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  • The current study demonstrates a link between heme metabolis

    2019-10-08

    The current study demonstrates a link between heme metabolism and mitochondrial Co-I, which deficits instigate abnormalities in the metabolism of heme and its downstream targets both in-vitro in patients and healthy subjects derived LCLs and in-vivo in brains of SZ-rat model. A further study of the link between heme metabolism and mitochondrial Co-I, in postmortem Ready-to-use Cell Proliferation Reagent, WST-1 specimens in comparison with peripheral cells of patients, as well as in Poly I:C rat model will further substantiate this link. The mechanism by which Co-I abnormal activity induces deficit in heme metabolism whether direct or indirect and the prevalence and functional importance of this process in the pathophysiology of SZ, is still an open question. Regardless, heme was shown to plays an important role in neuronal functioning. It was shown that a decrease in neuronal heme, suppresses NMDA receptor expression and instigates neurite damage (Chernova et al., 2007, Chernova et al., 2006) and that HO-1 enhances the expression of BDNF in dopaminergic neurons and GDNF in glia cells both eminent to neuronal survival (Hung et al., 2008, Mendoza et al., 2011). In addition, heme depletion can induce apoptosis via the pro-apoptotic JNK signaling pathway and suppressing of pro-survival Ras-ERK1/2 signaling pathway (Sengupta et al., 2005). These findings together with our data calls for a further study of heme metabolism impairments and its consequence in SZ.
    Funding source Funding for this study was provided by Israel Science Foundation-ISF grant 1517/1; the ISF had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
    Contributors
    Conflict of interest
    Introduction Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP) is a high production volume organophosphorus flame retardant (OPFR). It is used as an additive to polyurethane foam, which is commonly found in upholstered sofas, chairs, vehicles, and many baby products (Van der Veen and de Boer, 2012, Carignan et al., 2013). Like other additive flame-retardants, TDCIPP can leach out of materials, and is now a ubiquitous contaminant that is detected in the environment and biota (Meeker and Stapleton, 2010, Meeker et al., 2013, Yang et al., 2014, Cao et al., 2014, Wei et al., 2015). Furthermore, TDCIPP and its metabolites have been detected in human urine (including that of pregnant women and children), breast milk and human placenta (Sundkvist et al., 2010, Butt et al., 2014, Hoffman et al., 2015, Hoffman et al., 2016, Ding et al., 2016). This has led to great concern over its potential toxicity and environmental health effects. Recently, several studies have suggested that TDCIPP may be neurotoxic, because structurally related compounds including multiple organophosphorus flame retardants adversely affect nervous system development (Hendriks and Westerink, 2015). For example, an in vitro study showed that TDCIPP could affect neuron differentiation with similar or greater potency than chlorpyrifos (CPF) (Dishaw et al., 2011). TDCIPP also induced cytotoxicity and neurotoxicity in neuronal cells (PC12), resulting in decreased cell growth, increased apoptosis, altered cell morphology, and changes in related gene expression (Ta et al., 2014). However, the neurotoxic effects as well as the mechanisms responsible for apoptosis events associated with TDCIPP are not well known. Apoptosis, also called programmed cell death, is typically caused by exposure to abnormal conditions. Many environmental toxicants can induce apoptosis (Chen et al., 2013) Toxicant-induced oxidative stress (e.g. reactive oxygen species; ROS) and increase of intracellular calcium ions ([Ca2+]i) often trigger the induction of apoptosis (Boussabbeh et al., 2015, Swarnkar et al., 2012). Recently, the endoplasmic reticulum (ER) has been identified as a central player in many apoptotic pathways, and apoptotic cell death is closely related to ER stress (Lee et al., 2009). Increasing evidence suggests that increases in the levels of [Ca2+]i and ROS are closely related to ER stress and can lead to abnormal ER homeostasis (Chen et al., 2015, Eletto et al., 2014). ER stress triggers [Ca2+]i dysregulation, which could initiate mitochondrial apoptotic cell death (Hetz, 2012).