Mechanistic insight into toxicity of phthalates, the involved receptors, and the role of Nrf2, NF-κB, and PI3K/AKT signaling pathways

The wide use of phthalates, as phthalates are used in the manufacturing of not only plastics but also many others goods, has become a main concern in the current century because of their potency to induce deleterious effects on organism health. The toxic effects of phthalates such as reproductive toxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, teratogenicity, and tumor development have been widely indicated by previous experimental studies. Some of the important mechanisms of toxicity by phthalates are the induction and promotion of inflammation, oxidative stress, and apoptosis. Awareness of the involved molecular pathways of these mechanisms will permit the detection of exact molecular targets of phthalates to protect or treat their toxicity. Up to now, various transcription factors and signaling pathways have been associated with phthalate-induced toxicity which by influencing on nuclear surface and the expression of different genes can alter cell hemostasis. In different studies, the role of nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor-κB (NF-κB), and phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathways in processes of oxidative stress, inflammation, apoptosis, and cancer has been shown following exposure to phthalates. In the present review, we aim to survey experimental studies (in vitro and in vivo) in order to show firstly the most involved receptors and also the importance and the role of the mentioned signaling pathways in phthalate-induced toxicity, and with considering this point, the future studies can focus on these molecular targets as a strategic method to reduce environmental chemicals-induced toxicity especially phthalates toxic effects.