Biasi Alessandra, Ambruosi Maria Rosaria, Romano Maria Zelinda, Boccella Serena, Falvo Sara, Guida Francesca, Aniello Francesco, Maione Sabatino, Venditti Massimo, Minucci Sergio
Dipartimento di Medicina Sperimentale, Università degli Studi della Campania "Luigi Vanvitelli", 80138 Napoli, Italy.
Dipartimento di Science e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania "Luigi Vanvitelli", 81100 Caserta, Italy.
Int J Mol Sci. 2025 May 10;26(10):4579. doi: 10.3390/ijms26104579.
Type 1 diabetes (T1D) is a chronic metabolic disease defined by sustained hyperglycemia, leading to oxidative stress (OS) and systemic complications, including male subfertility. This study investigates the potential impact of T1D-induced OS on microtubule (MTs) dynamics and microtubule-associated proteins (MAPs) in the testis and spermatozoa (SPZ). Using a streptozotocin-induced T1D rat model, we examined the expression and localization of key MAPs, including Microtubule Affinity-Regulating Kinase 4 (MARK4), Microtubule-Associated Protein 1A (MAP1A), Dynein Light Chain LC8-Type 1 (DYNLL1), Prolyl Endopeptidase (PREP), and Radial Spoke Head 6 Homolog A (RSPH6A), alongside sperm functional parameters. Our findings showed that T1D significantly impaired the expression and distribution of these proteins, which may affect MTs organization and be associated with cytoskeletal disorganization, and impaired germ cell differentiation. Moreover, T1D rats exhibited reduced sperm count, viability, and motility, accompanied by increased DNA fragmentation and chromatin defects. Elevated levels of 4-hydroxy-2-nonenal (4-HNE), a marker of OS, were detected in SPZ, particularly in the acrosome and flagellum, correlating with mitochondrial dysfunction and ATP depletion. Additionally, decreased intracellular Ca levels, downregulation of Cation Channel of Sperm (CATSPER) and Voltage-Dependent Anion Channel 3 (VDAC3), and altered tubulin acetylation, possibly due to imbalanced Alpha-Tubulin N-Acetyltransferase 1 (ATAT1) and Histone Deacetylase 6 (HDAC6) expression, were also associated with impaired sperm motility. The combined data suggest that T1D-induced OS is linked to disrupted MTs dynamics, which may contribute to testicular dysfunction and reduced sperm quality, potentially affecting male fertility. A better understanding of these associations may support the development of therapeutic strategies to mitigate the reproductive consequences of T1D and improve male fertility outcomes.
1型糖尿病（T1D）是一种慢性代谢性疾病，其特征为持续性高血糖，可导致氧化应激（OS）和全身性并发症，包括男性生育力低下。本研究调查了T1D诱导的OS对睾丸和精子中微管（MTs）动力学及微管相关蛋白（MAPs）的潜在影响。使用链脲佐菌素诱导的T1D大鼠模型，我们检测了关键MAPs的表达和定位，包括微管亲和力调节激酶4（MARK4）、微管相关蛋白1A（MAP1A）、动力蛋白轻链LC8型1（DYNLL1）、脯氨酰内肽酶（PREP）和放射辐条头6同源物A（RSPH6A），同时检测了精子功能参数。我们的研究结果表明，T1D显著损害了这些蛋白的表达和分布，这可能影响MTs的组织，并与细胞骨架紊乱以及生殖细胞分化受损有关。此外，T1D大鼠的精子数量、活力和运动能力降低，同时DNA片段化和染色质缺陷增加。在精子中检测到氧化应激标志物4-羟基-2-壬烯醛（4-HNE）水平升高，特别是在顶体和鞭毛中，这与线粒体功能障碍和ATP耗竭相关。此外，细胞内钙水平降低、精子阳离子通道（CATSPER）和电压依赖性阴离子通道3（VDAC3）下调，以及微管蛋白乙酰化改变，可能是由于α-微管蛋白N-乙酰转移酶1（ATAT1）和组蛋白脱乙酰酶6（HDAC6）表达失衡所致，这些也与精子运动能力受损有关。综合数据表明，T1D诱导的OS与MTs动力学破坏有关，这可能导致睾丸功能障碍和精子质量下降，从而潜在影响男性生育能力。更好地理解这些关联可能有助于制定治疗策略，以减轻T1D对生殖的影响并改善男性生育结局。
