title: The p-eIF2α/ATF4 pathway links endoplasmic reticulum stress to autophagy following the production of reactive oxygen species in mouse spermatocyte-derived cells exposed to dibutyl phthalate.
abstract: Dibutyl phthalate (DBP) is a widely used plasticizer that has been shown to induce germ cell apoptosis-related testicular atrophy and cause reproductive toxicity. Our previous results indicated that endoplasmic reticulum (ER) stress-activated autophagy served as a self-defense mechanism against DBP-induced germ cell apoptosis. However, the specific pathways that link ER stress and autophagy remain unclear. Here, we showed that exposure to DBP enhanced autophagic flux in mouse spermatocyte-derived GC-2 cells and that the eukaryotic translation initiation factor 2/activating transcription factor 4 pathway mediated ER stress-related autophagy independent of the mTOR and Beclin-1 pathways. Moreover, we demonstrated that DBP treatment led to the generation of reactive oxygen species (ROS) and that the inhibition of ROS by melatonin abrogated both ER stress and autophagy. The results indicated that excessive ROS production might be involved in DBP-induced ER stress and autophagy in GC-2 cells. Thus, ROS may serve as upstream mediators of ER stress and autophagy in DBP-treated GC-2 cells.
authors.affiliation: a Institute of Toxicology, College of Preventive Medicine, Third Military Medical University , Chongqing , P.R. China.
authors.forename: Guowei
authors.initials: G
authors.lastname: Zhang
authors.affiliation: a Institute of Toxicology, College of Preventive Medicine, Third Military Medical University , Chongqing , P.R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Ling
authors.affiliation: a Institute of Toxicology, College of Preventive Medicine, Third Military Medical University , Chongqing , P.R. China.
authors.forename: Kaijun
authors.initials: K
authors.lastname: Liu
authors.affiliation: a Institute of Toxicology, College of Preventive Medicine, Third Military Medical University , Chongqing , P.R. China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: a Institute of Toxicology, College of Preventive Medicine, Third Military Medical University , Chongqing , P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.affiliation: a Institute of Toxicology, College of Preventive Medicine, Third Military Medical University , Chongqing , P.R. China.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Gao
authors.affiliation: a Institute of Toxicology, College of Preventive Medicine, Third Military Medical University , Chongqing , P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Cao
authors.affiliation: a Institute of Toxicology, College of Preventive Medicine, Third Military Medical University , Chongqing , P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ao
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003993:Dibutyl Phthalate / Q000494:pharmacology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology*; D055785:Gene Knockdown Techniques; D008297:Male; D008550:Melatonin / Q000494:pharmacology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013090:Spermatocytes / Q000187:drug effects / Q000378:metabolism*
chemical_list: C081452:Atf4 protein, mouse; D017382:Reactive Oxygen Species; D051701:Activating Transcription Factor 4; D003993:Dibutyl Phthalate; D017346:Protein Serine-Threonine Kinases; C531557:eIF2alpha kinase, mouse; D008550:Melatonin
keywords: Autophagy; dibutyl phthalate; endoplasmic reticulum stress; reactive oxygen species