Glucose 6-phosphate dehydrogenase deficiency enhances germ cell apoptosis and causes defective embryogenesis in Caenorhabditis elegans

Abstract

Glucose 6-phosphate dehydrogenase (G6PD) deficiency, known as favism, is classically manifested by hemolytic anemia in human. More recently, it has been shown that mild G6PD deficiency moderately affects cardiac function, whereas severe G6PD deficiency leads to embryonic lethality in mice. How G6PD deficiency affects organisms has not been fully elucidated due to the lack of a suitable animal model. In this study, G6PD-deficient Caenorhabditis elegans was established by RNA interference (RNAi) knockdown to delineate the role of G6PD in animal physiology. Upon G6PD RNAi knockdown, G6PD activity was significantly hampered in C. elegans in parallel with increased oxidative stress and DNA oxidative damage. Phenotypically, G6PD-knockdown enhanced germ cell apoptosis (2-fold increase), reduced egg production (65% of mock), and hatching (10% of mock). To determine whether oxidative stress is associated with G6PD knockdown-induced reproduction defects, C. elegans was challenged with a short-term hydrogen peroxide (H2O2). The early phase egg production of both mock and G6PD-knockdown C. elegans were significantly affected by H2O2. However, H2O2-induced germ cell apoptosis was more dramatic in mock than that in G6PD-deficient C. elegans. To investigate the signaling pathways involved in defective oogenesis and embryogenesis caused by G6PD knockdown, mutants of p53 and mitogen-activated protein kinase (MAPK) pathways were examined. Despite the upregulation of CEP-1 (p53), cep-1 mutation did not affect egg production and hatching in G6PD-deficient C. elegans. Neither pmk-1 nor mek-1 mutation significantly affected egg production, whereas sek-1 mutation further decreased egg production in G6PD-deficient C. elegans. Intriguingly, loss of function of sek-1 or mek-1 dramatically rescued defective hatching (8.3- and 9.6-fold increase, respectively) induced by G6PD knockdown. Taken together, these findings show that G6PD knockdown reduces egg production and hatching in C. elegans, which are possibly associated with enhanced oxidative stress and altered MAPK pathways, respectively.

Impaired embryonic development in glucose-6-phosphate dehydrogenase-deficient Caenorhabditis elegans due to abnormal redox homeostasis induced activation of calcium-independent phospholipase and alteration of glycerophospholipid metabolism

“…7 The morphology of G6PD-deficient embryos was examined by microscopy (Figure 1). Unlike normal embryos, G6PD-deficient embryos displayed irregular, flattened and an egg-filling phenotype, indicating that the structure of G6PD-deficient embryos may be influenced by osmotic changes (Figure 1a).…”

“…7 Reduced NADPH production and enhanced lipid peroxidation are associated with increased iPLA activity in G6PD-deficient embryos. Inhibition of multiple iPLAs by genetic manipulation can alleviate the embryonic impairment caused by G6PD deficiency.…”

Do worms protect against the metabolic syndrome? A systematic review and meta-analysis

“…There is a growing body of evidence from animal research supporting the hypothesis that specific helminth infections protect against metabolic disease. Mouse studies have shown that experimental infection with helminths can result in reduced fasting glucose concentrations, decreased fasting insulin concentrations, improved glucose and insulin tolerance, and less insulin resistance in comparison to non-infected controls [25][26][27][28][29].…”

Bioinformatics analysis of the serine and glycine pathway in cancer cells

“…Pre-clinical and clinical studies have shown that reducing glucose intake was associated with negative effect on tumor growth [ 107 – 111 ]. Moreover, it has been show that in a tumor in xenograft mouse model, the tumor growth of p53n −/− cells was reduced in mice fed with a diet containing no serine and glycine [ 52 ].…”