Epigenetic histone modification regulates developmental lead exposure induced hyperactivity in rats

Luo, Manyu; Xu, Yi; Cai, Rong; Tang, Yuqing; Ge, Ming; Liu, Zhihua; Xu, Li; Hu, Fan; Ruan, Di‐Yun; Wang, Huili

doi:10.1016/j.toxlet.2013.11.025

Cited by 81 publications

(41 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…At the same time, this work should encourage further research on other neurotoxicants and neurodevelopmental disorders. For example, even lowlevel lead exposure may result in epigenetic changes during development (e.g., histone modification), and such changes can mediate increased hyperactive behavior (Luo et al, 2014). Thus, future work could specifically examine changes in expression in ADHD-relevant genes related to lead, as well as other toxicants.…”

Section: Discussionmentioning

confidence: 99%

“…Although many potential confounders have been statistically covaried in this research, and animal studies have demonstrated a causal effect of lead exposure on activity level (Luo et al, 2014), what appear to be causal effects of lead on ADHD in humans could still be due to unmeasured confounders. One approach to clarify causality is Mendelian randomization (Lewis, Relton, Zammit, & Smith, 2013), which is a type of natural experiment.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Variation in an Iron Metabolism Gene Moderates the Association Between Blood Lead Levels and Attention-Deficit/Hyperactivity Disorder in Children

et al. 2015

View full text Add to dashboard Cite

Although attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental condition, there is also considerable scientific and public interest in environmental modulators of its etiology. Exposure to neurotoxins is one potential source of perturbation of neural, and hence psychological, development. Exposure to lead in particular has been widely investigated and is correlated with neurodevelopmental outcomes, including ADHD. To investigate whether this effect is likely to be causal, we used a Mendelian randomization design with a functional gene variant. In a case-control study, we examined the association between ADHD symptoms in children and blood lead level as moderated by variants in the hemochromatosis (HFE) gene. The HFE gene regulates iron uptake and secondarily modulates lead metabolism. Statistical moderation was observed: The magnitude of the association of blood lead with symptoms of ADHD was altered by functional HFE genotype, which is consistent with a causal hypothesis.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Variation in an Iron Metabolism Gene Moderates the Association Between Blood Lead Levels and Attention-Deficit/Hyperactivity Disorder in Children

et al. 2015

View full text Add to dashboard Cite

show abstract

“…As histone modifications and DNA methylation also respond to various environmental and cellular cues, epigenetic marks may provide a link between genetic variation and susceptibility to ethanol-induced cell death (Meaney, 2010; Kobor and Weinberg, 2011). Previous studies have investigated the effect of different exposure paradigms on histone modifications in the brain, finding that chromatin structure responds to various teratogens during development (Cronican et al, 2013; Jordi et al, 2013; Luo et al, 2014). Recent evidence also shows that acute ethanol exposure alters dimethylation levels on lysine 9 and 27 of histone 3, which partially mediate ethanol’s teratogenic effects in the brain (Subbanna et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Molecular pathways underpinning ethanol-induced neurodegeneration

et al. 2014

View full text Add to dashboard Cite

While genetics impacts the type and severity of damage following developmental ethanol exposure, little is currently known about the molecular pathways that mediate these effects. Traditionally, research in this area has used a candidate gene approach and evaluated effects on a gene-by-gene basis. Recent studies, however, have begun to use unbiased approaches and genetic reference populations to evaluate the roles of genotype and epigenetic modifications in phenotypic changes following developmental ethanol exposure, similar to studies that evaluated numerous alcohol-related phenotypes in adults. Here, we present work assessing the role of genetics and chromatin-based alterations in mediating ethanol-induced apoptosis in the developing nervous system. Utilizing the expanded family of BXD recombinant inbred mice, animals were exposed to ethanol at postnatal day 7 via subcutaneous injection (5.0 g/kg in 2 doses). Tissue was collected 7 h after the initial ethanol treatment and analyzed by activated caspase-3 immunostaining to visualize dying cells in the cerebral cortex and hippocampus. In parallel, the levels of two histone modifications relevant to apoptosis, γH2AX and H3K14 acetylation, were examined in the cerebral cortex using protein blot analysis. Activated caspase-3 staining identified marked differences in cell death across brain regions between different mouse strains. Genetic analysis of ethanol susceptibility in the hippocampus led to the identification of a quantitative trait locus on chromosome 12, which mediates, at least in part, strain-specific differential vulnerability to ethanol-induced apoptosis. Furthermore, analysis of chromatin modifications in the cerebral cortex revealed a global increase in γH2AX levels following ethanol exposure, but did not show any change in H3K14 acetylation levels. Together, these findings provide new insights into the molecular mechanisms and genetic contributions underlying ethanol-induced neurodegeneration.

show abstract

“…12 Historically, the heavy metal lead (Pb) has been studied as a potent developmental toxicant, and recent studies implicate epigenetic modifications as drivers of Pb's developmental dysregulation. 13,14 Pb is a persistent environmental pollutant with uptake via air, soil, water, and old paint as avenues for ingestion. 15 Currently, the reference level at which the US.…”

Section: Introductionmentioning

confidence: 99%