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Arsenic Induces Differential Neurotoxicity in Male, Female, and E2-Deficient Females: Comparative Effects on Hippocampal Neurons and Cognition in Adult Rats

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Abstract

We earlier reported that arsenic induced hippocampal neuronal loss, causing cognitive dysfunctions in male rats. This neuronal damage mechanism involved an altered bone morphogenetic protein (BMP2)/Smad and brain-derived neurotrophic factor (BDNF)/TrkB signaling. Susceptibility to toxicants is often sex-dependent, and hence we studied the comparative effects of arsenic in adult male and female rats. We observed that a lower dose of arsenic reduced learning-memory ability, examined through passive avoidance and Y-maze tests, in male but not female rats. Again, male rats exhibited greater learning-memory loss at a higher dose of arsenic. Supporting this, arsenic-treated male rats demonstrated larger reduction in the hippocampal NeuN and %-surviving neurons, together with increased apoptosis and altered BMP2/Smad and BDNF/TrkB pathways compared to their female counterparts. Since the primary female hormone, estrogen (E2), regulates normal brain functions, we next probed whether endogenous E2 levels in females offered resistance against arsenic-induced neurotoxicity. We used ovariectomized (OVX) rat as the model for E2 deficiency. We primarily identified that OVX itself induced hippocampal neuronal damage and cognitive decline, involving an increased BMP2/Smad and reduced BDNF/TrkB. Further, these effects appeared greater in arsenic + OVX compared to arsenic + sham (ovary intact) or OVX rats alone. The OVX-induced adverse effects were significantly reduced by E2 treatment. Overall, our study suggests that adult males could be more susceptible than females to arsenic-induced neurotoxicity. It also indicates that endogenous E2 regulates hippocampal BMP and BDNF signaling and restrains arsenic-induced neuronal dysfunctions in females, which may be inhibited in E2-deficient conditions, such as menopause or ovarian failure.

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Data have been deposited to the CSIR-IITR repository, which could be obtained from the corresponding author when needed.

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Acknowledgements

RP, AG, and KM were supported by UGC fellowship, Government of India; KG was supported by CSIR fellowship, Government of India; and PS was supported by Science and Engineering Research Board (SERB), Government of India.

Jitendra Vishwakarma (SRF, CSIR-IITR) helped in the surgical procedures. The CSIR-IITR communication number of this article is 3744.

Funding

This study was supported by SERB, Government of India, GAP406.

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Author notes

  1. Rukmani Pandey

    Present address: Department of Psychiatry, Center for Molecular Biology and Genetics of Neurodegeneration, Icahn School of Medicine at Mount Sinai, New York City, USA

  2. Pallavi Shukla

    Present address: Division of Microbial Technology, CSIR-National Botanical Research Institute, Lucknow, 226001, India

  3. Asmita Garg and Keerti Gupta are equal contributors.

Authors and Affiliations

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

    Rukmani Pandey, Asmita Garg, Keerti Gupta, Pallavi Shukla & Sanghamitra Bandyopadhyay

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Rukmani Pandey, Asmita Garg, Keerti Gupta, Kapil Mandrah, Somendu Roy, Naibedya Chattopadhyay & Sanghamitra Bandyopadhyay

  3. Analytical Chemistry Laboratory, Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR–IITR), Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India

    Kapil Mandrah & Somendu Roy

  4. Division of Endocrinology, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, 226031, Uttar Pradesh, India

    Naibedya Chattopadhyay

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  1. Rukmani Pandey
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Contributions

Rukmani Pandey contributed to the experimental planning, animal treatments, animal surgeries, major Western blotting, IF (Figs. 4d and 5b and d), TUNEL assay (Fig. 6c), neurobehavioral assays, serum estradiol estimation, data analysis, and data compilation. Asmita Garg performed IF (Figs. 3c and 4b), TUNEL assay (Fig. 3d) and Nissl staining, data analysis, and data compilation. Keerti Gupta contributed to animal treatment, animal surgery, neurobehavioral experiments, and data analysis. Pallavi Shukla contributed to a few Western blots. Kapil Mandrah and Somendu Roy contributed to the arsenic estimation. Naibedya Chattopadhyay contributed to experimental designing. Sanghamitra Bandyopadhyay contributed to the overall experimental planning, designing, supervision, and paper writing.

Corresponding author

Correspondence to Sanghamitra Bandyopadhyay.

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Wistar rats were used after obtaining approval from the Institutional Animal Ethics Committee of CSIR-CDRI and CSIR-IITR. Guidelines and regulations of the Ethics Committee were followed for maintenance and handling of the rats.

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Pandey, R., Garg, A., Gupta, K. et al. Arsenic Induces Differential Neurotoxicity in Male, Female, and E2-Deficient Females: Comparative Effects on Hippocampal Neurons and Cognition in Adult Rats. Mol Neurobiol 59, 2729–2744 (2022). https://doi.org/10.1007/s12035-022-02770-1

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