Cadmium modulates proliferation and differentiation of human neuroblasts

Gulisano, Massimo; Pacini, Stefania; Punzi, Tiziana; Morucci, Gabriele; Quagliata, Sara; Delfino, Giovanni; Sarchielli, Erica; Marini, Mirca; Vannelli, Gabriella Barbara

doi:10.1002/jnr.21830

Cited by 27 publications

(27 citation statements)

References 48 publications

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“…It is worth mentioning, in the context of our hypothesis, that attention and memory deficit are among the most debilitating symptoms in ME/CFS patients [20,21]. Although the effects of cadmium on neuronal cells in culture have been described in several papers [22], its effects on human central nervous system neurons in vivo have not yet been demonstrated. However, the recently described cadmium-induced apoptosis of the motor neurons of the ventral horns in cultured explants from human foetal spinal cords (10-11 weeks gestational age) [23], suggests that the effects observed in vitro could actually occur also in vivo.…”

Section: Cadmium and Neuronal Cell Death In Me/cfsmentioning

confidence: 91%

Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

et al. 2012

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a b s t r a c tAccording to the World Health Organization, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/ CFS) is a neurological disease characterized by widespread inflammation and multi-systemic neuropathology. Aetiology and pathogenesis are unknown, and several agents have been proposed as causative agents or as factors perpetuating the syndrome. Exposure to heavy metals, with particular reference to mercury and gold in dental amalgams, has been considered among the triggers of ME/CFS. Here we hypothesize that cadmium, a widespread occupational and environmental heavy metal pollutant, might be associated with some of the neurological findings described in ME/CFS. In fact, ME/CFS patients show a decrease of the volume of the gray matter in turn associated with objective reduction of physical activity. Cadmium induces neuronal death in cortical neurons through a combined mechanism of apoptosis and necrosis and it could then be hypothesized that cadmium-induced neuronal cell death is responsible for some of the effects of cadmium on the central nervous system, i.e. a decrease in attention level and memory in exposed humans as well as to a diminished ability for training and learning in rats, that are symptoms typical of ME/CFS. This hypothesis can be tested by measuring cadmium exposure in a cohort of ME/CFS patients compared with matched healthy controls, and by measuring gray matter volume in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. In addition, we hypothesize that cadmium exposure could be associated with reduced cerebral blood flow in ME/CFS patients because of the disruptive effects of cadmium on angiogenesis. In fact, cadmium inhibits angiogenesis and low global cerebral flow is associated with abnormal brain neuroimaging results and brain dysfunction in the form of reduced cognitive testing scores in ME/CFS patients. This hypothesis can be tested by measuring cerebral cortex blood flow in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. If our hypothesis is demonstrated correct, the consequences could affect prevention, early diagnosis, and treatment of ME/CFS. Implications in early diagnosis could entail the evaluation of symptoms typical of ME/CFS in cadmium-exposed subjects as well as the search for signs of exposure to cadmium in subjects diagnosed with ME/CFS. Nutritional supplementation of magnesium and zinc could then be considered, since these elements have been proposed in the prophylaxis and therapy of cadmium exposure, and magnesium was demonstrated effective on ME/CFS patients' symptom profiles.

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Section: Cadmium and Neuronal Cell Death In Me/cfsmentioning

confidence: 91%

Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

et al. 2012

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“…Membranes were blocked 1 h at room temperature in a 5% BSA-TTBS buffer (0.1% Tween-20, 20 mM Tris-HCl, 150 mM NaCl, pH 7.5), washed in TTBS, and incubated at 4°C overnight with the following primary antibodies: anti-b Actin (dilution 1:10,000), anti-GFAP (dilution 1:1,000), anti-b Tubulin III (dilution 1:2,000), anti-Caspase 8 (dilution 1:600), anti-NGFRp75 (dilution 1:1,000), and anti-PARP (dilution 1:1,000) (Santa Cruz Biotechnology). GFAP and b Tubulin III were used for the quantification of the glial and neuronal components, respectively, in the control spinal cord samples and after CdCl 2 exposure (Gulisano et al 2009). The activation of the apoptotic pathway following CdCl 2 treatment was studied analysing NGFRp75, PARP and Caspase 8 expression (Pehar et al 2007;Gulisano et al 2009;Keane et al 2001).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…GFAP and b Tubulin III were used for the quantification of the glial and neuronal components, respectively, in the control spinal cord samples and after CdCl 2 exposure (Gulisano et al 2009). The activation of the apoptotic pathway following CdCl 2 treatment was studied analysing NGFRp75, PARP and Caspase 8 expression (Pehar et al 2007;Gulisano et al 2009;Keane et al 2001). The primary antibodies' incubation was followed by peroxidase conjugated secondary IgG treatment (Santa Cruz Biotechnology).…”

