Gu Hanwen, Li Bin, Liu Liang, Li Xufeng, Wang Hui, Chen Liaobin
Division of Joint Surgery and Sports Medicine, Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
Toxicol Appl Pharmacol. 2023 Mar 15;463:116429. doi: 10.1016/j.taap.2023.116429. Epub 2023 Feb 14.
Amoxicillin is widely used in the treatment of infectious diseases during pregnancy; however, the effects of prenatal amoxicillin exposure (PAE) on fetal development remain largely unknown. Therefore, this study aimed to investigate the toxic effects of PAE on fetal cartilage at different stage-, dose-, and course. Pregnant Kunming mice were orally administered 300 mg/kg·d (converted from clinical dose) amoxicillin on gestational days (GD) 10-12 or 16-18 (mid or late pregnancy stage), 150 or 300 mg/kg.d amoxicillin on GD16-18 (different doses), 300 mg/kg·d amoxicillin on GD16 (single course) or 16-18 (multiple courses), respectively. The fetal articular cartilage of the knee was collected on GD18. The number of chondrocytes and the expression of matrix synthesis/degradation, proliferation/apoptosis-related markers, and the TGF-β signaling pathway were detected. The results showed that the number of chondrocytes and the expression of matrix synthesis markers were reduced in male fetal mice treated with PAE (GD16-18, 300 mg/kg.d, single course and multiple courses), whereas the above indices in female mice showed no changes. The inhibited expression of PCNA, increased expression of Caspase-3, and down-regulated expression of the TGF-β signaling pathway were found in male PAE fetal mice. Accordingly, PAE exerted its "toxic effect window" on the knee cartilage development in male fetal mice, which manifested as reduced chondrocyte number and inhibited expression of matrix synthesis at a clinical dose of multiple courses in the late pregnancy stage. This study provides a theoretical and experimental basis for elucidating the risk of chondrodevelopmental toxicity associated with amoxicillin during pregnancy.
阿莫西林广泛用于孕期传染病的治疗；然而，产前暴露于阿莫西林（PAE）对胎儿发育的影响仍 largely 未知。因此，本研究旨在探讨 PAE 在不同阶段、剂量和疗程对胎儿软骨的毒性作用。将怀孕的昆明小鼠在妊娠第 10 - 12 天或 16 - 18 天（妊娠中期或晚期）口服给予 300 mg/kg·d（从临床剂量换算而来）阿莫西林，在妊娠第 16 - 18 天给予 150 或 300 mg/kg·d 阿莫西林（不同剂量），分别在妊娠第 16 天（单疗程）或 16 - 18 天（多疗程）给予 300 mg/kg·d 阿莫西林。在妊娠第 18 天收集胎儿膝关节的关节软骨。检测软骨细胞数量以及基质合成/降解、增殖/凋亡相关标志物和 TGF-β 信号通路的表达。结果显示，PAE 处理的雄性胎儿小鼠（妊娠第 16 - 18 天，300 mg/kg·d，单疗程和多疗程）中软骨细胞数量和基质合成标志物的表达降低，而雌性小鼠的上述指标无变化。在雄性 PAE 胎儿小鼠中发现 PCNA 表达受抑制、Caspase - 3 表达增加以及 TGF-β 信号通路表达下调。因此，PAE 对雄性胎儿小鼠膝关节软骨发育产生其“毒性作用窗口”，表现为在妊娠晚期多疗程临床剂量下软骨细胞数量减少和基质合成表达受抑制。本研究为阐明孕期阿莫西林相关软骨发育毒性风险提供了理论和实验依据。
