Glutamate Cysteine Ligase Modifier Subunit (Gclm) Null Mice Have Increased Ovarian Oxidative Stress and Accelerated Age-Related Ovarian Failure

Abstract

Glutathione (GSH) is the one of the most abundant intracellular antioxidants. Mice lacking the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, have decreased GSH. Our prior work showed that GSH plays antiapoptotic roles in ovarian follicles. We hypothesized that Gclm(-/-) mice have accelerated ovarian aging due to ovarian oxidative stress. We found significantly decreased ovarian GSH concentrations and oxidized GSH/oxidized glutathione redox potential in Gclm(-/-) vs Gclm(+/+) ovaries. Prepubertal Gclm(-/-) and Gclm(+/+) mice had similar numbers of ovarian follicles, and as expected, the total number of ovarian follicles declined with age in both genotypes. However, the rate of decline in follicles was significantly more rapid in Gclm(-/-) mice, and this was driven by accelerated declines in primordial follicles, which constitute the ovarian reserve. We found significantly increased 4-hydroxynonenal immunostaining (oxidative lipid damage marker) and significantly increased nitrotyrosine immunostaining (oxidative protein damage marker) in prepubertal and adult Gclm(-/-) ovaries compared with controls. The percentage of small ovarian follicles with increased granulosa cell proliferation was significantly higher in prepubertal and 2-month-old Gclm(-/-) vs Gclm(+/+) ovaries, indicating accelerated recruitment of primordial follicles into the growing pool. The percentages of growing follicles with apoptotic granulosa cells were increased in young adult ovaries. Our results demonstrate increased ovarian oxidative stress and oxidative damage in young Gclm(-/-) mice, associated with an accelerated decline in ovarian follicles that appears to be mediated by increased recruitment of follicles into the growing pool, followed by apoptosis at later stages of follicular development.

Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice

“…In our study, we observed an up-regulation of Cox4 and Cox5a mRNA in the adipose tissue of O 3 -exposed mice. The proteins encoded by Gclm and Scd1 are rate-limiting enzymes in glutathione synthesis and fatty acid metabolism respectively, and are both important regulators in oxidative stress (Lim et al 2015; Liu et al 2011; Yang et al 2002). The expressions of Gclm and Scd1 both increased in visceral adipose tissue after exposure to O 3 .…”

Does air pollution play a role in infertility?: a systematic review

“…Excess ROS, however, leads to a state of oxidative stress and appears to be harmful to ovarian functions. In their study of mutated mice with a deficit of glutathione, the most abundant intracellular antioxidant, Lim et al described a faster decrease in the number of ovarian follicles in these mutated mice, related to an acceleration in primordial follicle depletion [101]. They also reported a higher percentage of small follicles with a heavy proliferation of granulosa cells, reflecting the accelerated recruitment of primordial follicles.…”

Resveratrol protects the ovary against chromium-toxicity by enhancing endogenous antioxidant enzymes and inhibiting metabolic clearance of estradiol

“…CrVI also caused POF in F1 offspring by disrupting POF marker protein X-prolyl aminopeptidase-2 in a rat model (Banu et al, 2015). A recent study by Lim et al reports that increased ovarian oxidative stress in young Gclm knock-out mice suffer from ovarian failure due to an accelerated decline in ovarian follicles mediated by increased recruitment of follicles into the growing pool, followed by apoptosis at later stages of follicular development (Lim et al, 2015). We have recently shown that AOXs, vitamin C and edaravone mitigated CrVI-induced ovarian toxicity (Banu et al, 2008; Stanley et al, 2011; Stanley et al, 2013; Stanley et al, 2014).…”