Sex-related differences in retinal function in Wistar rats: implications for toxicity and safety studies

Frontiers in Toxicology

Toxicology

Cheryl Tyszkiewicz¹  Ben Jakubczak¹  Seo-Kyoung Hwang¹  Rosemary Santos¹  Chang-Ning Liu¹  Michael W. Bolt²  Karen M. Walters³  Balasubramanian Manickam³ 

[1] Comparative Medicine, Pfizer, Groton, CT, United States;Drug Safety Research and Development, Pfizer, Cambridge, Massachusetts, United States;Drug Safety Research and Development, Pfizer, Groton, CT, United States;

关键词: retinal function;    toxicity;    Wistar Han;    sex;    electroretinography (ERG);   

DOI  :  10.3389/ftox.2023.1176665

 received in 2023-02-28, accepted in 2023-05-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

Unknown   
Copyright © 2023 Tyszkiewicz, Hwang, Manickam, Jakubczak, Walters, Bolt, Santos and Liu.