Di-(2-ethyl hexyl) phthalate induced oxidative stress promotes microplastics mediated apoptosis and necroptosis in mice skeletal muscle by inhibiting PI3K/AKT/mTOR pathway

The plastic decomposition product microplastics (MPs) and the plastic additive Di (2-ethylhexyl) phthalate (DEHP) in the environment can damage various organs of the organism by inducing oxidative stress. The PI3K/AKT/mTOR signaling pathway participate in toxin-induced apoptosis and necroptosis. However, the effects of DEHP/MPs alone and combined exposure on skeletal muscle cell injury in mice and the role of PI3K/AKT/mTOR axis remain unclear. To investigate the effect of DEHP or/and MPs on skeletal muscle in mice and its possible toxicological mechanism, 60 mice were randomly divided into control group, DEHP group (DEHP 200 mg/kg dissolved in 50 mL corn oil mixed with 2.5 kg diet), MPs group (10 mg/L MPs in drinking water) and combined exposure group. In vitro, C2C12 cells were exposed to DEHP 600 mu M/MPs 800 mu M alone or in combination for 24 h. The results showed that DEHP/MPs exposure alone or in combination increased MDA content, decreased activities of CAT, T-AOC, SOD and GSH-Px, increased mRNA and protein expressions of Caspase-3, BAX, RIPK1, RIPK3 and MLKL, and decreased BCL-2 expression. The expression of PI3K/AKT/mTOR signaling pathway was significantly down-regulated. All the above results showed that the combined exposure group was more toxic, and similar experimental results were obtained by DEHP/MPs exposure test of C2C12 cells in vitro. It is suggested that DEHP/MPs can induce apoptosis and necroptosis by activating oxidative stress and down-regulating PI3K/AKT/mTOR pathway. This study provides new evidence for clarifying the possible mechanism of toxicity of DEHP and MPs to skeletal muscle of mice.

Automated summary

DEHP and MPs exposure alone or in combination can induce skeletal muscle cell injury by activating oxidative stress and down-regulating the PI3K/AKT/mTOR signaling pathway, and the combined exposure group exhibits higher toxicity.