Arsenic-induced inhibition of hippocampal neurogenesis and its reversibility

Liu, Shuang; Piao, Fengyuan; Sun, Xiance; Bai, Lulu; Peng, Yan; Zhong, Yuanxia; Ma, Ning; Sun, Wei

doi:10.1016/j.neuro.2012.04.020

Cited by 43 publications

(24 citation statements)

References 40 publications

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“…Developmental exposure to heavy metals reduces NSC proliferation and/or differentiation in the adult brain [14,23,42,49,50,53]. We have demonstrated that perinatal exposure of 50 µg/L arsenic (through all three trimesters of development) results in reduced differentiation but not proliferation of NSCs in adult male mice [56,60]; these findings are corroborated by other studies using in vivo and in vitro models of arsenic exposure at different time points [34,35]. Additionally, arsenic-induced deficits in neuronal differentiation are associated with reduced expression of neural-specific transcription factors in the adult [20,56,61,63], yet the effect of arsenic on the regulation and expression of transcription factors during embryonic neurogenesis has not been studied to date.…”

Section: Introductionsupporting

confidence: 84%

Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner

Tyler

Labrecque

Solomon

et al. 2017

Neurotoxicology and Teratology

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Exposure to arsenic, a common environmental toxin found in drinking water, leads to a host of neurological pathologies. We have previously demonstrated that developmental exposure to a low level of arsenic (50 ppb) alters epigenetic processes that underlie deficits in adult hippocampal neurogenesis leading to aberrant behavior. It is unclear if arsenic impacts the programming and regulation of embryonic neurogenesis during development when exposure occurs. The master negative regulator of neural-lineage, REST/NRSF, controls the precise timing of fate specification and differentiation of neural stem cells (NSCs). Early in development (embryonic day 14), we observed increased expression of Rest, its co-repressor, CoREST, and the inhibitory RNA binding/splicing protein, Ptbp1, and altered expression of mRNA spliced isoforms of Pbx1 that are directly regulated by these factors in the male brain in response to prenatal 50 ppb arsenic exposure. These increases were concurrent with decreased expression of microRNA-9 (miR-9), miR-9*, and miR-124, all of which are REST/NRSF targets and inversely regulate Rest expression to allow for maturation of NSCs. Exposure to arsenic decreased the formation of neuroblasts in vitro from NSCs derived from male pup brains. The female response to arsenic was limited to increased expression of CoREST and Ptbp2, an RNA binding protein that allows for appropriate splicing of genes involved in the progression of neurogenesis. These changes were accompanied by increased neuroblast formation in vitro from NSCs derived from female pups. Unexposed male mice express transcriptomic factors to induce differentiation earlier in development compared to unexposed females. Thus, arsenic exposure likely delays differentiation of NSCs in males while potentially inducing precocious differentiation in females early in development. These effects are mitigated by embryonic day 18 of development. Arsenic-induced dysregulation of the regulatory loop formed by REST/NRSF, its target microRNAs, miR-9 and miR-124, and RNA splicing proteins, PTBP1 and 2, leads to aberrant programming of NSC function that is perhaps perpetuated into adulthood inducing deficits in differentiation we have previously observed.

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Section: Introductionsupporting

confidence: 84%

Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner

Tyler

Labrecque

Solomon

et al. 2017

Neurotoxicology and Teratology

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“…Recent studies have demonstrated deficits in adult neurogenesis in the dentate gyrus of the hippocampus in both developmental and adult exposures to arsenic. Treatment for four months with 4 μg/L arsenic in drinking water reduced proliferation of neural progenitor cells and the number of mature neurons [104•]. Developmental exposure of 50 μg/L arsenic (in utero and postnatal) altered differentiation but not proliferation of neural progenitor cells in the adult hippocampus at PND63 [72].…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

“…Developmental exposure of 50 μg/L arsenic (in utero and postnatal) altered differentiation but not proliferation of neural progenitor cells in the adult hippocampus at PND63 [72]. In both studies, deficits in adult neurogenesis were ameliorated either after cessation of the use of arsenic in water [104•] or with experience in an enriched environment [72]. In vitro studies using P19 pluripotent cells cultured with varying concentrations of arsenic (7.5-75.0 μg/L) demonstrated that arsenic inhibited the formation of muscle and neuronal cells during P19 cell differentiation in a dose dependent manner.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

