2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline Alters Autophagosome Maturation, Cellular Lipidomic Profiles, and Expression of Core Pluripotent Factors

Abstract

2-Amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx), one of the most abundant heterocyclic aromatic amines (HAAs) found in the human diet, is primarily produced during high-temperature meat or fish cooking. While MeIQx has been investigated as a potential carcinogen, the cytotoxicity and related molecular mechanisms remain unclear. Here, we demonstrate that autophagosome maturation is blocked by MeIQx. Mechanistically, MeIQx inhibits acidification of lysosomes rather than prevents autophagosome−lysosome fusion. Moreover, cellular lipid profiles are altered by MeIQx treatment. Notably, many phospholipids and sphingolipids are significantly upregulated after exposure to MeIQx. Furthermore, MeIQx decreases expression of pluripotency-associated proteins in mouse embryonic stem cells (ESCs). Together, MeIQx blocks autophagosome maturation through inhibiting acidification of lysosomes, alters lipid metabolism, and decreases expression of pluripotent factors. Our studies provide more cytotoxic evidence and elucidate related mechanisms on the risk of HAA exposure and are expected to promote supervision of food safety and human health.

Protective Effect of Phloretin against Hydrogen Peroxide-Induced Oxidative Damage by Enhancing Autophagic Flux in DF-1 Cells

“…Lysotracker Red Staining. Lysosomal pH was determined as previously described [25]. The treated cells were incubated with 1 μM Lysotracker Red dye for 30 min at 37 °C cell incubator and protected from light.…”

Combining metabolomics with bioanalysis methods to investigate the potential toxicity of dihexyl phthalate

“…RNA extraction and quantitative real-time PCR (qPCR) procedures were performed as described previously. 41 The gene for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was used as an internal control. The primer sequences used for qPCR are listed in Table S1.…”

Three‐dimensional printed microfluidic mixer/extractor for cell lysis and lipidomic profiling by matrix‐assisted laser desorption/ionization mass spectrometry

“…Lipids in cell membranes play critical roles in many aspects of cellular functions, such as membrane formation, bioactive inter‐ and intracellular signaling, and energy storage 4,5 . Understanding the composition and changes of lipid membranes under various conditions/states are essential to the deciphering of many cellular mechanisms and disease progression 6,7 . Lipidomics, a study aiming at the identification and quantification of a large scale of lipid species in organisms, has attracted widespread attention, 8 and has proved to be a powerful tool for cytotoxicity studies by tracking changes in lipid composition associated with environmental changes induced by chemicals/drugs/toxicants, as we have recently demonstrated 9 .…”

“…4,5 Understanding the composition and changes of lipid membranes under various conditions/states are essential to the deciphering of many cellular mechanisms and disease progression. 6,7 Lipidomics, a study aiming at the identification and quantification of a large scale of lipid species in organisms, has attracted widespread attention, 8 and has proved to be a powerful tool for cytotoxicity studies by tracking changes in lipid composition associated with environmental changes induced by chemicals/drugs/toxicants, as we have recently demonstrated. 9 Considerable progress has been reported that spans the fields of drug screening, biomarkers discovery, and cancer diagnosis.…”