化疗方案的成功使癌症存活率在过去几十年中显著提高。尽管梅尔法兰具有生殖毒性，但已被广泛用于治疗多种癌症。由于梅尔法兰具有在精原干细胞和精子发生细胞中引起突变的能力，因此对年轻的癌症幸存者的男性生殖健康会产生负面影响。骨骼肌释放的一种肌肽β-氨基异丁酸（BAIBA）已被报告具有在糖尿病肾病、心肌病和肝毒性方面的益处。然而，BAIBA在化疗诱导的生殖细胞毒性中的确切作用仍未得到探索。本研究旨在确定BAIBA对SD大鼠梅尔法兰诱导的生殖细胞毒性（1.5mg/kg）的剂量依赖性（25、50和100mg/kg）作用。评估参数包括氧化应激生物标志物的定量、精子计数、精子运动和头形态、精子和睾丸DNA损伤、精子线粒体膜电位、精子的超微结构变化、睾丸的组织学和蛋白质表达研究。梅尔法兰治疗显著改变了上述所有参数，高剂量（100mg/kg）的BAIBA通过发挥抗氧化、抗炎和抗凋亡作用显著恢复了梅尔法兰诱导的毒性。然而，中等剂量（50mg/kg）的BAIBA减少了梅尔法兰的毒性，低剂量（25mg/kg）的BAIBA无法抵消梅尔法兰诱导的雄性生殖细胞毒性以及外周血液微核诱导。BAIBA在梅尔法兰诱导的性腺损伤中的抗氧化、抗炎和抗凋亡作用是实验大鼠模型中的一个新发现。©2023 Wiley Periodicals LLC。

The success of chemotherapy regimens has led to an increase in cancer survival rate over the last decades. Melphalan has been widely used for the treatment of several types of cancers despite its gonadotoxic effects. Due to its ability to cause mutations in the spermatogonial stem cells and spermatids, melphalan can exert a negative impact on male reproductive health in young cancer survivors. β-aminoisobutyric acid (BAIBA), a myokine released by skeletal muscles, has been reported to have beneficial effects in diabetic nephropathy, cardiomyopathy and hepatic toxicity. However, the exact role of BAIBA in chemotherapy-induced germ cell toxicity is still unexplored. The present study aims to determine the dose-dependent (25, 50, and 100 mg/kg) effects of BAIBA on melphalan-induced (1.5 mg/kg) germ cell toxicity in sprague-dawley (SD) rats. The evaluation parameters included quantification of oxidative stress biomarkers, sperm count, sperm motility and head morphology, sperm and testicular DNA damage, sperm mitochondrial membrane potential, ultrastructural changes in sperms, histological and protein expression studies in testes. Melphalan treatment significantly altered all the above-mentioned parameters and the high dose (100 mg/kg) of BAIBA restored melphalan-induced toxicity in a significant manner by exerting antioxidant, anti-inflammatory and antiapoptotic effects. However, the medium dose (50 mg/kg) of BAIBA decreased the toxicity of melphalan and the low dose (25 mg/kg) of BAIBA failed to counteract the melphalan-induced male germ cell toxicity as well as the peripheral blood micronucleus induction. The antioxidant, anti-inflammatory and antiapoptotic role of BAIBA in melphalan-induced gonadal damage is a novel finding in an experimental rat model.© 2023 Wiley Periodicals LLC.