RESUMEN
AIMS: Amoxicillin is a broad-spectrum beta-lactam antibiotic used to treat infectious diseases in pregnant women. Studies have shown that prenatal amoxicillin exposure (PAmE) has developmental toxicity on fetal development. However, the effect of PAmE on long bone development has not been reported. This study aimed to investigate the "toxic window" of PAmE on long bone development and explore its possible mechanism in fetal mice. MATERIALS AND METHODS: Pregnant mice were administered amoxicillin by gavage at different stages (gestational day (GD)10-12 and GD16-18), different doses (150 and 300 mg/kg·d) and different courses (single and multiple courses). Fetal femurs were collected at GD18 and bone development related indicators were detected. KEY FINDINGS: The results showed that PAmE significantly reduced the length of the femur and primary ossification center of fetal mice, and inhibited the development of fetal growth plate. Meanwhile, PAmE inhibited the development of bone marrow mesenchymal stem cells, osteoclasts and endothelial cells in fetal long bone. Further, we found the fetal long bone developmental toxicity induced by PAmE was most significant at late-pregnancy (GD16-18), high dose (300 mg/kg·d) and multiple-course group. Besides, PAmE inhibited the expression of Wnt/ß-catenin signaling pathway in fetal long bone. The ß-catenin mRNA expression was significantly positively correlated with the development indexes of fetal long bone. SIGNIFICANCE: PAmE has toxic effects on long bone development, and there was an obvious "toxic window" of PAmE on the long bone development in fetal mice. The Wnt/ß-catenin signaling pathway may mediate PAmE-induced fetal long bone development inhibition.
Asunto(s)
Amoxicilina , Antibacterianos , Desarrollo Óseo , Vía de Señalización Wnt , Animales , Femenino , Embarazo , Ratones , Amoxicilina/toxicidad , Desarrollo Óseo/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Antibacterianos/toxicidad , Desarrollo Fetal/efectos de los fármacos , Fémur/efectos de los fármacos , Fémur/embriología , Osteogénesis/efectos de los fármacos , beta Catenina/metabolismo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Masculino , Feto/efectos de los fármacosRESUMEN
Pregnant women are usually treated with amoxicillin before cesarean section to prevent infection. This study aimed to investigate the effects of amoxicillin exposure on fetal adrenal development at different stages, doses and courses of pregnancy. We found prenatal amoxicillin exposure (PAmE) could cause adrenal developmental toxicity in both male and female fetal mice in a stage, dose and course-dependent manner, among which the third trimester, high dose and multiple courses of PAmE could significantly reduce the maximum cross-sectional area and diameter. Besides, the proliferation was inhibited, the apoptosis was enhanced, and the serum corticosterone level and expression of steroidogenic enzymes were decreased in the PAmE group. Further, the insulin-like growth factor 1 (IGF1) signaling pathway were inhibited in the male and female fetal mice at the third trimester, high dose and multiple courses of treatment, and adrenal IGF1 expression was positively correlated with the indicators of adrenal development. In conclusion, PAmE could induce adrenal dysplasia in fetal mice in the stage, dose and course-dependent manner, which was related to the inhibition of IGF1 signaling pathway. This study provides guidance for evaluating the toxicity and risk of fetal adrenal development and the rational use of amoxicillin during pregnancy.
Asunto(s)
Cesárea , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratones , Embarazo , Femenino , Masculino , Humanos , Animales , Ratas Wistar , Efectos Tardíos de la Exposición Prenatal/metabolismo , Corticosterona , Desarrollo FetalRESUMEN
Amoxicillin is widely used in the clinical treatment of syphilis, gonorrhea and other infectious diseases during pregnancy, but the effects of prenatal amoxicillin exposure (PAmE) on fetal testicular development have not been reported. Based on the characteristics of clinical medication, Kunming mice were orally gavaged with amoxicillin during pregnancy at different time (mid- or late-pregnancy), doses (75, 150 or 300 mg/kg·d) or courses (single- or multi-course). The results showed that compared with the control group, PAmE resulted in fetal testicular abnormal morphological development, cell proliferation inhibition and apoptosis enhancement, Leydig cell steroid synthase system (SF1, StAR, P450scc, CYP17a1) expression inhibition, and fetal blood testosterone levels decreased. Among them, the late-pregnancy and high-dose amoxicillin groups had severe damage, while the damage in different course groups was basically the same. Meanwhile, PAmE could damage the number and function of germ cells at all time, doses and courses, but had no obvious effect on Sertoli cells. It was further found that PAmE inhibited fetal testis AKT and ERK signaling pathways in late pregnancy and high dose, while the damage in different course groups was basically the same. In summary, this study proposed the developmental toxicity window of fetal testicular injury induced by PAmE in late-pregnancy and high-dose and its related mechanism of AKT and ERK signaling pathway, which provided a theoretical and experimental basis for guiding rational drug use during pregnancy and effectively evaluating the risk of fetal testicular developmental toxicity.