New perspectives for multi-level regulations of neuronal acetylcholinesterase by dioxins

Abstract

a b s t r a c tAcetylcholinesterase (AChE; EC 3.1.1.7) is a vital functional enzyme in cholinergic neurotransmission which can rapidly hydrolyze neurotransmitter, acetylcholine, in the central and peripheral nervous systems. Emerging evidence showed that in addition to classical environmental AChE inhibitors, e.g. organophosphate and carbamate pesticides, dioxins are a new type of xenobiotic causing impairment of AChE. Dioxin can transcriptionally or post-transcriptionally suppress AChE expression in human neuroblastoma cells or mouse immune cells via the aryl hydrocarbon receptor (AhR) pathway, respectively. Dioxins can affect gene expression through other mechanisms, such as cross-talk with other signaling cascades and epigenetic modulations. Therefore, in this review, by summarizing the known mechanisms of AChE regulation and dioxin-induced gene alteration, potential signaling cascades and epigenetic mechanisms are proposed for dioxin-mediated AChE regulation. Mitogen activated protein (MAP) kinase, 3 0 , 5 0 -cyclic adenosine monophosphate (cAMP) and calcium-related singaling pathways, as well as potential epigenetic mechanisms, such as DNA methylation, and post-transcriptional regulation via microRNAs, including hsa-miR-132, hsa-miR-212 and hsa-miR-25-3p are discussed here. These proposed mechanisms may be invaluable not only to promote comprehensive understanding of the action mechanisms for dioxin, but to illustrate the molecular basis of dioxin-induced health impacts.

CDC42 expression is altered by dioxin exposure and mediated by multilevel regulations via AhR in human neuroblastoma cells

“…The aryl hydrocarbon receptor (AhR) is known as a key mediator of transcriptional regulation of the altered gene expression caused by dioxin exposure 6 , 8 , in which dioxin binds to the AhR to form the dioxin-receptor complex, undergoes nuclear translocation and coupling with AhR nuclear translocator, and finally interacts with the dioxin responsive elements (DREs) in promoters of target genes to manipulate gene expression 12 . With the recent rise of epigenetics, emerging evidence suggested possible involvement of dioxins or DLCs in epigenetic regulation 13 . However, whether this epigenetic regulation by dioxins could be present and participate in the adverse effects on the nervous system remains unclear.…”

New perspective on the regulation of acetylcholinesterase via the aryl hydrocarbon receptor

“…Inspiringly, TCDD treatment (0.05–0.2 nM) was found to induce the expression of miR‐608 in a time‐ and dose‐dependent manner in SK‐N‐SH cells, and AhR was documented to mediate the up‐regulation of miR‐608 by TCDD (Xu et al., 2017). Thus, it was proposed that such dysregulation of AChE‐targeting miR(s) by dioxin might participate in the dioxin‐induced regulation of AChE, in which AhR might be an important upstream regulatory factor (Xie et al., 2016; Xu et al., 2018). Other known AChE‐targeting miRs could be candidates for searching the miRs involved in dioxin‐induced dysregulation of AChE.…”

A myriad of roles of miR-25 in health and disease

“…Acetylcholinesterase (AChE) plays a central role in cholinergic neurotransmission in central and peripheral nervous systems by hydrolysation of the neurotransmitter, acetylcholine [ 56 ]. Dioxins were shown to decrease AChE expression directly in neuroblastoma cells and immune cells by transcriptional regulation via aryl hydrocarbon receptor and by post-translational regulation via microRNAs including miR-25 [ 59 ]. Proposed mechanisms of dioxin toxicity are reviewed in detail by Xie et al [ 59 ].…”

“…Dioxins were shown to decrease AChE expression directly in neuroblastoma cells and immune cells by transcriptional regulation via aryl hydrocarbon receptor and by post-translational regulation via microRNAs including miR-25 [ 59 ]. Proposed mechanisms of dioxin toxicity are reviewed in detail by Xie et al [ 59 ].…”