Abstract 202: Sex Differences In Ischemic Stroke: The Role Of Genetic Sex

Abstract

Background/Purpose— Ischemic stroke is now recognized as a sexually dimorphic disease with women enjoying lower stroke incidence relative to men until an advanced age. This has largely been attributed to the neuroprotective effects of estrogen in females. However, recent failure of estrogen supplementation clinical trials and in vitro studies showing differences in ischemic sensitivity in sex steroid depleted media, suggest that factors other than hormones may shape this dichotomy. Since the sex chromosomal complement differs in men (XY) and women (XX), this may contribute to the underlying etiology of sex differences. The objective of this study was to investigate the genetic sex contributions to the etiology of sex differences in cerebral ischemia. Since it is extremely difficult to dissect the effects of sex chromosomes from hormones, we used a four core genotype (FCG) mouse model in this study where, Sry, the testis determining gene is deleted from the Y chromosome and inserted on an autosome in XY - SryMale(XYM). The four different genotypes, XXM(XX male), XYM(XY male), XXF(XX female) and XYF(XY female) derived by a cross between XXF and XYM can be compared to study the influence of sex chromosome(XX/XY) or sex(Sry/hormones) in stroke sensitivity. Methods— Stroke was induced by 90 minutes MCAO in FCG mice. Histological assessment was performed at 24 and 72 hours after stroke using cresyl violet staining. Sry PCR was done on brain samples from these mice. Results— At 24 hrs after MCAO, XXF’s(18.7±1.6%) and XYF’s(15.6±4%) had significantly smaller total hemispheric infarcts compared to either XYM’s(35±6.8%) or XXM’s(28±6.5%). ANOVA revealed a main effect of sex, F(1,12)=4.9,p<0.05. Hemispheric infarcts at 72 hours post stroke show a similar trend, with XXF’s(22±3.2%) and XYF’s(21±1%) having smaller hemispheric infarcts vs. XYM’s(35±7%) or XXM’s(30±2%). Sry mRNA expression was seen in brains of XXM’s and XYM’s. Conclusions- We found a sex effect in this study as all mice with Sry gene(XXM, XYM) had higher injury. It remains possible that these effects were secondary to the protective effects of estrogen (in XXF and XYF). However, this is unlikely as our preliminary studies have shown that XYF’s have very low estrogen levels (equivalent to males). Thus, we conclude that these differences may be due to the detrimental effects of Sry gene in the male brain. It is speculated that Sry may be the missing piece of puzzle that mediates sex specific cell death after stroke. Studies in gonadectomized FCG mice to further dissociate hormonal effects from direct effects of Sry are ongoing.