Low concentrations of bisphenol A induce lipid accumulation mediated by the production of reactive oxygen species in the mitochondria of HepG2 cells

International audienceBisphenol A (BPA) is an endocrine-disrupting chemical that leaches from polycarbonate plastics that consequently leads to low-dose human exposure. In addition to its known xenoendocrine action, BPA exerts a wide variety of metabolic effects, but no data are available on its actions on the functions of liver mitochondrial. To assess these effects, HepG2 cells were exposed to BPA (10(-4)-10(-12)M) and physiological parameters were measured by flow cytometry. We demonstrated a significant mitochondrial dysfunction including ROS production, ΔΨ(M) hyperpolarization, lipid accumulation, lipoperoxidation and the release of pro-inflammatory cytokines. In conclusion, we showed that low concentrations of BPA promote lipid accumulation in hepatic cells triggered by disturbances in mitochondrial function, alterations in lipid metabolism and by inflammation that can therefore contribute to steatosis

Stefan Grimm, 1963-2014, a tragic loss for the scientific community Obituary

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Chemistry and biochemistry of lipid peroxidation products

Oxidative stress and resulting lipid peroxidation is involved in various and numerous pathological states including inflammation, atherosclerosis, neurodegenerative diseases and cancer. This review is focused on recent advances concerning the formation, metabolism and reactivity towards macromolecules of lipid peroxidation breakdown products, some of which being considered as 'second messengers' of oxidative stress. This review relates also new advances regarding apoptosis induction, survival/proliferation processes and autophagy regulated by 4-hydroxynonenal, a major product of omega-6 fatty acid peroxidation, in relationship with detoxication mechanisms. The use of these lipid peroxidation products as oxidative stress/lipid peroxidation biomarkers is also addressed

NHE-1 Relocation Outside Cholesterol-rich Membrane Microdomains is Associated with its Benzo[a]pyrene-related Apoptotic Function

Background: Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene ( B[a] P), are ubiquitous toxic environmental pollutants capable of inducing cell death. Intracellular pH plays a key role in the regulation of cell survival and death. Our previous works have demonstrated that intracellular alkalinization mediated by Na+/H+ exchanger 1 (NHE-1) is a critical event involved in B[a] P-induced apoptosis. The aim of this study was to further elucidate the mechanisms of NHE-1 activation upon B[a] P exposure. Methods: We tested the effects of plasma membrane cholesterol enrichment or depletion on B[a] P-induced NHE-1 activation related to apoptosis. We isolated cholesterol-rich plasma membrane microdomains to assess NHE-1 sub-membrane location and immunoprecipitated NHE-1 from the different sub-membrane fractions obtained to examine NHE-1 protein interactions during B[a]P-induced apoptosis. Results: We found that NHE-1 is preferentially located in cholesterol-rich microdomains and that B[a] P activates NHE-1 via its relocation and binding of calmodulin outside these specialized plasma membrane microstructures; these events are necessary for the execution of the apoptosis-related intracellular alkalinization. Conclusion: Plasma membrane location of NHE-1 affects its protein interactions and apoptotic function

The environmental carcinogen benzo[a]pyrene induces a Warburg-like metabolic reprogramming dependent on NHE1 and associated with cell survival

International audienceCancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na+/H+ exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration)