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
Authors: Rao Sethumadhavan
Pratibha Maurya
Mohana K R Mudiam
Anshuman Singh
Devendra Parmar
Mohammad Imran Siddiqi
Rajendra K Shukla
Rajnish Kumar Chaturvedi
Sanjay Yadav
Rajeev Jain
Anubha Mudawal
Saumya Nair
Vinay Kumar Khanna
Dhirendra Singh
Journal: Molecular Neurobiology (2016)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: Cypermethrin; Cytochrome P450s; Development; In silico; Neurotransmitter synthesis
Affiliations: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226 001, Uttar Pradesh, India., School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India., Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India., Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India., Analytical Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226001, Uttar Pradesh, India., Animal Facility Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226001, Uttar Pradesh, India., Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226 001, Uttar Pradesh, India. .

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. 

Retracted: No

PubPeer comments:
 ![file] Same image used as different treatment group. ,