Female sex is a risk factor for exacerbated lipid peroxidation and disease in murine retinitis pigmentosa

Abstract Oxidative stress is an important aspect in retinal degenerations that could be targeted in various forms of currently untreatable diseases. It is generally believed that males are more predisposed to oxidative stress than females due to their higher metabolic activity and/or lower antioxidant capacity. However, studies using mouse disease models have demonstrated that photoreceptor degeneration progresses faster in females. Sex hormones likely play a role, but the cellular mechanism behind the sex difference is unclear. In the current study, we confirmed that the accelerated disease phenotype in female rd10 and P23H retinitis pigmentosa mice coincides with sexual maturity, and further, we found that it co-occurs with increased retinal lipid peroxidation. Instead, protein oxidation and inflammatory marker levels were similar between the sexes. Retinal lipid profiling revealed higher levels of polyunsaturated fatty acid (PUFA)-containing lipids in healthy 2-month-old female mice compared to males, whereas before puberty the sex difference in retinal PUFAs was absent. Analysis of open bulk retina transcriptomic data from middle-aged humans found supplemental evidence of sex-related differences in retinal energy metabolism pathways. Besides mechanistic study directed to reveal the reasons for differential lipid peroxidation between sexes, more research needs to be directed to study sex differences in retinal metabolism and lipid composition across animal species. The current results highlight the need to consider the impact of sex differences when undertaking preclinical experiments with RP models. Significance statement This article suggests female sex as a significant risk factor for progressive photoreceptor degenerative disease, based on experiments in two widely used retinitis pigmentosa mouse models. The disease phenotype in females accelerates markedly after sexual maturity, especially in mice carrying the autosomal dominant P23H rhodopsin mutation. This acceleration is associated with intensified retinal lipid peroxidation. Given the retina’s high energy demand, continuous photoreceptor cilia renewal, and constant light exposure that generates reactive oxygen species, the susceptibility of photoreceptor membranes to oxidative damage is substantial. Our findings suggest that retinal metabolism may differ between sexes after puberty, potentially influenced by sex hormones, which could contribute to the increased vulnerability of females to photoreceptor degenerative diseases.