Elsevier

Toxicology Letters

Volume 225, Issue 1, 10 February 2014, Pages 78-85
Toxicology Letters

Epigenetic histone modification regulates developmental lead exposure induced hyperactivity in rats

https://doi.org/10.1016/j.toxlet.2013.11.025Get rights and content

Highlights

  • Epigenetic changes in the histone modification level were proposed to be associated with lead induced hyperactivity.

  • Hyperactivity caused by lead exposure was significantly influenced by doses.

  • Dopaminergic proteins remained unchanged in the process of lead induced ADHD.

  • Impairment caused by high-dose lead was hypothesized to be partly antagonized by histone acetylation.

  • The increased expression of p300 was responsible for the hisone changes.

Abstract

Lead (Pb) exposure was commonly considered as a high environmental risk factor for the development of attention-deficit/hyperactivity disorder (ADHD). However, the molecular basis of this pathological process still remains elusive. In light of the role of epigenetics in modulating the neurological disease and the causative environment, the alterations of histone modifications in the hippocampus of rats exposed by various doses of lead, along with concomitant behavioral deficits, were investigated in this study. According to the free and forced open field test, there showed that in a dosage-dependent manner, lead exposure could result in the increased locomotor activity of rats, that is, hyperactivity: a subtype of ADHD. Western blotting assays revealed that the levels of histone acetylation increased significantly in the hippocampus by chronic lead exposure, while no dramatic changes were detected in terms of expression yields of ADHD-related dopaminergic proteins, indicating that histone acetylation plays essential roles in this toxicant-involved pathogenesis. In addition, the increased level of histone acetylation might be attributed to the enzymatic activity of p300, a typical histone acetyltransferase, as the transcriptional level of p300 was significantly increased upon higher-dose Pb exposure. In summary, this study first discovered the epigenetic mechanism bridging the environmental influence (Pb) and the disease itself (ADHD) in the histone modification level, paving the way for the comprehensive understanding of ADHD's etiology and in further steps, establishing the therapy strategy of this widespread neurological disorder.

Introduction

Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood neuropsychiatric disorders, occuring in an estimated 3% to 7% of school-aged children (Nigg et al., 2010). The etiology of ADHD was reported to be associated with both genetic and epigenetic factors, and a growing number of research suggested that exposure to environmental lead is a high risk factor for ADHD (Braun et al., 2006, Nigg et al., 2008, Wang et al., 2008). The heavy metal lead (Pb) is a well-studied toxicant known to cause the deficits of cognition (Cho et al., 2010, Ha et al., 2009), and has been proved to be associated with symptoms of inattention (Jakubowski, 2011).

There were a variety of causes including genetic factors, neurophysiological factors, mild brain injuries, psychological and social factors or multiple combinations of them leading to ADHD (Jones and Miller, 2008, Laucht et al., 2007). In addition, there was mounting evidence to suggest the pathophysiologically relevant contribution of monoaminergic pathways in the etiology of ADHD (Faraone and Mick, 2010, Peterson et al., 2011, Szczerbak et al., 2007, White et al., 2007, Zuch et al., 1998). It was demonstrated that dopamine transport gene (DAT1) and dopamine receptor gene (DRD4) were involved in the risk for ADHD (Hawi et al., 2005, Hoefgen et al., 2006, McCracken et al., 2000, Shumay et al., 2010).

The epigenetic factors, with particular relevance in psychopathology, could either strengthen or weaken the genetic effects through modifying the expression of individuals’ genetic background on phenotypes (Archer et al., 2011, Rutten and Mill, 2009, Wilson, 2008). The post-translational modification of histones, the basic proteins around which DNA is wrapped to form nucleosomes, modulates gene expression via alterations in chromatin structure (Kaufmann et al., 2005, Pons et al., 2009, Timmermann et al., 2001). According to the limited epigenetic profiles reported by several studies on ADHD, histone modification patterns have the potential to become a useful marker to measure the disease (Egger et al., 2004, Seligson et al., 2005). But whether histone modification was involved in chronic lead-induced hyperactivity remains unknown.

Histone acetylation was considered to be the result of complex interaction between histone acetyltransferase (HAT) and histone deacetylase (HDAC) (Jakovcevski and Akbarian, 2012). HDAC1 was an important HDAC belonging to Class I and usually used as the model enzyme to investigate the function of HDAC inhibitors (Phiel et al., 2001). Besides, p300 was a critical trancription coactivator involved in extensive cellular processes and identified as a novel type of HAT (Ogryzko et al., 1996).

In this study, we performed a preliminary assessment of behavioral dysfunction and patterns of histone acetylation in lead-associated ADHD rats, and attempted to establish an exploratory correlation of these histone parameters with neurologic severity. The study could shed light on the epigenetic mechanisms lying behind the lead-associated ADHD.

Section snippets

Experimental animals

Sprague-Dawley (SD) rats were supplied by the Laboratory Animal Center, Anhui Medical University, P.R. China, and were maintained in compliance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. The study was approved by the institutional animal care and use committee at Hefei University of Technology. Four female SD rats, weighing at 200–220 g, were randomly placed in four cages after mating. The rats were subsequently treated with distilled water containing

Lead accumulations in hippocampus and blood after chronic lead exposure

To examine lead accumulation within hippocampus and blood, the lead concentration was determined by the graphite furnace atomic spectrophotometry. Lead concentration in hippocampus was 0.025 ± 0.001 μg/g in control animals, whereas it could reach 0.211 ± 0.04 μg/g (Fig. 1A, n = 12, p < 0.05) and 0.890 ± 0.06 μg/g (Fig. 1A, n = 8, p < 0.001) in 5 mg/L and 25 mg/L lead-exposed rats, respectively.

On the other hand, blood lead concentration was 23.5 ± 4.2 μg/L in control animals, whereas it could reach 87.8 ± 9.4 μg/L and

Discussion

Attention-deficit/hyperactivity disorder (ADHD) is a neurological disease with complex interactive operations of genetic and environmental factors (Archer et al., 2011). It is known that environment could manifest itself in the development of disease involving epigenetic processes. To date, the precise epigenetic mechanisms leading to ADHD still remains elusive. Here we report an increase of histone acetylation in the hippocampus of rats exposed to various doses of lead, highlighting the exact

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgment

This work was supported by the National Key Basic Research Program of China (973 Program, No. 2012CB525003), the National Science Foundation of China (No. 31200851, 21307024), the Program for New Century Excellent Talents in University (NCET-12-0835), Specialized Research Fund for the Doctoral Program of Higher Education (No. 20130111110024), the China Postdoctoral Science Foundation (2013M531500), the Huangshan Young Scholar Fund of Hefei University of Technology (407-037030) and the

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