Developmental toxicity window of fetal testicular injury in offspring mice induced by prenatal amoxicillin exposure at different time, doses and courses

Abstract

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.