title: 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.
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.
authors.affiliation: 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.
authors.forename: Anshuman
authors.initials: A
authors.lastname: Singh
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226 001, Uttar Pradesh, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, 110025, India.
authors.forename: Anubha
authors.initials: A
authors.lastname: Mudawal
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Pratibha
authors.initials: P
authors.lastname: Maurya
authors.affiliation: Analytical Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226001, Uttar Pradesh, India.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Jain
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Saumya
authors.initials: S
authors.lastname: Nair
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Shukla
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Yadav
authors.affiliation: Animal Facility Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226001, Uttar Pradesh, India.
authors.forename: Dhirendra
authors.initials: D
authors.lastname: Singh
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Vinay Kumar
authors.initials: VK
authors.lastname: Khanna
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226 001, Uttar Pradesh, India.
authors.forename: Rajnish Kumar
authors.initials: RK
authors.lastname: Chaturvedi
authors.affiliation: Analytical Chemistry Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226001, Uttar Pradesh, India.
authors.forename: Mohana K R
authors.initials: MKR
authors.lastname: Mudiam
authors.affiliation: School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, Tamil Nadu, India.
authors.forename: Rao
authors.initials: R
authors.lastname: Sethumadhavan
authors.affiliation: Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, Uttar Pradesh, India.
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Post Box No. 80, M.G. Marg, Lucknow, 226 001, Uttar Pradesh, India. parmar_devendra@hotmail.com.
authors.forename: Devendra
authors.initials: D
authors.lastname: Parmar
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D055162:Biocatalysis; D001921:Brain / Q000201:enzymology / Q000473:pathology*; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D007858:Learning / Q000187:drug effects; D008297:Male; D055442:Metabolome / Q000235:genetics; D062105:Molecular Docking Simulation; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D011722:Pyrethrins / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D017422:Sequence Analysis, DNA; D065852:Spatial Memory / Q000187:drug effects; D040681:Structural Homology, Protein; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D018377:Neurotransmitter Agents; D011722:Pyrethrins; D012333:RNA, Messenger; D015262:Xenobiotics; C017160:cypermethrin; D003577:Cytochrome P-450 Enzyme System
keywords: Cypermethrin; Cytochrome P450s; Development; In silico; Neurotransmitter synthesis; Prenatal exposure; Rechallenge