Cadmium impairs the survival and proliferation of cultured adult subventricular neural stem cells through activation of the JNK and p38 MAP kinases

Abstract

Cadmium (Cd) is a heavy metal with a long biological half-life in humans and is recognized as a toxic pollutant. Cd is also a potential neurotoxicant and its exposure is associated with olfactory impairment in humans. However, the molecular and cellular mechanisms of Cd neurotoxicity are not well defined. Adult neurogenesis is a process that generates functional neurons from adult neural stem/progenitor cells (aNPCs). It occurs in specific regions of the adult brain including the subventricular zone (SVZ) along the lateral ventricles in mammals, a process that is critical for olfaction. Various external stimuli can modulate adult neurogenesis and the effect of neurotoxicants on adult neurogenesis is just beginning to be elucidated. Since Cd exposure can impair olfaction in humans, the goal of this study is to investigate the effects of Cd on SVZ adult neurogenesis and underlying mechanisms using primary cultured SVZ-aNPCs. In this study, we report that low-level Cd exposure decreases cell number, induces apoptosis, and inhibits cell proliferation in SVZ-aNPCs. Furthermore, Cd exposure significantly increases phosphorylation of c-Jun NH2-terminal kinase (JNK), and p38 MAP kinase in these cells, indicative of JNK and p38 activation. Pharmacological inhibition of JNK or p38 MAPK kinases attenuated Cd-induced cell loss and apoptosis. Cd treatment did not cause cell loss or apoptosis in SVZ-aNPCs prepared from transgenic mice null for the neural-specific JNK3 isoform. These data suggest a critical role for p38 and JNK3 MAP kinases in Cd neurotoxicity. These results are, to our knowledge, the first demonstration that Cd impairs SVZ adult neurogenesis in vitro, which may contribute to its neurotoxicity in olfaction.

Zinc interference with Cd‐induced hormetic effect in differentiated Caco‐2 cells: Evidence for inhibition downstream ERK activation

“…Depending on the concentration and time of exposure, Cd may modify the cell cycle progression and stimulate or conversely inhibit cell proliferation . It may promote tumorigenicity or apoptosis .…”

“…Depending on the concentration and time of exposure, Cd may modify the cell cycle progression and stimulate or conversely inhibit cell proliferation. [12][13][14] It may promote tumorigenicity or apoptosis. [15,16] A significant effect of Cd toxicity is its ability to indirectly favor the production of reactive oxygen species (ROS), leading to oxidative stress, at least redox imbalance.…”

Identification of ARNT-regulated BIRC3 as the target factor in cadmium renal toxicity

“…Although unbound Cd stimulates MT production in the kidney and then binds to MT, the toxic effects occur when unbound Cd accumulates in renal tubular cells 2 , 6 . At the molecular level, Cd induces apoptosis and also has adverse effects on cellular proliferation, cell signaling, and DNA repair in various cell lines 7 – 10 . Cd induces apoptotic cell death through endoplasmic reticulum (ER)-mediated, mitochondrial-mediated and p53-mediated pathways 8 .…”

“…Cd induces apoptotic cell death through endoplasmic reticulum (ER)-mediated, mitochondrial-mediated and p53-mediated pathways 8 . Cd impairs cell survival and proliferation through an increase in the phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase 10 . Cd inhibits the initial steps of base excision repair system and suppresses the capacity of the nucleotide excision system through interference with various enzymes 9 .…”

Influência de células trofoblásticas BeWo e infecção por Toxoplasma gondii na modulação dos mecanismos de morte celular em células THP-1

“…Diversos estudos têm demonstrado que a regulação da apoptose é modulada pela fosforilação de diferentes proteínas quinases, dentre elas, ERK, JNK e P38, que representam os maiores subtipos pertencentes à família das MAPK (KATO et al, 2005;CAI et al, 2006;SHIN et al, 2009;RODRIGUES et al, 2012, WANG et al, 2017. Dessa forma, este trabalho também avaliou a fosforilação destas três proteínas com o objetivo de avaliar a participação delas na modulação da apoptose em células THP-1.…”