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

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. However, the association between elevated long-chain PUFAs in female C57BL/6J mouse retinas and the increased lipid peroxidation in female RP mice on the same background remains correlative rather than causal. Analysis of open bulk retina transcriptomic data from middle-aged humans found supplemental evidence of sex-related differences in retinal energy metabolism pathways. In addition to mechanistic studies aimed at uncovering the causes of differential lipid peroxidation between sexes, further research is needed to investigate sex differences in retinal metabolism and lipid composition across animal species. Our findings highlight the importance of considering sex differences when conducting preclinical experiments using RP models.