Wnt/β-Catenin Signaling Pathway Is Strongly Implicated in Cadmium-Induced Developmental Neurotoxicity and Neuroinflammation: Clues from Zebrafish Neurobehavior and In Vivo Neuroimaging

Abstract

Cadmium (Cd) is a toxic heavy metal and worldwide environmental pollutant which seriously threatens human health and ecosystems. It is easy to be adsorbed and deposited in organisms, exerting adverse effects on various organs including the brain. In a very recent study, making full use of a zebrafish model in both high-throughput behavioral tracking and live neuroimaging, we explored the potential developmental neurotoxicity of Cd2+ at environmentally relevant levels and identified multiple connections between Cd2+ exposure and neurodevelopmental disorders as well as microglia-mediated neuroinflammation, whereas the underlying neurotoxic mechanisms remained unclear. The canonical Wnt/β-catenin signaling pathway plays crucial roles in many biological processes including neurodevelopment, cell survival, and cell cycle regulation, as well as microglial activation, thereby potentially presenting one of the key targets of Cd2+ neurotoxicity. Therefore, in this follow-up study, we investigated the implication of the Wnt/β-catenin signaling pathway in Cd2+-induced developmental disorders and neuroinflammation and revealed that environmental Cd2+ exposure significantly affected the expression of key factors in the zebrafish Wnt/β-catenin signaling pathway. In addition, pharmacological intervention of this pathway via TWS119, which can increase the protein level of β-catenin and act as a classical activator of the Wnt signaling pathway, could significantly repress the Cd2+-induced cell cycle arrest and apoptosis, thereby attenuating the inhibitory effects of Cd2+ on the early development, behavior, and activity, as well as neurodevelopment of zebrafish larvae to a certain degree. Furthermore, activation and proliferation of microglia, as well as the altered expression profiles of genes associated with neuroimmune homeostasis triggered by Cd2+ exposure could also be significantly alleviated by the activation of the Wnt/β-catenin signaling pathway. Thus, this study provided novel insights into the cellular and molecular mechanisms of Cd2+ toxicity on the vertebrate central nervous system (CNS), which might be helpful in developing pharmacotherapies to mitigate the neurological disorders resulting from exposure to Cd2+ and many other environmental heavy metals.

Characterization of Inflammatory Signals in BV-2 Microglia in Response to Wnt3a

“…Our results showed that the phosphorylation of NF-κB was significantly reduced ( Figure 5 a–c), while the baseline level of proteins was unaffected. Moreover, the expression of iNOS expression in microglia mainly depends on the activation of ERK1/2 [ 19 ]. Our results further showed that the phosphorylation of ERK1/2 was decreased in Wnt3a-overexpressed BV-2 cells ( Figure 5 d–f).…”

“…The Wnt/β-catenin signaling pathway is crucial in maintaining neuronal homeostasis [ 18 ]. It has been reported that activation of the Wnt/β-catenin signaling pathway can inhibit pathological neuroinflammation [ 17 , 19 ]. In addition, the Wnt/β-catenin signaling pathway is involved in anti-tumor immunity, in which β-catenin can regulate NF-κB activation [ 17 , 20 , 21 , 22 ].…”

Nicotinic acetylcholine receptors and learning and memory deficits in Neuroinflammatory diseases

“…A complex combination of genetic factors, life events, and lifestyles triggers these pathological processes. Mental triggers include traumatic events, depression ( Gu et al, 2022 ), physical stressors such as radiotherapy ( Gu et al, 2022 ; Gutierrez-Quintana et al, 2022 ), traumatic brain injury, viral or bacterial infections ( Akinci et al, 2022 ; Francis et al, 2023 ), and exposure to toxins such as toxic heavy metals ( Mani et al, 2022 ; Xu et al, 2022 ), insecticides, chemotherapy agents, medicaments, and a fatty diet. A recent study showed that neuroinflammation could also be associated with epigenetic changes induced by Posttraumatic Stress Disorder (PTSD) ( Wolf et al, 2018 ) (see Figure 1 ).…”

