Department of Pharmaceutical Sciences, System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107-2699, USA.
Biol Sex Differ. 2024 Apr 25;15(1):38. doi: 10.1186/s13293-024-00613-3.
Obstructive sleep apnea (OSA) affects 10-26% of adults in the United States with known sex differences in prevalence and severity. OSA is characterized by elevated inflammation, oxidative stress (OS), and cognitive dysfunction. However, there is a paucity of data regarding the role of sex in the OSA phenotype. Prior findings suggest women exhibit different OSA phenotypes than men, which could result in under-reported OSA prevalence in women. To examine the relationship between OSA and sex, we used chronic intermittent hypoxia (CIH) to model OSA in rats. We hypothesized that CIH would produce sex-dependent phenotypes of inflammation, OS, and cognitive dysfunction, and these sex differences would be dependent on mitochondrial oxidative stress (mtOS).
Adult male and female Sprague Dawley rats were exposed to CIH or normoxia for 14 days to examine the impact of sex on CIH-associated circulating inflammation (IL-1β, IL-6, IL-10, TNF-α), circulating steroid hormones, circulating OS, and behavior (recollective and spatial memory; gross and fine motor function; anxiety-like behaviors; and compulsive behaviors). Rats were implanted with osmotic minipumps containing either a mitochondria-targeting antioxidant (MitoTEMPOL) or saline vehicle 1 week prior to CIH initiation to examine how inhibiting mtOS would affect the CIH phenotype.
Sex-specific differences in CIH-induced inflammation, OS, motor function, and compulsive behavior were observed. In female rats, CIH increased inflammation (plasma IL-6 and IL-6/IL-10 ratio) and impaired fine motor function. Conversely, CIH elevated circulating OS and compulsivity in males. These sex-dependent effects of CIH were blocked by inhibiting mtOS. Interestingly, CIH impaired recollective memory in both sexes but these effects were not mediated by mtOS. No effects of CIH were observed on spatial memory, gross motor function, or anxiety-like behavior, regardless of sex.
Our results indicate that the impact of CIH is dependent on sex, such as an inflammatory response and OS response in females and males, respectively, that are mediated by mtOS. Interestingly, there was no effect of sex or mtOS in CIH-induced impairment of recollective memory. These results indicate that mtOS is involved in the sex differences observed in CIH, but a different mechanism underlies CIH-induced memory impairments.
阻塞性睡眠呼吸暂停（OSA）影响美国 10-26%的成年人，其患病率和严重程度存在明显的性别差异。OSA 的特征是炎症、氧化应激（OS）和认知功能障碍升高。然而，关于性别在 OSA 表型中的作用的数据很少。先前的研究结果表明，女性的 OSA 表型与男性不同，这可能导致女性 OSA 的患病率被低估。为了研究 OSA 与性别的关系，我们使用慢性间歇性缺氧（CIH）来建立大鼠 OSA 模型。我们假设 CIH 会导致炎症、OS 和认知功能障碍的性别依赖性表型，这些性别差异将依赖于线粒体氧化应激（mtOS）。
成年雄性和雌性 Sprague Dawley 大鼠分别接受 CIH 或常氧处理 14 天，以研究性别对 CIH 相关循环炎症（IL-1β、IL-6、IL-10、TNF-α）、循环类固醇激素、循环 OS 和行为（再认和空间记忆；大运动和精细运动功能；焦虑样行为；和强迫行为）的影响。大鼠在 CIH 开始前 1 周植入含有线粒体靶向抗氧化剂（MitoTEMPOL）或盐水载体的渗透微型泵，以研究抑制 mtOS 如何影响 CIH 表型。
观察到 CIH 诱导的炎症、OS、运动功能和强迫行为存在性别特异性差异。在雌性大鼠中，CIH 增加了炎症（血浆 IL-6 和 IL-6/IL-10 比值）和精细运动功能障碍。相反，CIH 增加了雄性的循环 OS 和强迫行为。这些 CIH 的性别依赖性效应被抑制 mtOS 所阻断。有趣的是，CIH 损害了两性的再认记忆，但这些影响不受 mtOS 介导。无论性别如何，CIH 均未观察到对空间记忆、大运动功能或焦虑样行为的影响。
我们的结果表明，CIH 的影响取决于性别，例如女性的炎症反应和男性的 OS 反应，这些反应受 mtOS 介导。有趣的是，在 CIH 引起的再认记忆损伤中，性别或 mtOS 没有影响。这些结果表明，mtOS 参与了 CIH 中观察到的性别差异，但导致 CIH 引起的记忆损伤的机制不同。
