Di-n-butyl phthalate epigenetically induces reproductive toxicity via the PTEN/AKT pathway

Abstract

Di-n-butyl phthalate (DBP) is a kind of ubiquitous chemical linked to hormonal disruptions that affects male reproductive system. However, the mechanism of DBP-induced germ cells toxicity remains unclear. Here, we demonstrate that DBP induces reduction of proliferation, increase of apoptosis and DNA damage dependent on the PTEN/AKT pathway. Mechanistically, DBP decreases PTEN promoter methylation and increases its transcriptional activity, leading to increased PTEN expression. Notably, DNMT3b is confirmed as a target of miR-29b and miR-29b-mediated status of PTEN methylation is involved in the effects of DBP treatment. Meanwhile, DBP decreases AKT pathway expression via increasing PTEN expression. In addition, the fact that DBP decreases the sperm number and the percentage of motile and progressive sperm is associated with downregulated AKT pathway and sperm flagellum-related genes. Collectively, these findings indicate that DBP induces aberrant PTEN demethylation, leading to inhibition of the AKT pathway, which contributes to the reproductive toxicity.

Cross Sectional Study on Exposure to BPA and Phthalates and Semen Parameters in Men Attending a Fertility Center

“…Endocrine disrupting pollution, particularly mediated by phthalates and alkyl phenols, represents a ubiquitous risk factor that might strongly affect global male reproductive health. The reproductive toxicity of these substances has emerged in both animal and cell models [60,61]. There is still debate about the possible mechanisms by which phthalates and/or BPA may damage the male reproductive system, but from the literature, multiple pathways (Nrf2-mediated Notch1 signaling [25], PTEN/AKN pathway [62], ERK1/2 pathway [26]) and multiple target cells might be involved [63].…”

The role of epigenetics in the reproductive toxicity of environmental endocrine disruptors

“…Recent evidence has demonstrated DNA methylation involvement in human reproductive toxicity induced by EEDs (Chen et al ., 2018; Bowman et al ., 2019; Tian et al ., 2019). Gametes DNA methylation have been shown to be modified by EEDs including phthalates, BPA, and TCDD both in vivo and in vitro (Zhang et al ., 2018; Li et al ., 2019; Tian et al ., 2019).…”

“…The phosphatase and tensin homolog (PTEN), which inhibits the AKT–mTOR pathway through its lipid phosphatase activity, is also involved in cell proliferation, survival, and energy metabolism. Dibutyl phthalate (DBP) can induce PTEN demethylation through DNMT3b, increasing PTEN's transcriptional activity, which leads to increased PTEN expression (Li et al ., 2019). Over expression of PTEN inhibits the PI3K/AKT/mTOR signaling pathway, which is related to DBP‐induced apoptosis of testicular support cells (Wang et al ., 2017b).…”

“…Epigenetic effects play an important role in EEDs induced reproductive toxicity (Khazaie and Nasr Esfahani, 2014; Li et al ., 2019; Santangeli et al ., 2019). In this review, we summarize the effects of EEDs on DNA methylation, noncoding RNAs, chromatin remodeling, histone modification, and genomic imprinting that result in reproductive toxicity.…”

Research Progress of Male Reproductive Toxicity of Chinese Materia Medicas

“…Artesunate has strong killing effect on plasmodium [58] and the ability to quickly control symptoms of dysentery. However, it is found to damage DNA double strands in Sertoli cells of mice testes.…”