Cadmium exposure-induced rat testicular dysfunction and its mechanism of chronic stress.

Cadmium is a common environmental pollutant in daily life, the toxic mechanisms of chronic cadmium exposure on the testes have not been fully elucidated. This study aimed to explore the effects of cadmium exposure on male reproductive health and its mechanism. The results showed that cadmium exposure led widened interstitial spaces, abnormal seminiferous tubule morphology, and decreased Leydig cell numbers. Moreover, sperm quality was significantly reduced, along with a decrease in fertility rate. And cadmium exposure could activate the hypothalamic-pituitary-adrenal (HPA) axis, elevate blood glucocorticoid levels, subsequently increase glucocorticoid receptor (GR) expression and activation in testicular Leydig cells. Then GR act on the glucocorticoid receptor element (GRE) in the DNA methyltransferase 3 A (DNMT3A) promoter region and upregulate DNMT3A expression. Consequently, this led to an increase in DNA methylation levels in the angiotensin II receptor 2 (AT2R) promoter region, resulting in reduced AT2R expression and inhibiting testicular steroidogenesis. This study systematically elucidated that cadmium exposure could lead to testicular steroidogenesis suppression and decreased fertility through the GR/DNMT3A/AT2R signaling pathway. This research further provides theoretical and experimental evidence for confirming the threat of cadmium exposure to human reproduction, and contributes to the guidance and protection of male reproductive health.

Prenatal exposure to acetaminophen at different doses, courses and time causes testicular dysplasia in offspring mice and its mechanism.

Epidemiological investigation suggested that the use of acetaminophen during pregnancy may cause offspring testicular dysplasia, but no systematic study has been conducted. In this study, Kunming mice were given acetaminophen at different doses (100/200/400 mg/kg.d), courses (single/multiple), time (second/third trimester) during pregnancy. Fetal blood and testes were collected on gestaional day 18 for detection. The results indicated abnormal testicular development in the PAcE (prenatal acetaminophen exposure) groups. The maximum diameter/cross-sectional area decreased, the interstitial space widened, and decreased proliferation/increased apoptosis were observed, especially in the high-dose, multi-course and second-trimester groups. Meanwhile, the serum testosterone level decreased in PAcE groups, and the steroid synthesis function in Leydig cells, Sertoli and spermatogenic cell function were inhibited, it was more significant in high-dose, multi-course and second-trimester groups. Furthermore, Wnt signal pathway was activated but Notch signal pathway was inhibited in the PAcE groups. Finally, in vitro experiment, acetaminophen could inhibit spermatogonial cell proliferation, enhance apoptosis, and change Wnt/Notch signal pathway. In conclusion, this study confirmed that PAcE can change fetal testicular development in a dose, course and time-dependent manner, and found that multicellular function impaired. This study provides theoretical and experimental basis for systematically elucidating the developmental toxicity of acetaminophen in testis.

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

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.