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Prenatal Exposure of Cypermethrin Induces Similar Alterations in Xenobiotic-Metabolizing Cytochrome P450s and Rate-Limiting Enzymes of Neurotransmitter Synthesis in Brain Regions of Rat Offsprings During Postnatal Development

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Abstract

Oral administration of low doses of cypermethrin to pregnant Wistar rats led to a dose-dependent differences in the induction of xenobiotic-metabolizing cytochrome P450s (CYPs) messenger RNA (mRNA) and protein in brain regions isolated from the offsprings postnatally at 3 weeks that persisted up to adulthood. Similar alterations were observed in the expression of rate-limiting enzymes of neurotransmitter synthesis in brain regions of rat offsprings. These persistent changes were associated with alterations in circulating levels of growth hormone (GH), cognitive functions, and accumulation of cypermethrin and its metabolites in brain regions of exposed offsprings. Though molecular docking studies failed to identify similarities between the docked conformations of cypermethrin with CYPs and neurotransmitter receptors, in silico analysis identified regulatory sequences of CYPs in the promoter region of rate-limiting enzymes of neurotransmitter synthesis. Further, rechallenge of the prenatally exposed offsprings at adulthood with cypermethrin (p.o. 10 mg/kg × 6 days) led to a greater magnitude of alterations in the expression of CYPs and rate-limiting enzymes of neurotransmitter synthesis in different brain regions. These alterations were associated with a greater magnitude of decrease in the circulating levels of GH and cognitive functions in rechallenged offsprings. Our data has led us to suggest that due to the immaturity of CYPs in fetus or during early development, even the low-level exposure of cypermethrin may be sufficient to interact with the CYPs, which in turn affect the neurotransmission processes and may help in explaining the developmental neurotoxicity of cypermethrin.

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  • 26 June 2019

    The original version of this article unfortunately contained an error at Fig.��10.

  • 26 June 2019

    The original version of this article unfortunately contained an error at Fig.��10.

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Acknowledgments

The authors are grateful to the Director, CSIR-Indian Institute of Toxicology Research, Lucknow for his keen interest and support in carrying out the study. AS is thankful to CSIR, N. Delhi for providing Senior Research Fellowship. The financial assistance of Department of Biotechnology, N. Delhi is also gratefully acknowledged. IITR Publication No. 3141b.

Compliance with Ethical Standards

The submitted manuscript is in accordance with COPE guidelines. The authors have no potential conflicts of interest for disclosure and have no competing financial interests. The animal research has been conducted in accordance with the Declaration of Helsinki and/or with the Guide for the care and use of laboratory animals as adopted by the United States National Institute of Health. The animal experimentation was approved by the Ethical Committee of the CSIR-IITR, and all the animals were maintained in accordance to the policy laid down by the Animal Care Committee of CSIR-IITR. Informed consent received from all coauthors.

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Authors and Affiliations

  1. Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226 001, Uttar Pradesh, India

    Anshuman Singh, Anubha Mudawal, Saumya Nair, Rajendra K. Shukla, Sanjay Yadav, Vinay Kumar Khanna, Rajnish Kumar Chaturvedi & Devendra Parmar

  2. Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India

    Pratibha Maurya & Mohammad Imran Siddiqi

  3. Analytical Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226001, Uttar Pradesh, India

    Rajeev Jain & Mohana K. R. Mudiam

  4. Animal Facility Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226001, Uttar Pradesh, India

    Dhirendra Singh

  5. School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India

    Anshuman Singh & Rao Sethumadhavan

  6. Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India

    Anubha Mudawal

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  1. Anshuman Singh
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Fig. S

Homology modeling and superimposition of modeled structures over their template structures (S1a). Homology model of CYP2B1: Modeled CYP2B1 is shown in orange color. Haem group is shown in blue color. (S1b). CYP2B1 model (shown in blue) superimposed with its template structure 1suo-A (shown in Yellow color). Haem group is shown with orange color. (S2a). Homology model of CYP2E1: Modeled CYP2E1 is shown in yellow color. Haem group is shown in blue color. (S2b). CYP2E1 model (shown in green color) superimposed with its template structure 3e4e (shown in orange color). Haem group is shown in violet color. (S3a). Homology model of GABAAα1γ2 interface: Modeled GABAAα1 (shown in green color) and GABAAγ2 (shown in blue color). (S3b). GABAAα1γ2 interface (shown in blue color) superimposed over its template structure 3RHW (shown in forest green color). (S4a). Homology model of DA-D2: Model of DAD2 (shown in violet color). (S4b). Homology model of DA-D2 (shown in violet color) superimposed with its template structure 3PBL (shown in yellow color). (PPTX 2117 kb)

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Singh, A., Mudawal, A., Maurya, P. et al. Prenatal Exposure of Cypermethrin Induces Similar Alterations in Xenobiotic-Metabolizing Cytochrome P450s and Rate-Limiting Enzymes of Neurotransmitter Synthesis in Brain Regions of Rat Offsprings During Postnatal Development. Mol Neurobiol 53, 3670–3689 (2016). https://doi.org/10.1007/s12035-015-9307-y

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