Table1_Sex-related differences in retinal function in Wistar rats: implications for toxicity and safety studies.docx

Introduction: Wistar Han rats are a preferred strain of rodents for general toxicology and safety pharmacology studies in drug development. In some of these studies, visual functional tests that assess for retinal toxicity are included as an additional endpoint. Although the influence of gender on human retinal function has been documented for more than 6 decades, preclinically it is still uncertain if there are differences in retinal function between naïve male and female Wistar Han rats.Methods: In this study, sex-related differences in the retinal function were quantified by analyzing electroretinography (ERG) in 7-9-week-old (n = 52 males and 51 females) and 21–23-week-old Wistar Han rats (n = 48 males and 51 females). Optokinetic tracking response, brainstem auditory evoked potential, ultrasonic vocalization and histology were tested and evaluated in a subset of animals to investigate the potential compensation mechanisms of spontaneous blindness.Results/Discussion: Absence of scotopic and photopic ERG responses was found in 13% of 7-9-week-old (7/52) and 19% of 21–23-week-old males (9/48), but none of female rats (0/51). The averaged amplitudes of rod- and cone-mediated ERG b-wave responses obtained from males were significantly smaller than the amplitudes of the same responses from age-matched females (−43% and −26%, respectively) at 7–9 weeks of age. There was no difference in the retinal and brain morphology, brainstem auditory responses, or ultrasonic vocalizations between the animals with normal and abnormal ERGs at 21–23 weeks of age. In summary, male Wistar Han rats had altered retinal responses, including a complete lack of responses to test flash stimuli (i.e., blindness), when compared with female rats at 7–9 and 21–23 weeks of age. Therefore, sex differences should be considered when using Wistar Han rats in toxicity and safety pharmacology studies with regards to data interpretation of retinal functional assessments.

引言：威斯塔耳汉大鼠是药物开发中用于一般毒理学和安全性药理学研究的一种优选啮齿动物品系。在这些研究中的某些案例中，评估视网膜毒性的视觉功能测试被纳入作为额外的终点指标。尽管性别对人类视网膜功能的影响已被记录超过六十载，但在临床前研究阶段，关于未经训练的雄性和雌性威斯塔耳汉大鼠之间是否存在视网膜功能差异仍存在不确定性。方法：在本研究中，通过分析7-9周龄（n = 52雄性，51雌性）和21-23周龄的威斯塔耳汉大鼠（n = 48雄性，51雌性）的电视网膜电图（ERG），量化了性别相关的视网膜功能差异。对部分动物进行了视动跟踪反应、脑干听觉诱发电位、超声波发声和病理学检测与评估，以研究自发性盲目的潜在补偿机制。结果/讨论：在7-9周龄的13%（7/52）和21-23周龄的19%（9/48）雄性大鼠中发现了暗适应和光适应ERG反应的缺失，但在雌性大鼠中则无此现象（0/51）。从雄性大鼠获得的棒体和锥体介导的ERG b波反应的平均幅度在7-9周龄时显著小于同年龄匹配雌性大鼠的反应幅度（分别减少43%和26%）。在21-23周龄时，在正常和异常ERG的动物之间，视网膜和大脑形态、脑干听觉反应或超声波发声均无差异。综上所述，与雌性大鼠相比，雄性威斯塔耳汉大鼠在7-9周和21-23周龄时表现出改变的视网膜反应，包括对测试闪光刺激的完全无反应（即失明）。因此，在使用威斯塔耳汉大鼠进行毒理学和安全性药理学研究时，应考虑性别差异，尤其是在解读视网膜功能评估数据时。