MEHP interferes with mitochondrial functions and homeostasis in skeletal muscle cells

Abstract

Di (2-ethylhexyl) phthalate (DEHP) is a plasticizer frequently leached out from polyvinyl chloride (PVC) products and is quickly metabolized to its monoester equivalent mono(2-ethylhexyl) phthalate (MEHP) once enters organisms. Exposure to DEHP/MEHP through food chain intake has been shown to modified metabolism but its effect on the development of metabolic myopathy of skeletal muscle (SKM) has not been revealed so far. Here, we found that MEHP repressed myogenic terminal differentiation of proliferating myoblasts (PMB) and confluent myoblasts (CMB) but had weak effect on this process once it had been initiated. The transition of mitochondria (MITO) morphology from high efficient filamentary network to low efficient vesicles was triggered by MEHP, implying its negative effects on MITO functions. The impaired MITO functions was further demonstrated by reduced MITO DNA (mtDNA) level and SDH enzyme activity as well as highly increased reactive oxygen species (ROS) in cells after MEHP treatment. The expression of metabolic genes, including PDK4, CPT1b, UCP2, and HO1, was highly increased by MEHP and the promoters of PDK4 and CPT1b were also activated by MEHP. Additionally, the stability of some subunits in the oxidative phosphorylation system (OXPHOS) complexes was found to be reduced by MEHP, implying defective oxidative metabolism in MITO and which was confirmed by repressed palmitic acid oxidation in MEHP-treated cells. Besides, MEHP also blocked insulin-induced glucose uptake. Taken together, our results suggest that MEHP is inhibitory to myogenesis and is harmful to MITO functions in SKM, so its exposure should be avoided or limited.

Increased maternal non-oxidative energy metabolism mediates association between prenatal DEHP exposure and offspring ASD symptoms: a birth cohort study

“…For instance, DEHP exposure is associated with an elevation in cellular oxidative stress, 68 which is linked to a subsequent increase in carbon intermediates. 27, 69 DEHP may also contribute to mitochondrial dysfunction, 70, 71 which diminishes cellular energy supply and increases the utilization of non-oxidative energy metabolism pathways. Alternatively, a DEHP-induced elevation of non-oxidative metabolites could be due to a high glycolytic rate that strains the oxidative capacity of the mitochondria 72 ; however, there is inconsistent evidence of hyperactive glycolysis after DEHP exposure.…”

Highly Flexible Polylactide Food Packaging Plasticized with Nontoxic, Biosourced Glycerol Plasticizers

“…Although the addition of plasticizers to PLA is an accepted method to improve its mechanical properties, plasticizers are prone to migration and leaching out of the blend as they are not covalently bound to the polymer backbone . This compromises the integrity of the product and can lead to widespread environmental contamination and potential human exposure. , Consequently, the investigation of plasticizer accumulation in the environment as well as the health effects of plasticizer exposure on both humans , and animals remains an area of active research. To date, there have been numerous plasticizers developed for the production of flexible PLA including but not limited to citrate esters, polyethylene glycol analogues, levulinic acids, tartaric acids, malic acids, and functionalized epoxidized soybean oils .…”

Effects of DEHP, DEHT and DINP Alone or in a Mixture on Cell Viability and Mitochondrial Metabolism of Endothelial Cells In Vitro

“…Impairment of the oxidative phosphorylation was previously described on skeletal muscle cells exposed to MEHP; the authors reported a degradation of complex I, which was triggered by ROS production [ 56 ]. In the present study, the redox imbalance was found subsequently to the mitochondrial respiration alteration, but it is not excluded that early mitochondrial ROS production occurs.…”