>>39727243https://pmc.ncbi.nlm.nih.gov/articles/PMC6606734/The biological underpinnings of sexual differentiation in males and females have traditionally been considered to be based on sex chromosomes and production of sex hormones that interact with their cellular receptors. Many conditions in human health and disease are sexually dimorphic with different manifestations and outcomes in males and females. More recently it has become apparent that these differences exist independent of hormonal differences and that the differences are not just in the input of signal through the receptor to the cell but there are differences in the cellular output and response. The anatomic and pathologic correlates of this have been well-described with many clinical conditions, including cerebral ischemia and stroke, in the developing male and female brain (6, 7).
In a series of experiments conducted using developing neurons derived separately from male (XY) and female (XX) rats, Du et al. have delineated the innate differences in cell death pathways (41). Male cells are more susceptible to nitrosative stress and glutamate related excitotoxicity with triggering of Apoptosis Inducible Factor (AIF) and caspase independent cell death or necrosis. On the contrary, when female cells were exposed to a cytotoxic agent such as etopside and sturosporine they were able to trigger a caspase-3 mediated programmed cell-death response mediated by cytochrome-c. They explained this by the innate difference in cellular glutathione anti-oxidant effects where female cells were able to maintain a higher glutathione levels under stress, irrespective of effect of sex hormones