“…For example, in rodent studies, deficits in adult neurogenesis can be attenuated either by abolishment of exposure to arsenic water [104•], experience in an enriched environment [72], or chronic antidepressant treatment (our unpublished observations). Reduced expression of monoamines after arsenic exposure can be reversed by treatment with curcumin [85] or taurine [102].…”

Section: Therapeuticsmentioning

confidence: 99%

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The Effects of Arsenic Exposure on Neurological and Cognitive Dysfunction in Human and Rodent Studies: A Review

Tyler

Allan

2014

Curr Envir Health Rpt

418

233

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Arsenic toxicity is a worldwide health concern as several millions of people are exposed to this toxicant via drinking water, and exposure affects almost every organ system in the body including the brain. Recent studies have shown that even low concentrations of arsenic impair neurological function, particularly in children. This review will focus on the current epidemiological evidence of arsenic neurotoxicity in children and adults, with emphasis on cognitive dysfunction, including learning and memory deficits and mood disorders. We provide a cohesive synthesis of the animal studies that have focused on neural mechanisms of dysfunction after arsenic exposure including altered epigenetics; hippocampal function; glucocorticoid and hypothalamus-pituitary-adrenal axis (HPA) pathway signaling; glutamatergic, cholinergic and monoaminergic signaling; adult neurogenesis; and increased Alzheimer’s-associated pathologies. Finally, we briefly discuss new studies focusing on therapeutic strategies to combat arsenic toxicity including the use of selenium and zinc.

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“…These mechanisms, identified in experimental animal studies, include oxidative stress and the production of free radicals resulting in neuronal apoptosis [12,13], impaired hippocampal neurogenesis [14], dysregulation of the hypothalamo-pituitary-adrenal axis including reduced levels of corticosterone receptors in the hippocampus [15,16], epigenetic effects such as reduced DNA methylation in the hippocampus and frontal cortex [17], reductions in brain levels of biogenic amines and other neurotransmitters [18][19][20][21], changes in the expression of the NMDA receptor complex [22], inhibition of neurite outgrowth [23], structural malformation of white matter (e.g., myelin sheaths) [24] and of hippocampal mossy fibers [25], and endocrine disruption, including down-regulation of thyroid hormone receptor genes [26,27].…”

Section: Introductionmentioning

confidence: 99%

Inorganic Arsenic Exposure and Children’s Neurodevelopment: A Review of the Evidence

Bellinger

2013

Toxics

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Experimental studies suggest a myriad of mechanisms by which inorganic arsenic can interfere with central nervous system development, and, indeed, epidemiological studies published in the last dozen years suggest that exposure to arsenic impairs children's cognitive development. Most of the studies have been conducted in developing countries (e.g., Bangladesh, India, Mexico), where exposure to arsenic is thought to be considerably higher than it is in developed countries. This review summarizes the results of these studies, focusing in particular on issues pertinent to risk assessment, including the existence of critical windows of vulnerability, characteristics of the dose-effect relationships (e.g., the lowest adverse effect level, the functional form), the most sensitive neurodevelopmental endpoints, and potential effect modifiers such as host characteristics (e.g., methylation efficiency, sex) and co-exposures to other neurotoxicants (e.g., lead, manganese). At present, the epidemiological data do not permit firm conclusions to be drawn regarding these issues. Several factors that complicate an effort to compare the results of studies are identified, including use of a variety of indices of external and internal exposure, and inconsistency in the measurement of important potential confounders for neurodevelopmental outcomes.

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Arsenic-induced inhibition of hippocampal neurogenesis and its reversibility

Cited by 43 publications

References 40 publications

Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner

Prenatal arsenic exposure alters REST/NRSF and microRNA regulators of embryonic neural stem cell fate in a sex-dependent manner

The Effects of Arsenic Exposure on Neurological and Cognitive Dysfunction in Human and Rodent Studies: A Review

Inorganic Arsenic Exposure and Children’s Neurodevelopment: A Review of the Evidence

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