title: Reactive oxygen species-triggered trophoblast apoptosis is initiated by endoplasmic reticulum stress via activation of caspase-12, CHOP, and the JNK pathway in Toxoplasma gondii infection in mice.
abstract: Toxoplasma gondii infection in pregnant women may result in abortion or in fetal teratogenesis; however, the underlying mechanisms are still unclear. In this paper, based on a murine model, we showed that maternal infection with RH strain T. gondii tachyzoites induced elevated production of reactive oxygen species (ROS), local oxidative stress, and subsequent apoptosis of placental trophoblasts. PCR array analysis of 84 oxidative stress-related genes demonstrated that 27 genes were upregulated at least 2-fold and that 9 genes were downregulated at least 2-fold in the T. gondii infection group compared with levels in the control group. The expression of NADPH oxidase 1 (Nox1) and glutathione peroxidase 6 (Gpx6) increased significantly, about 25-fold. The levels of malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) increased significantly with T. gondii infection, and levels of glutathione (GSH) decreased rapidly. T. gondii infection increased the early expression of endoplasmic reticulum stress (ERS) markers, followed by cleavage of caspase-12, activation of ASK1/JNK, and increased apoptosis of trophoblasts, both in vivo and in vitro. The apoptosis of trophoblasts, the activation of caspase-12 and the ASK1/JNK pathway, and the production of peroxides were dramatically inhibited by pretreatment with N-acetylcysteine (NAC). The upregulation of Nox1 was contact dependent and preceded the increase in levels of ERS markers and the activation of the proapoptosis cascade. Thus, we concluded that apoptosis in placental trophoblasts was initiated predominantly by ROS-mediated ERS via activation of caspase-12, CHOP, and the JNK pathway in acute T. gondii infection. Elevated ROS production is the central event in T. gondii-induced apoptosis of placental trophoblasts.
authors.affiliation: Anhui Provincial Laboratories of Pathogen Biology and Zoonoses, Department of Microbiology and Parasitology, Anhui Medical University, Hefei, China.
authors.forename: Xiucai
authors.initials: X
authors.lastname: Xu
authors.forename: Tingting
authors.initials: T
authors.lastname: Liu
authors.forename: Aimei
authors.initials: A
authors.lastname: Zhang
authors.forename: Xingxing
authors.initials: X
authors.lastname: Huo
authors.forename: Qingli
authors.initials: Q
authors.lastname: Luo
authors.forename: Zhaowu
authors.initials: Z
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
authors.forename: Zhao-rong
authors.initials: ZR
authors.lastname: Lun
authors.forename: Jilong
authors.initials: J
authors.lastname: Shen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000074624:NADPH Oxidase 1; D018384:Oxidative Stress; D010920:Placenta / Q000378:metabolism / Q000469:parasitology; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D014124:Toxoplasmosis, Animal / Q000378:metabolism* / Q000473:pathology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects*
chemical_list: C497250:Ddit3 protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; D004247:DNA; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D048670:MAP Kinase Kinase 4; C506440:Casp12 protein, mouse; D053454:Caspase 12; D005978:Glutathione