Abstract
Exposure to persistent environmental pollutants may constitute an important factor on the onset of a number of neurological disorders such as autism, Parkinson’s disease, and Attention Deficit Disorder (ADD), which have also been linked to reduced GABAergic neuronal function. GABAergic neurons produce γ-aminobutyric acid (GABA), which is the main inhibitory neurotransmitter in the brain. However, the lack of appropriate models has hindered the study of suspected environmental pollutants on GABAergic function. In this work, we have examined the effect of hexachlorobenzene (HCB), a persistent and bioaccumulative environmental pollutant, on the function and morphology of GABAergic neurons generated in vitro from mouse embryonic stem (ES) cells. We observed that: (1) treatment with 0.5 nM HCB did not affect cell viability, but affected the neuronal differentiation of ES cells; (2) HCB induced the production of reactive oxygen species (ROS); and (3) HCB repressed neurite outgrowth in GABAergic neurons, but this effect was reversed by the ROS scavenger N-acetylcysteine (NAC). Our study also revealed that HCB did not significantly interfere with the function of K+ ion channels in the neuronal soma, which indicates that this pollutant does not affect the maturation of the GABAergic neuronal soma. Our results suggest a mechanism by which environmental pollutants interfere with normal GABAergic neuronal function and may promote the onset of a number of neurological disorders such as autism and ADD.
Highlights
Embryonic stem (ES) cells are derived from the inner cell mass (ICM) of blastocyte stageembryos [1]
Results from our RT-PCR analyses suggest that HCB interferes with the neuronal differentiation of encapsulated ES cells
In order to investigate whether HCB affects the maturation of cells committed to a neuronal lineage, we examined the effect of 0.5 nM HCB on the maturation of neuronal precursors in vitro
Summary
Embryonic stem (ES) cells are derived from the inner cell mass (ICM) of blastocyte stage (day 3.5). Due to their intrinsic properties, ES cells can be differentiated in culture into specific cell lineages with potential applications for the treatment of diseases such as spinal cord injuries, diabetes, stroke, heart disease, muscle damage, bone disorders, Parkinson’s and Alzheimer’s disease [2,3]. We first showed that the lowest dose of HCB tested (0.5 nM) did not significantly affect cell viability, but interfered with neurite outgrowth in GABAergic neurons generated from mouse ES cells This effect was shown to result from the HCB-induced generation of Reactive Oxygen Species (ROS) and it was reversed by pretreatment with the ROS scavenger N-acetylcysteine (NAC). Antioxidants may help prevent the onset of neurological diseases in fetuses that result from chronic exposure to low HCB levels during pregnancy
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