Tert-Butyl Hydroperoxide (tBHP)-Induced Lipid Peroxidation and Embryonic Defects Resemble Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency in C. elegans.

Hung-Chi Yang,Arnold Stern,Daniel Chiu,Wen-Ye Tjong,Tian-Hsiang Ma,Hsiang Yu

doi:10.3390/ijms21228688

Abstract

G6PD is required for embryonic development in animals, as severe G6PD deficiency is lethal to mice, zebrafish and nematode. Lipid peroxidation is linked to membrane-associated embryonic defects in Caenorhabditis elegans (C. elegans). However, the direct link between lipid peroxidation and embryonic lethality has not been established. The aim of this study was to delineate the role of lipid peroxidation in gspd-1-knockdown (ortholog of g6pd) C. elegans during reproduction. tert-butyl hydroperoxide (tBHP) was used as an exogenous inducer. Short-term tBHP administration reduced brood size and enhanced germ cell death in C. elegans. The altered phenotypes caused by tBHP resembled GSPD-1 deficiency in C. elegans. Mechanistically, tBHP-induced malondialdehyde (MDA) production and stimulated calcium-independent phospholipase A2 (iPLA) activity, leading to disturbed oogenesis and embryogenesis. The current study provides strong evidence to support the notion that enhanced lipid peroxidation in G6PD deficiency promotes death of germ cells and impairs embryogenesis in C. elegans.

Highlights

The production of nicotinamide adenine dinucleotide phosphate (NADPH) by glucose-6-phosphate dehydrogenase (G6PD) is crucial for cellular reductive biosynthesis and redox homeostasis [1]
The current study revealed for the first time that a short-term tert-butyl hydroperoxide (tBHP) administration can reduce brood size similar to that observed with GSPD-1 deficiency in C. elegans [5]
Such administration phenocopies elevated germ cell apoptosis induced by GSPD-1 deficiency. Both malondialdehyde (MDA) and independent phospholipase A2 (iPLA) activity were shown to be increased by tBHP administration, which resembles GSPD-1 deficiency in C. elegans [6]. These findings clearly demonstrate that tBHP-mediated lipid peroxidation can render reproductive activities of GSPD-1 deficient C. elegans abnormal due to the activation of iPLA by MDA leading to eventual germ cell death and embryonic lethality

Summary

Introduction

The production of nicotinamide adenine dinucleotide phosphate (NADPH) by glucose-6-phosphate dehydrogenase (G6PD) is crucial for cellular reductive biosynthesis and redox homeostasis [1]. G6PD deficiency in humans is an X-linked disorder affecting 400 million people globally and is highly prevalent across malarial endemic regions [3]. Similar to the G6PD-deficient murine models, the gspd-1-knockdown (ortholog of g6pd) nematode Caenorhabditis elegans (C. elegans) exhibits a severe hatching defect [5]. It displays multiple embryonic impairments, including abnormal eggshell structure, enhanced permeability, defective polarity and cytokinesis [6]. These membrane-associated defects have been linked to disturbed membrane lipid composition caused by the activation of calcium-independent phospholipase A2 (iPLA) due to elevated lipid peroxidation [6]

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