Temperature- and chemical-induced neurotoxicity in zebrafish

“…The impact of the neurotoxic agent can also be evaluated by analysing the expression of genes associated with neuronal development and differentiation ( Supplementary Table S2 ). These genes encompass immature neuronal markers like nestin ( Chen et al, 2012 ; Ho et al, 2013 ; Soares et al, 2017 ; Qian et al, 2018 ; Cheng et al, 2020 ; Xia et al, 2021 ; Xu et al, 2022a ; Xu et al, 2022b ; Yu et al, 2022 ; Xu et al, 2023 ), as well as mature neuronal markers like growth associated protein 43 ( gap43 ) ( Chen et al, 2012 ; Sun et al, 2016 ; Soares et al, 2017 ; Faria et al, 2018 ; Qian et al, 2018 ; Shi et al, 2018 ; Jin et al, 2019b ; Li et al, 2019 ; Cheng et al, 2020 ; Zhu et al, 2020 ; Chen et al, 2021 ; Gyimah et al, 2021 ; Li et al, 2021 ; Tian et al, 2021 ; Xu et al, 2021 ; Xu et al, 2022a ; Xu et al, 2022b ; Yu et al, 2022 ; Shi et al, 2023 ; Xiong et al, 2023 ; Xu et al, 2023 ; Zhu et al, 2023 ), and elav like RNA binding protein 3 ( elavl3 ) ( Chen et al, 2012 ; Sun et al, 2016 ; Qian et al, 2018 ; Shi et al, 2018 ; Yang et al, 2019 ; Zhu et al, 2020 ; Chen et al, 2021 ; Gyimah et al, 2021 ; Wang et al, 2021 ; Xu et al, 2021 ; Xu et al, 2022a ; Xu et al, 2022b ; Fan et al, 2022 ; Wang et al, 2022 ; Yu et al, 2022 ; Xiong et al, 2023 ; Zhu et al, 2023 ). Additionally, astrocyte markers such as glial fibrillary acidic protein ( gfap ) ( Chen et al, 2012 ; Sun et al, 2016 ; Soares et al, 2017 ; ...…”

“…Gene expression analysis related to axons has demonstrated alteration in the expression of regeneration-associated genes such as growth-associated protein Gap-43 ( gap43 ) ( Chen et al, 2012 ; Sun et al, 2016 ; Soares et al, 2017 ; Faria et al, 2018 ; Qian et al, 2018 ; Shi et al, 2018 ; Jin et al, 2019b ; Li et al, 2019 ; Cheng et al, 2020 ; Zhu et al, 2020 ; Chen et al, 2021 ; Gyimah et al, 2021 ; Li et al, 2021 ; Tian et al, 2021 ; Xu et al, 2021 ; Xu et al, 2022a ; Xu et al, 2022b ; Chang et al, 2022 ; Yu et al, 2022 ; Shi et al, 2023 ; Xiong et al, 2023 ; Xu et al, 2023 ; Zhu et al, 2023 ) and α1 tubulin ( Sun et al, 2016 ; Li et al, 2018 ; Shi et al, 2018 ; Yang et al, 2019 ; Fu et al, 2020 ; Zhu et al, 2020 ; Chen et al, 2021 ; Gyimah et al, 2021 ; Xu et al, 2021 ; Xu et al, 2022a ; Xu et al, 2022b ; Heredia-García et al, 2023 ; Shi et al, 2023 ; Xu et al, 2023 ). Additionally, nerve related genes like pax6a ( Ho et al, 2013 ; Li et al, 2019 ; Wang et al, 2021 ; Gyimah et al, 2022 ), elavl3 ( Chen et al, 2012 ; Sun et al, 2016 ; Qian et al, 2018 ; Shi et al, 2018 ; Yang et al, 2019 ; Zhu et al, 2020 ; Chen et al, 2021 ; Gyimah et al, 2021 ; Wang et al, 2021 ; Xu et al, 2021 ; Xu et al, 2022a ; Xu et al, 2022b ; Fan et al, 2022 ; Wang et al, 2022 ; Yu et al, 2022 ;…”