The impact of the endocrine-disrupting chemicals on the glucose-6-phosphate dehydrogenase enzyme activity

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TL;DR

This narrative review examines how endocrine-disrupting chemicals (EDCs) impair glucose-6-phosphate dehydrogenase (G6PD) activity, the rate-limiting enzyme of the pentose phosphate pathway critical for NADPH production and antioxidant defense. Both natural EDCs (e.g., phytoestrogens, genistein, catechins) and environmental EDCs (e.g., BPA, phthalates, butylparaben, cadmium) alter G6PD activity at transcriptional, translational, and posttranslational levels across multiple species and tissues. The authors conclude that EDC-induced G6PD dysregulation contributes to oxidative stress, lipid dysregulation, insulin resistance, and obesity, with G6PD-deficient individuals being particularly vulnerable to adverse health outcomes.

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**Background:** Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme of the pentose phosphate pathway (PPP), catalyzing the conversion of glucose-6-phosphate to 6-phosphogluconolactone while reducing NADP+ to NADPH. NADPH is essential for reductive biosynthesis, maintaining reduced glutathione (GSH), protection against reactive oxygen species (ROS), and detoxification of xenobiotics. G6PD activity is tightly regulated via the NADPH/NADP+ ratio, extracellular oxidants, and posttranslational modifications including phosphorylation, acetylation, glycosylation, ubiquitinylation, and glutarylation. Endocrine-disrupting chemicals (EDCs) are synthetic chemicals found in cosmetics, pharmaceuticals, food packaging, pesticides, and hygiene products that interfere with hormone metabolism. Since EDCs activate peroxisome proliferator-activated receptors (PPARs) and disrupt lipid, glucose, and energy metabolism, they are referred to as obesogens. This narrative review synthesizes evidence on how EDCs impact G6PD enzyme activity across different species and tissues.

**Methods:** This is a narrative review summarizing published literature on the effects of natural and environmental EDCs on G6PD activity. The authors compiled data from studies examining EDC exposure in human cell lines, rat and mouse models, lamb kidney tissue, and purified enzyme preparations. Natural EDCs reviewed include dehydroepiandrosterone (DHEA), 17β-estradiol, genistein, plant extracts (Ferula assafoetida, Melia azedarach, Saraca asoca), green tea catechins (epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin), testosterone, and estradiol. Environmental EDCs reviewed include butylparaben, di(2-ethylhexyl) phthalate (DEHP), methoxychlor, bisphenol A (BPA), 4-nonylphenol (NP), 4-octylphenol (OP), zinc, and cadmium.

**Key Results:** The effects of EDCs on G6PD activity are tissue- and chemical-specific. Natural EDCs: DHEA decreases G6PD activity in human breast cancer cells; 17β-estradiol increases G6PD activity in breast cancer cells; genistein increases G6PD activity in mouse testis; Ferula assafoetida and Melia azedarach extracts decrease G6PD activity in rat uterus; Saraca asoca extracts show dose-dependent effects on blood G6PD activity in rats; epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin inhibit purified G6PD enzyme from Leuconostoc mesenteroides; testosterone and estradiol increase G6PD activity in rat muscle in a dose-dependent manner. Environmental EDCs: butylparaben decreases G6PD activity in rat liver but increases activity in kidney and spleen; DEHP increases G6PD activity in rat liver with mixed effects in kidney; methoxychlor increases G6PD activity in mouse uterus; BPA, 4-nonylphenol, and 4-octylphenol increase G6PD activity in human breast cancer (MCF-7) cells in a concentration-dependent manner; zinc and cadmium inhibit G6PD activity in lamb kidney. Mechanistically, EDCs influence G6PD through multiple pathways: BPA activates hypoxia-inducible factor 1α (HIF-α) and vascular endothelial growth factor (VEGF) via G-protein estrogen receptor (GPER) signaling; bisphenols regulate nuclear factor erythroid 2-related factor 2 (Nrf2), which transcriptionally induces G6PD; BPA activates ataxia-telangiectasia mutated kinase (ATM); 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces the TGF-beta1-Smad pathway and oxidative stress, increasing G6PD activity. BPA administration reduces G6PD activity in erythrocytes, leading to hemolysis and morphological changes, which may be life-threatening in G6PD-deficient individuals. Toxic metals including cadmium, lead, silver nitrate, thallium sulfate, cobalt, nitrate, arsenic oxide, and arsenic, as well as essential trace metals copper, nickel, and manganese, are associated with G6PD enzyme inhibition. Cadmium and zinc specifically inhibit G6PD in lamb kidneys. Heavy metals can denature enzymes by disrupting disulfide bonds in secondary and tertiary protein structures.

**Clinical Implications:** Altered G6PD activity is associated with lipid dysregulation, insulin resistance, increased body weight, and obesity, as G6PD is a common player in glycolysis, gluconeogenesis, PPP, and lipid metabolism. The authors suggest that EDCs dysregulate oxidative stress, lipid, and glucose metabolism by interfering with G6PD enzyme activity. G6PD has been proposed as a sensitive biomarker for predicting BPA-mediated diseases in colon cancer cells (SW480), mammary glands, and Sertoli cells. Individuals with G6PD deficiency are more vulnerable to EDC-induced adverse health effects, including endocrine, cardiovascular, and metabolic disorders, as well as oxidative stress-induced disorders. Workplace exposure to heavy metals such as lead can cause hematotoxicity, hematopoietic malignancies, and mortality in G6PD-deficient individuals. The review emphasizes that since EDCs are ubiquitous in industrial products and humans are exposed daily via inhalation, ingestion, and dermal routes, understanding their impact on G6PD activity is critical for public health, particularly for G6PD-deficient populations.