Selective effects of estradiol on human corneal endothelial cells.

In Fuchs endothelial corneal dystrophy (FECD), mitochondrial and oxidative stresses in corneal endothelial cells (HCEnCs) contribute to cell demise and disease progression. FECD is more common in women than men, but the basis for this observation is poorly understood. To understand the sex disparity in FECD prevalence, we studied the effects of the sex hormone 17-ß estradiol (E2) on growth, oxidative stress, and metabolism in primary cultures of HCEnCs grown under physiologic ([O2]2.5) and hyperoxic ([O2]A) conditions. We hypothesized that E2 would counter the damage of oxidative stress generated at [O2]A. HCEnCs were treated with or without E2 (10 nM) for 7-10 days under both conditions. Treatment with E2 did not significantly alter HCEnC density, viability, ROS levels, oxidative DNA damage, oxygen consumption rates, or extracellular acidification rates in either condition. E2 disrupted mitochondrial morphology in HCEnCs solely from female donors in the [O2]A condition. ATP levels were significantly higher at [O2]2.5 than at [O2]A in HCEnCs from female donors only, but were not affected by E2. Our findings demonstrate the resilience of HCEnCs against hyperoxic stress. The effects of hyperoxia and E2 on HCEnCs from female donors suggest cell sex-specific mechanisms of toxicity and hormonal influences.

Selective effects of estradiol on human corneal endothelial cells.

Fuchs endothelial corneal dystrophy (FECD) results from genetic and environmental factors triggering mitochondrial and oxidative stress in corneal endothelial cells (CEnCs) leading to CEnC death and corneal opacification. FECD is more common in women than men, but the basis for this observation is unknown. Because FECD is commonly diagnosed around the time of the menopausal transition in women when estrogen levels decrease precipitously, we studied the effects of the potent estrogen,17-ß estradiol (E2) on growth, oxidative stress, and metabolism in primary cultures of human CEnCs (HCEnCs) under conditions of physiologic 2.5% O 2 ([O 2 ] 2.5 ) and under hyperoxic stress ([O 2 ] A : room air + 5% CO 2 ). We hypothesized that E2 would counter the stresses of the hyperoxic environment in HCEnCs. HCEnCs were treated ± 10 nM E2 for 7-10 days at [O 2 ] 2.5 and [O 2 ] A followed by measurements of cell density, viability, reactive oxygen species (ROS), mitochondrial morphology, oxidative DNA damage, ATP levels, mitochondrial respiration (O 2 consumption rate [OCR]), and glycolysis (extracellular acidification rate [ECAR]). There were no significant changes in HCEnC density, viability, ROS levels, oxidative DNA damage, OCR, and ECAR in response to E2 under either O 2 condition. We found that E2 disrupted mitochondrial morphology in HCEnCs from female donors but not male donors at the [O 2 ] A condition. ATP levels were significantly higher at [O 2 ] 2.5 compared to [O 2 ] A in HCEnCs from female donors only, but were not affected by E2. Our findings demonstrate the overall resilience of primary HCEnCs against hyperoxic stress. The selective detrimental effects of hyperoxia and estradiol on HCEnCs from female but not male donors suggests mechanisms of toxicity based upon cell-sex in addition to hormonal environment.