Impact of early developmental arsenic exposure on promotor CpG-island methylation of genes involved in neuronal plasticity

Martínez, Liborio; Jiménez, Verónica; García-Sepúlveda, Christian A.; Ceballos, Fátima; Delgado, Juan Manuel; Niño-Moreno, Perla; Doniz, Lesly; Saavedra-Alanís, Víctor; Castillo, Claudia G.; Santoyo, Martha; González‐Amaro, Roberto; Jiménez‐Capdeville, María E.

doi:10.1016/j.neuint.2011.01.020

Cited by 67 publications

(35 citation statements)

References 44 publications

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“…While there have been several studies determining the impact of arsenic on epigenetic regulation in cancer cells, the liver, and other parts of the body, very few have focused the brain. Exposure to 3 and 36 ppm arsenic throughout gestation increased DNA methylation on two genes involved in neural plasticity in rat cortex and hippocampus at one month of age [54•]. Hypomethylation of these genes in both regions was observed after four months of cumulative exposure to arsenic; these animals also displayed deficits in fear memory as well, although the link between hypomethylation and memory was correlational.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

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

Tyler

Allan

2014

Curr Envir Health Rpt

431

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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Section: Mechanisms Of Actionmentioning

confidence: 99%

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

Tyler

Allan

2014

Curr Envir Health Rpt

431

233

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“…The immunohistochemistry procedure in the hippocampus was performed as previously described [37] with slight modifications. Mounted and dried sections were rehydrated and subjected to a sequence of incubation steps in a humidity chamber, starting with sodium citrate at 100 °C (pH 6) during 30 min for epitope recovery [38], followed by …”

Section: Dna Methylationmentioning

confidence: 99%

Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour

Paternain

Martišová

Campión

et al. 2016

Behavioural Brain Research

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Adverse early life events are associated with altered stress responsiveness and metabolic disturbances in the adult life. Dietary methyl donor supplementation could be able to reverse the negative effects of maternal separation by affecting DNA methylation in the brain. In this study, maternal separation during lactation reduced body weight gain in the female adult offspring without affecting food intake, and altered total and HDLcholesterol levels. Also, maternal separation induced a cognitive deficit as measured by NORT and an increase in the immobility time in the Porsolt forced swimming test, consistent with increased depression-like behaviour. An 18-week dietary supplementation with methyl donors (choline, betaine, folate and vitamin B12) from postnatal day 60 also reduced body weight without affecting food intake. Some of the deleterious effects induced by maternal separation, such as the abnormal levels of total and HDL-cholesterol, but especially the depression-like behaviour as measured by the Porsolt test, were reversed by methyl donor supplementation. Also, the administration of methyl donors increased total DNA methylation (measured by immunohistochemistry) and affected the expression of insulin receptor in the hippocampus of the adult offspring. However, no changes were observed in the DNA methylation status of insulin receptor and corticotropin-releasing hormone (CRH) promoter regions in the hypothalamus. In summary, methyl donor supplementation reversed some of the deleterious effects of an early life-induced model of depression in rats and altered the DNA methylation profile in the brain.

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“…However, the impact of arsenic on the epigenetic status of the brain has not been thoroughly investigated, particularly in the context of developmental exposure. To date, there have been three studies on the effects of developmental exposure to arsenic in the brain, suggesting an impact of arsenic on histone acetylation and DNA methylation with concurrent deficits in proteins that may underlie learning and memory deficits (Zarazua et al, 2010, Martinez et al, 2011, Cronican et al, 2013). Conversely, the literature on the effect of arsenic on the epigenome is quite extensive in the context of cancer (Ray et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Developmental exposure to 50 parts-per-billion arsenic influences histone modifications and associated epigenetic machinery in a region- and sex-specific manner in the adult mouse brain

Tyler

Hafez

Solomon

et al. 2015

Toxicology and Applied Pharmacology

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Epidemiological studies report that arsenic exposure via drinking water adversely impacts cognitive development in children and, in adults, can lead to greater psychiatric disease susceptibility, among other conditions. While it is known that arsenic toxicity alters the epigenome, very few studies have investigated its effects on chromatin architecture in the brain. We have previously demonstrated that exposure to a low level of arsenic (50 ppb) during all three trimesters of fetal/neonatal development induces deficits in adult hippocampal neurogenesis in the dentate gyrus (DG), depressive-like symptoms, and alterations in gene expression in the adult mouse brain. As epigenetic processes control these outcomes, here we assess the impact of our developmental arsenic exposure (DAE) paradigm on global histone posttranslational modifications and expression of associated chromatin-modifying proteins in the dentate gyrus and frontal cortex (FC) of adult male and female mice. DAE influenced histone 3 K4 trimethylation with increased levels in the male DG and FC and decreased levels in the female DG (no change in female FC). The histone methyltransferase MLL exhibited a similar sex- and region- specific expression profile as H3K4me3 levels, while histone demethylase KDM5B expression trended in the opposite direction. DAE increased histone 3 K9 acetylation levels in the male DG along with histone acetyltransferase (HAT) expression of GCN5 and decreased H3K9ac levels in the male FC along with decreased HAT expression of GCN5 and PCAF. DAE decreased expression of histone deacetylase enzymes HDAC1 and HDAC2, which were concurrent with increased H3K9ac levels but only in the female DG. Levels of H3 and H3K9me3 were not influenced by DAE in either brain region of either sex. These findings suggest that exposure to a low, environmentally relevant level of arsenic during development induces alterations in the adult brain via histone modifications and chromatin modifiers a sex- and region-specific manner.

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Impact of early developmental arsenic exposure on promotor CpG-island methylation of genes involved in neuronal plasticity

Cited by 67 publications

References 44 publications

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

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

Methyl donor supplementation in rats reverses the deleterious effect of maternal separation on depression-like behaviour

Developmental exposure to 50 parts-per-billion arsenic influences histone modifications and associated epigenetic machinery in a region- and sex-specific manner in the adult mouse brain

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