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Arsenic, Cadmium, and Lead Like Troglitazone Trigger PPARγ-Dependent Poly (ADP-Ribose) Polymerase Expression and Subsequent Apoptosis in Rat Brain Astrocytes

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Abstract

We previously demonstrated that arsenic, cadmium, and lead mixture at environmentally relevant doses induces astrocyte apoptosis in the developing brain. Here, we investigated the mechanism and contribution of each metal in inducing the apoptosis. We hypothesized participation of transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), reported to affect astrocyte survival. We treated cultured rat astrocytes with single metals and their combinations and performed apoptosis assay and measured PPARγ expression levels. We found that cadmium demonstrated maximum increase in PPARγ as well as apoptosis, followed by arsenic and then lead. Interestingly, we observed that the metals mimicked PPARγ agonist, troglitazone, and enhanced PPARγ-transcriptional activity. Co-treatment with PPARγ-siRNA or PPARγ-antagonist, GW9662, suppressed the astrocyte apoptosis, suggesting a prominent participation of PPARγ in metal(s)-induced astrocyte loss. We explored PPARγ-transcriptional activity and identify its target gene in apoptosis, performed in silico screening. We spotted PPARγ-response elements (PPREs) within poly(ADP-ribose) polymerase (PARP) gene, and through gel-shift assay verified metal(s)-mediated increased PPARγ binding to PARP-PPREs. Chromatin-immunoprecipitation and luciferase-reporter assays followed by real-time PCR and Western blotting proved PPRE-mediated PARP expression, where cadmium contributed most and lead least, and the effects of metal mixture were comparable with troglitazone. Eventually, dose-dependent increased cleaved-PARP/PARP ratio confirmed astrocyte apoptosis. Additionally, we found that PPARγ and PARP expressions were c-Jun N-terminal kinases and cyclin-dependent kinase5-dependent. In vivo treatment of developing rats with the metals corroborated enhanced PPARγ-dependent PARP and astrocyte apoptosis, where yet again cadmium contributed most. Overall, our study enlightens a novel PPARγ-dependent mechanism of As-, Cd-, and Pb-induced astrocyte apoptosis.

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Abbreviations

PPARγ:

Peroxisome proliferator-activated receptor gamma

PARP:

Poly (ADP-ribose) polymerase

LC:

Lethal concentration

PPRE:

Peroxisome proliferator-activated receptorresponse elements

As:

Arsenic

Cd:

Cadmium

Pb:

Lead

GFAP:

Glial fibrillary acidic protein

EMSA:

Electrophoretic mobility shift assay

ChIP:

Chromatin immunoprecipitation

ABA:

3-aminobenzamide

GFP:

Green fluorescence protein

PND:

Postnatal day

TUNEL:

Terminal deoxynucleotidyl transferase dUTP nick end labeling

TBP:

Tata-binding protein

Trog:

Troglitazone

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Acknowledgement

We acknowledge Miss. Shipra Kartik and Mr. Devendra Pratap Singh for their help in Western blotting and primary rat astrocyte culture.

Author information

Authors and Affiliations

  1. Academy of Scientific and Innovative Research (AcSIR), CSIR-IITR campus, Lucknow, India

    Rajesh Kushwaha & Sanghamitra Bandyopadhyay

  2. Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma GandhiMarg, Lucknow, Uttar Pradesh, 226001, India

    Rajesh Kushwaha, Juhi Mishra, Sachin Tripathi & Sanghamitra Bandyopadhyay

  3. Babu Banarasi Das University, Lucknow, 226028, India

    Juhi Mishra

  4. Amity Institute of Biotechnology, Amity University (Lucknow campus), Lucknow, Uttar Pradesh, 226028, India

    Sachin Tripathi

  5. Central Instrumentation Facility, Developmental Toxicology Division, CSIR-IITR, Vishvigyan Bhavan, 31, Mahatma GandhiMarg, Lucknow, Uttar Pradesh, 226001, India

    Puneet Khare

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  1. Rajesh Kushwaha
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Correspondence to Sanghamitra Bandyopadhyay.

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Funding Information

This work was supported by Council of Scientific and Industrial Research-network miND; Department of Biotechnology, Govt. of India [GAP285] and Science and Engineering Research Board, Govt. of India [GAP278].

Conflict of Interest

The authors declare that they have no conflict of interest.

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Kushwaha, R., Mishra, J., Tripathi, S. et al. Arsenic, Cadmium, and Lead Like Troglitazone Trigger PPARγ-Dependent Poly (ADP-Ribose) Polymerase Expression and Subsequent Apoptosis in Rat Brain Astrocytes. Mol Neurobiol 55, 2125–2149 (2018). https://doi.org/10.1007/s12035-017-0469-7

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