Section: Western Blot Analysismentioning

confidence: 99%

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Cadmium induces alterations in the human spinal cord morphogenesis

et al. 2011

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The effects of cadmium on the central nervous system are still relatively poorly understood and its role in neurodegenerative diseases has been debated. In our research, cultured explants from 25 human foetal spinal cords (10-11 weeks gestational age) were incubated with 10 and 100 μM cadmium chloride (CdCl(2)) for 24 h. After treatment, an immunohistochemical study [for Sglial fibrillary acidic protein (GFAP) and choline acetyltransferase (ChAT)], a Western blot analysis (for GFAP, β-Tubulin III, nerve growth factor receptor, Caspase 8 and poly (ADP-ribose) polymerase), and a terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) assay (for detection of apoptotic bodies) were performed. The treatment with CdCl(2) induced a significant and dose-dependent change in the ratio motor neurons/glial cells in the ventral horns of human foetal spinal cord. The decrease of the choline acetyltransferase-positive cells (motor neurons) and the reduction of β Tubulin III indicate that CdCl(2) specifically affects motor neurons of the ventral horns. While the number of motor neurons decreased for the activation of apoptotic pathways (as shown by the increased expression of Caspase 8, nerve growth factor receptor, and poly (ADP-ribose) polymerase), glial cells, both in the subependymal zone and in the gray matter of the ventral horns, increased (as shown by the increase of GFAP expression). These results provide the evidence that during human spinal cord development, CdCl(2) may affect the fate of neural and glial cells thus, being potentially involved in the etiopathogenesis of neurodegenerative diseases.

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“…In addition, Gulisano et al (2009) established a primary long-term cell culture (FNC-B4) obtained from the human fetal olfactory neuroepithelium, which also showed effectively measuring NPC proliferation, cytoskeleton alterations, neuronal and glial differentiation (record number 3150).…”

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confidence: 99%

Literature review on in vitro and alternative Developmental Neurotoxicity (DNT) testing methods

Fritsche

Alm

Baumann

et al. 2015

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The goal of this systematic review performed under a contract with EFSA was the evaluation of information on assessment methods in the field of developmental neurotoxicity (DNT). Therefore, a systematic and comprehensive literature search and collection of scientific literature and all other relevant grey literature and website information (in English) from past 20 years until mid of April 2014 on the state of the art of in vivo DNT testing methods including novel and alternative non-mammalian models, in vitro test methods, in silico methods, read across and combination of testing methods in test batteries was performed. This systematic review identified a variety of methods covering early and later stages of neurodevelopment that have the ability to predict DNT of chemicals. Few in vivo models alternative to OECD TG 426 were identified. In general, the available published in vivo data is scattered and heterogeneous, making comparisons across exposure paradigms and compounds very difficult. Thus, to make more useful evaluations, publications with more consistent experimental designs are needed, and more focused in vivo-in vitro comparisons are needed to establish useful effect biomarkers and testing models. From the alternative methods, a testing strategy covering early and later neurodevelopmental stages (from stem cell to zebrafish larvae motor behaviour) can be assembled. For gaining regulatory acceptance, definition of biological application domains of alternative methods by performing e.g. in vitro -in vivo validation is needed. Moreover, protocols for cell-based and zebrafish assays need international standardization. With such standardized protocols, the test battery needs to be tested for its sensitivity and specificity by testing concentration-responses of known DNT positive and negative compounds across the different assays. Such data might then be used either for regulatory decision-making or compound prioritization in favour of a reduction of rodent guideline in vivo testing.

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Cadmium modulates proliferation and differentiation of human neuroblasts

Cited by 27 publications

References 48 publications

Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Cadmium induces alterations in the human spinal cord morphogenesis

Literature review on in vitro and alternative Developmental Neurotoxicity (DNT) testing methods

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