小鼠围生期应用抗生素可致雄性子鼠血清5-羟色胺水平升高及行为和肠道运动功能改变

Perinatal antibiotics exposure causes increase in serum 5-hydroxytryptamine level as well as changes in behavior and gastrointestinal motility in the male offspring in mice

本研究旨在探讨围生期母鼠使用抗生素对子代小鼠认知行为、肠道动力和外周血5-羟色胺(5-hydroxytryptamine,5-HT)水平的影响。在孕鼠分娩前一周至分娩后一周持续给予头孢克肟或青霉素处理,用三腔社交偏好实验、自我捋毛试验和高架十字迷宫实验检测4~10周龄子鼠行为学改变,检测子鼠的消化道动力,用ELISA检测血清5-HT水平,用RT-qPCR和Western blot检测子鼠结肠上皮组织钾/钠超极化激活环核苷酸门控通道2(potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2,HCN2)和色氨酸羟化酶1(tryptophan hydroxylase 1,TPH1)表达水平。结果显示,与对照组相比,头孢克肟组雌性子鼠社交积极性显著提高,雄性子鼠无显著变化;雄性子鼠的结直肠动力和全肠道动力显著降低,盲肠净质量和相对体重占比显著增加,雌性子鼠无显著变化。与对照组相比,头孢克肟组和青霉素组雄性子鼠血清5-HT含量显著升高,雌性子鼠无显著变化。相比对照组,头孢克肟组子鼠结肠上皮HCN2表达水平显著下调,TPH1表达水平无显著变化。以上结果提示,围生期抗生素暴露可能影响子代神经发育和肠道功能,而且这种影响可能与外周血5-HT的变化相关且具有性别差异性。

The current study was aimed to investigate the potential effects of perinatal exposure to therapeutic dose of penicillin and cefixime on the cognitive behaviors,gastrointestinal(GI)motility and serum 5-hydroxytryptamine(5-HT)level in the offspring.Pregnant rats were continuously treated with cefixime or penicillin in the period between 1 week before and 1 week after labor.Behavior tests,including social preference,self-grooming and elevated plus maze tests,and intestinal motility tests were carried out on the offspring at age of 4 to 10 weeks.Serum 5-HT levels were detected with ELISA,and potassium/sodium hyperpolarization activated cyclic nucleotide-gated channel 2(HCN2)and tryptophan hydroxylase 1(TPH1)expression levels in colon epithelium of offspring were detected by Western blot and RT-qPCR.The results showed that,compared with the naive group,cefixime increased social behavior in the female offspring,but did not affect the male offspring.Compared with the naive group,cefixime significantly decreased colonic and intestinal transits,and increased cecum net weight and standardized cecum net weight in the male offspring,but did not affect the female offspring.The serum 5-HT levels in the male offspring,rather than the female offspring,in cefixime and penicillin groups were significantly increased compared with that in the naive group.The protein expression level of HCN2 in colon epithelium of the offspring in cefixime group was significantly down-regulated,and the TPH1 expression level was not significantly changed,compared with that in the naive group.These results suggest that perinatal antibiotics exposure may affect neural development and GI functions of the offspring,and the mechanism may involve peripheral 5-HT and gender-dependent factor.