Xia Yanan, Feng Lihua, Lan Yuzhi, Chen Xiangxiang, Tang Xiaomin, Xu Hengyi, Liu Yang
Department of Pediatrics, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, China.
State Key Laboratory of Food Science and Resources, Nanchang University, Nanchang 330047, China.
Toxicol Appl Pharmacol. 2025 Sep;502:117425. doi: 10.1016/j.taap.2025.117425. Epub 2025 May 30.
Children's daily exposure to titanium dioxide nanoparticles (TiO₂ NPs) poses significant risks to the developing testes, yet few studies have examined their impact on young testicular growth. Given ghrelin's established antioxidant and testis-protective effects in animal models, we hypothesized that it could mitigate TiO₂ NPs-induced damage. In this first systematic investigation of young testicular responses, three-week-old male rats received oral gavage of TiO₂ NPs (100, 200, or 400 mg/kg), followed 30 min later by intraperitoneal ghrelin (50 mg/kg) for four weeks. Exposure to TiO₂ NPs disrupted seminiferous tubule architecture and reduced serum levels of key developmental and sex hormones, including IGF-1, FSH, LH, and testosterone. Mechanistically, TiO₂ NPs activated the ROS/AMPK/mTOR signaling pathway, resulting in a marked reduction of SOD, CAT, and GSH activities and the induction of oxidative imbalance, while simultaneously upregulating the autophagy protein ULK1 and autophagy-related genes to trigger excessive autophagy, ultimately compromising testicular architecture and function. We further assessed ghrelin's protective efficacy against TiO₂ NPs-induced reproductive injury in young rats, demonstrating that ghrelin inhibited the ROS/AMPK/mTOR signaling pathway, attenuated oxidative stress, and suppressed excessive autophagy, thereby mitigating testicular injury. These findings represent the first evidence of the developing testicular heightened vulnerability to TiO₂ NPs toxicity and underscore ghrelin's potential as a novel protective intervention. Our study provides new insights into the reproductive toxicology of engineered nanoparticles and supports targeted strategies to safeguard pediatric reproductive health.
儿童日常接触二氧化钛纳米颗粒（TiO₂ NPs）对发育中的睾丸构成重大风险，但很少有研究考察其对幼年睾丸生长的影响。鉴于胃饥饿素在动物模型中已确立的抗氧化和睾丸保护作用，我们推测它可以减轻TiO₂ NPs诱导的损伤。在这项对幼年睾丸反应的首次系统性研究中，3周龄雄性大鼠经口灌胃给予TiO₂ NPs（100、200或400 mg/kg），30分钟后腹腔注射胃饥饿素（50 mg/kg），持续4周。暴露于TiO₂ NPs会破坏生精小管结构，并降低包括IGF-1、FSH、LH和睾酮在内的关键发育和性激素的血清水平。从机制上讲，TiO₂ NPs激活了ROS/AMPK/mTOR信号通路，导致SOD、CAT和GSH活性显著降低，并诱导氧化失衡，同时上调自噬蛋白ULK1和自噬相关基因以触发过度自噬，最终损害睾丸结构和功能。我们进一步评估了胃饥饿素对幼年大鼠TiO₂ NPs诱导的生殖损伤的保护效果，证明胃饥饿素抑制了ROS/AMPK/mTOR信号通路，减轻了氧化应激，并抑制了过度自噬，从而减轻了睾丸损伤。这些发现首次证明了发育中的睾丸对TiO₂ NPs毒性的易感性增加，并强调了胃饥饿素作为一种新型保护干预措施的潜力。我们的研究为工程纳米颗粒的生殖毒理学提供了新的见解，并支持保护儿童生殖健康的靶向策略。
