Developmental exposure of aflatoxin B1 reversibly affects hippocampal neurogenesis targeting late-stage neural progenitor cells through suppression of cholinergic signaling in rats. (2nd October 2015)

• Record Type: Journal Article
• Authors: Tanaka, Takeshi; Mizukami, Sayaka; Hasegawa-Baba, Yasuko; Onda, Nobuhiko; Sugita-Konishi, Yoshiko; Yoshida, Toshinori; Shibutani, Makoto
• Is Part Of: Toxicology. Volume 336(2015)
• Page Start: 59
• Page End: 69
• Publication Date: 2015-10-02
• Subjects: AFB1 aflatoxin B1 -- AFM1 aflatoxin M1 -- BDNF brain-derived neurotrophic factor -- BW body weight -- CA3 Cornu ammonis 3 -- CALB1 calbindin-D-28K -- CALB2 calbindin-D-29K -- Cdkn1a cyclin-dependent kinase inhibitor 1A -- Chat choline O-acetyltransferase -- CHRNA7 acetylcholine receptor, nicotinic, alpha 7 (neuronal) -- CNTF ciliary neurotrophic factor -- CT threshold cycle -- DAB 3, 3′-diaminobenzidine -- DCX doublecortin -- Drd2 dopamine receptor D2 -- GABA γ-aminobutyric acid -- GFAP glial fibrillary acidic protein -- γ-H2AX gamma-H2A histone family, member X -- Gapdh glyceraldehyde 3-phosphate dehydrogenase -- GCL granule cell layer -- GD gestational day -- GFAP glial fibrillary acidic protein -- HPLC high-performance liquid chromatography -- Hprt1 hypoxanthine phosphoribosyltransferase 1 -- NTRK2 neurotrophic tyrosine kinase receptor, type 2 -- NeuN neuron-specific nuclear protein -- NOAEL no-observed-adverse-effect level -- PAX6 paired box 6 -- PCNA proliferating cell nuclear antigen -- PFA paraformaldehyde -- PND postnatal day -- PVALB parvalbumin -- p21Cip1 cyclin-dependent kinase inhibitor 1A -- RT-PCR reverse-transcription polymerase chain reaction -- SGZ subgranular zone -- SST somatostatin -- TBR2 T box brain 2 -- TRKB tropomyosin receptor kinase B -- TUBB3 tubulin, beta 3 class III -- TUNEL terminal deoxynucleotidyl transferase dUTP nick-end labeling; Aflatoxin B1 -- BDNF signaling -- Cholinergic signaling -- Hippocampal dentate gyrus -- Adult neurogenesis -- Rat; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2015.08.001
• Languages: English
• ISSNs: 0300-483X

Abstract

Highlights: Maternal AFB1 exposure effect on hippocampal neurogenesis was examined in rats. AFB1 reversibly reduced cell proliferation and type-3 progenitor cells in the SGZ. Suppressed cholinergic signals to GABAergic interneurons may reduce type-3 cells. Suppressed BDNF–TRKB signaling may contribute to aberration of neurogenesis. The NOAEL for offspring was determined to be 0.1 ppm (7.1–13.6 μg/kg BW/day). Abstract: To elucidate the maternal exposure effects of aflatoxin B1 (AFB1 ) and its metabolite aflatoxin M1, which is transferred into milk, on postnatal hippocampal neurogenesis, pregnant Sprague-Dawley rats were provided a diet containing AFB1 at 0, 0.1, 0.3, or 1.0 ppm from gestational day 6 to day 21 after delivery on weaning. Offspring were maintained through postnatal day (PND) 77 without AFB1 exposure. Following exposure to 1.0 ppm AFB1, offspring showed no apparent systemic toxicity at weaning, whereas dams showed increased liver weight and DNA repair gene upregulation in the liver. In the hippocampal dentate gyrus of male PND 21 offspring, the number of doublecortin + progenitor cells were decreased, which was associated with decreased proliferative cell population in the subgranular zone at ≥0.3 ppm, although T-box brain 2 + cells, tubulin beta III + cells, gamma-H2A histone family, member X + cells, and cyclin-dependent kinase inhibitor 1A + cells did not fluctuate in number. AFB1 exposure examined at 1.0 ppm also resulted in transcript downregulation of the cholinergic receptor subunit Chrna7 and dopaminergic receptor Drd2 in the dentate gyrus, although there was no change in transcript levels of DNA repair genes. In the hippocampal dentate hilus, interneurons expressing CHRNA7 or phosphorylated tropomyosin receptor kinase B (TRKB) decreased at ≥0.3 ppm. On PND 77, there were no changes in neurogenesis-related parameters. These results suggested that maternal AFB1 exposure reversibly affects hippocampal neurogenesis targeting type-3 progenitor cells. This mechanism likely involves suppression of cholinergic signals on hilar GABAergic interneurons and brain-derived neurotrophic factor-TRKB signaling from granule cells. The no-observed-adverse-effect level for offspring neurogenesis was determined to be 0.1 ppm (7.1–13.6 mg/kg body weight/day).