Journal Article

Prenatal Carbofuran Exposure Inhibits Hippocampal Neurogenesis and Causes Learning and Memory Deficits in Offspring

Divya Mishra, Shashi Kant Tiwari, Swati Agarwal, Vinod Praveen Sharma and Rajnish Kumar Chaturvedi

in Toxicological Sciences

Volume 127, issue 1, pages 84-100
Published in print May 2012 | ISSN: 1096-6080
Published online January 2012 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfs004
Prenatal Carbofuran Exposure Inhibits Hippocampal Neurogenesis and Causes Learning and Memory Deficits in Offspring

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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.

Keywords: neurogenesis; carbamate; neural stem cells; neural progenitor cells; hippocampus; neurotoxicity; carbofuran

Journal Article.  9440 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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