 9-20 of pregnancy. The articular cartilage was obtained at gestational day (GD) 20 and postnatal week (PW) 24, respectively. Further, the effect of nicotine on chondrogenic differentiation was explored by the chondrogenic differentiation model in human Wharton\'s jelly-derived mesenchymal stem cells (WJ-MSCs). The PNE group showed significantly shallower Safranin O staining and lower Collagen 2a1 content of articular cartilage in female offspring rats. Further, we found that PNE activated pyroptosis in the articular cartilage at GD20 and PW24. In vitro experiments revealed that nicotine inhibited chondrogenic differentiation and activated pyroptosis. After interfering with nod-like receptors3 (NLRP3) expression by SiRNA, it was found that pyroptosis mediated the chondrogenic differentiation inhibition of WJ-MSCs induced by nicotine. In addition, we found that α7-nAChR antagonist α-BTX reversed nicotine-induced NLRP3 and P300 high expression. And, P300 SiRNA reversed the increase of NLRP3 mRNA expression and histone acetylation level in its promoter region induced by nicotine. In conclusion, PNE caused chondrodysplasia and poor articular cartilage quality in female offspring rats. PNE increased the histone acetylation level of NLRP3 promoter region by α7-nAChR/P300, which resulting in the high expression of NLRP3. Further, NLRP3 mediated the inhibition of chondrogenic differentiation by activating pyroptosis.
摘要:
尼古丁具有发育毒性。产前尼古丁暴露(PNE)影响多个胎儿器官的发育,并导致后代对多种疾病的易感性。在这项研究中,我们旨在研究PNE对雌性子代大鼠软骨发育和骨关节炎易感性的影响。Wistar大鼠在怀孕的第9-20天口服尼古丁。关节软骨分别在妊娠日(GD)20和出生后(PW)24周获得。Further,通过人沃顿胶质来源的间充质干细胞(WJ-MSCs)的软骨分化模型研究了尼古丁对软骨分化的影响。PNE组雌性后代大鼠关节软骨中SafraninO染色明显较浅,胶原2a1含量较低。Further,我们发现PNE在GD20和PW24时激活了关节软骨中的焦凋亡。体外实验表明,尼古丁抑制软骨分化并激活焦亡。通过SiRNA干扰nod样受体3(NLRP3)表达后,结果发现,焦凋亡介导了尼古丁诱导的WJ-MSCs的软骨分化抑制。此外,我们发现α7-nAChR拮抗剂α-BTX可逆转尼古丁诱导的NLRP3和P300高表达。And,P300SiRNA逆转了尼古丁诱导的NLRP3mRNA表达和其启动子区域组蛋白乙酰化水平的增加。总之,PNE导致雌性后代大鼠软骨发育不良和关节软骨质量差。PNE通过α7-nAChR/P300增加了NLRP3启动子区的组蛋白乙酰化水平,从而导致NLRP3的高表达。Further,NLRP3通过激活焦亡介导软骨分化的抑制。