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2D and 3D assessment of neuropathology in rat brain after prenatal exposure to methylazoxymethanol, a model for developmental neurotoxicty

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Author: Groot, D.M.G. de · Hartgring, S. · Horst, L. van de · Moerkens, M. · Otto, M. · Bos-Kuijpers, M.H.M. · Kaufmann, W.S.H. · Lammers, J.H.C.M. · O'Callaghan, J.P. · Waalkens-Berendsen, I.D.H. · Pakkenberg, B. · Gundersen, H.G.
Type:article
Date:2005
Institution: TNO Kwaliteit van Leven
Source:Reproductive Toxicology, 3, 20, 417-432
Identifier: 238697
doi: doi:10.1016/j.reprotox.2005.04.006
Keywords: Biology · Toxicology and Applied Pharmacology · Cerebellum · Developmental neurotoxicity · Hippocampus · Linear morphometry · Methylazoxymethanol · Neuron numbers · Rat · Stereology · methylazoxymethanol · animal experiment · animal model · animal tissue · article · brain development · brain size · brain weight · cell count · cell proliferation · cell structure · cerebellum · controlled study · developmental disorder · evaluation · female · hippocampus · linear system · male · morphometrics · neuropathology · neurotoxicity · nonhuman · pregnancy · prenatal exposure · progeny · pyramidal nerve cell · quantitative analysis · rat · stereology · strength · three dimensional imaging · Abnormalities, Drug-Induced · Animals · Animals, Outbred Strains · Brain · Cell Count · Female · Imaging, Three-Dimensional · Injections, Intraperitoneal · Male · Maternal Exposure · Methylazoxymethanol Acetate · Organ Size · Pregnancy · Prenatal Exposure Delayed Effects · Rats · Rats, Wistar · Specific Pathogen-Free Organisms · Teratogens · Toxicity Tests

Abstract

To evaluate the ability of a tiered quantitative morphological approach to reveal developmental neurotoxicity, morphometric parameters were measured in the offspring of rats treated with methylazoxymethanol (MAM) during days 13-15 of pregnancy. Treatment was aimed at inhibiting the proliferation phase of hippocampal neurons while leaving cerebellar neurons unaffected. 2D and 3D assessment of brain morphology combined with straightforward measurement of brain size, weight and volume, and the usefulness of estimation of total neuron numbers were studied. Each tier indicated major effects of MAM, from macroscopic effects in the cerebrum (first tier) to a considerable loss of neurons in the hippocampal CA1 pyramidal layer (third tier). The cerebellum and the number of cerebellar granular neurons were not changed. Along with each step of the proposed tiered approach (brain size → linear morphometry → stereology), the discriminative strength of the endpoints, and thus the probability to pinpoint the extent and location of developmental brain lesions increased. © 2005 Elsevier Inc. All rights reserved.