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Dichlorvos-induced cell cycle arrest and DNA damage repair activation in primary rat microglial cells
Aditya Sunkaria1, Willayat Yousuf Wani, Deep Raj Sharma
1Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Abstract:
Dichlorvos, an organophosphate (OP), is known to cause oxidative stress in the central nervous system (CNS). Previously we have shown that dichlorvos treatment promoted the levels of proinflammatory molecules and ultimately induced apoptotic cell death in primary microglial cells. Here we studied the effect of dichlorvos on crucial cell cycle regulatory proteins and the DNA damage sensor ataxia-telangiectasia mutated (ATM). We found a significant increase in p53 and its downstream target, p21, levels in dichlorvos-treated microglial cells compared with control cells. Moreover, dichlorvos exposure promoted the levels of different cell cycle regulatory proteins. These results along with flow cytometry results suggested that primary microglial cells were arrested at G1 and G2/M phase after dichlorvos exposure. We have shown in a previous study that dichlorvos can induce DNA damage in microglia; here we found that microglial cells also tried to repair this damage by inducing a DNA repair enzyme, i.e., ATM. We observed a significant increase in the levels of ATM after dichlorvos treatment compared with control.
Insights
Dichlorvos, an organophosphate pesticide, disrupts cell cycle progression in microglial cells, leading to G1 and G2/M phase arrest. This study reveals dichlorvos induces DNA damage and activates repair mechanisms, including ATM signaling.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Dichlorvos (an organophosphate) induces oxidative stress and apoptosis in central nervous system (CNS) microglial cells.
- Previous research demonstrated dichlorvos elevates proinflammatory molecules in primary microglial cells.
Purpose of the Study:
- To investigate the impact of dichlorvos on cell cycle regulatory proteins and the DNA damage sensor, ataxia-telangiectasia mutated (ATM).
- To elucidate the cell cycle effects and DNA damage response pathways activated by dichlorvos in microglial cells.
Main Methods:
- Primary microglial cells were treated with dichlorvos.
- Levels of p53, p21, cell cycle regulatory proteins, and ATM were analyzed.
- Flow cytometry was used to assess cell cycle distribution.
Main Results:
- Dichlorvos exposure significantly increased levels of p53 and p21 in microglial cells.
- Dichlorvos promoted cell cycle regulatory proteins, leading to G1 and G2/M phase arrest.
- Increased levels of the DNA repair enzyme ATM were observed post-dichlorvos treatment.
Conclusions:
- Dichlorvos disrupts microglial cell cycle regulation, causing arrest at G1 and G2/M phases.
- Microglial cells activate DNA damage response pathways, including ATM, to repair dichlorvos-induced DNA damage.
- These findings highlight the neurotoxic effects of dichlorvos on microglial cells and their intricate response mechanisms.
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