Abstract
Purpose :
We recently described that male sex is associated with a more severe corneal edema phenotype in children with CHED and in a mouse model of CHED. Therefore, we investigated the roles of gonadal sex hormones in causing this sex difference.
Methods :
Slc4a11-/- (KO, n=41) mice and Slc4a11+/+ (WT, n=42) littermate controls were subject to gonadectomy (GDX) at 4 weeks of age. A total of 41 mice received GDX and 42 mice received sham surgery with balanced numbers in each sex (Table 1). Central corneal thickness (CCT) was measured in both eyes of each mouse by anterior segment OCT once before surgery and monthly thereafter for 5 months. The CCT used for statistical analysis was the average CCT of both eyes at a given time in each mouse. Generalized Linear Mixed Model (GLMM) was used to analyze the interaction effect of surgery type (GDX vs Sham), sex (Female vs Male) and genotype (KO vs WT) on CCT when controlling for age, followed by post-hoc pairwise comparisons of CCT between groups with Šidák correction.
Results :
GLMM revealed significant interaction effect between surgery type, sex and genotype (p < 0.0001). Model estimated CCT (µm) at 25 weeks of age for each group are shown in mean ± SEM (95% CI) as follows: KO-Male-Sham 213.8 ± 4.9 (204.3 – 223.4), KO-Male-GDX 226.8 ± 7.2 (212.7 – 240.9), KO-Female-Sham 181.3 ± 5.0 (171.4 – 191.1), KO-Female-GDX 204.6 ± 4.6 (195.6 – 213.7), WT-Male-Sham 92.4 ± 0.8 (90.9 – 94.0), WT-Male-GDX 95.1 ± 2.0 (91.1 – 99.2), WT-Female-Sham 91.9 ± 1.4 (89.1 – 94.7), and WT-Female-GDX 92.9 ± 1.1 (90.8 – 94.9). The increase of CCT in KO-Female-GDX is significant (p < 0.0001) compared to KO-Female-Sham. There is no significant difference in CCT in KO-Male-GDX compared to KO-Male-Sham (p = 0.077). While the difference of CCT between KO-Female-GDX and KO-Male-Sham is not significant, CCTs between KO-Female-GDX and KO-Male-GDX remained significant (p = 0.003). CCT values in WT-Male-Sham, WT-Male-GDX, WT-Female-Sham and WT-Female-GDX are not different among each other.
Conclusions :
Removal of gonadal sex hormones by GDX worsens corneal edema only in KO female mice, eliminating the sex difference observed in Sham groups between male and female KO mice. These data suggest gonadal estrogens play a protective role in maintaining corneal deturgescence in the setting of loss of SLC4A11 function.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.