title: Prenatal carbofuran exposure inhibits hippocampal neurogenesis and causes learning and memory deficits in offspring.
abstract: Neurogenesis is a process of generation of new neurons in the hippocampus and associated with learning and memory. Carbofuran, a carbamate pesticide, elicits several neurochemical, neurophysiological, and neurobehavioral deficits. We evaluated whether chronic prenatal oral exposure of carbofuran during gestational days 7-21 alters postnatal hippocampal neurogenesis at postnatal day 21. We found carbofuran treatment significantly decreased bromodeoxyuridine (BrdU) positive cell proliferation and long-term survival in the hippocampus only but not in the cerebellum. We observed a reduced number of transcription factor SOX-2 and glial fibrillary acidic protein (GFAP) colabeled cells, decreased nestin messenger RNA (mRNA) expression, and decreased histone-H3 phosphorylation following carbofuran treatment, suggesting a decreased pool of neural progenitor cells (NPC). Colocalization of BrdU with doublecortin (DCX), neuronal nuclei (NeuN), and GFAP suggested decreased neuronal differentiation and increased glial differentiation by carbofuran. The number of DCX(+) and NeuN(+) neurons, NeuN protein levels, and fibers length of DCX(+) neurons were decreased by carbofuran. Carbofuran caused a significant downregulation of mRNA expression of the neurogenic genes/transcription factors such as neuregulin, neurogenin, and neuroD1 and upregulation of the gliogenic gene Stat3. Carbofuran exposure led to increased BrdU/caspase 3 colabeled cells, an increased number of degenerative neurons and profound deficits in learning and memory processes. The number and size of primary neurospheres derived from the hippocampus of carbofuran-treated rats were decreased. These results suggest that early gestational carbofuran exposure diminishes neurogenesis, reduces the NPC pool, produces neurodegeneration in the hippocampus, and causes cognitive impairments in rat offspring.
authors.affiliation: Developmental Toxicology Division, Systems Toxicology Group, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research, Lucknow-226001, India.
authors.forename: Divya
authors.initials: D
authors.lastname: Mishra
authors.forename: Shashi Kant
authors.initials: SK
authors.lastname: Tiwari
authors.forename: Swati
authors.initials: S
authors.lastname: Agarwal
authors.forename: Vinod Praveen
authors.initials: VP
authors.lastname: Sharma
authors.forename: Rajnish Kumar
authors.initials: RK
authors.lastname: Chaturvedi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002235:Carbofuran / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000089662:Doublecortin Protein; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000196:embryology / Q000502:physiology; D007306:Insecticides / Q000633:toxicity*; D007859:Learning Disabilities / Q000139:chemically induced* / Q000378:metabolism; D018811:Maternal Exposure; D008569:Memory Disorders / Q000139:chemically induced* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D007306:Insecticides; D009419:Nerve Tissue Proteins; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D002235:Carbofuran