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Cost-effective optimization of a neuropathology protocol for use in regulatory developmental neurotoxicity studies.

de Groot-D; Moerkens-M; Waanders-M; Horst-L; Hartgring-S; Pelgrim-M; Waalkens-D; Lammers-J; Bos-Kuijpers-M; Kaufman-W; O'Callaghan-J; Gundersen-H; Lundberg-M
Toxicologist 2006 Mar; 90(1):10
In a regulatory developmental neurotoxicity (DNT) study (EPA OPPTS 870.6300) with rats we used a tiered morphological approach (brain size -> 2D linear morphometry -> 3D stereology) to demonstrate that prenatal exposure to methylazoxy methanol (MAM; doses up to 7.5 mg/kg/day; PD 13-15) causes substantial effects on brain morphology, as shown by 2D and 3D morphometry /stereology, which go unrecognized during slide reading. Significant effects of perinatal exposure to methyl mercury (MeHg; doses up to 1 mg/kg/day; GD6-PD10) were demonstrated by 3D stereology only and missed by 2D morphometry. Together, the results demonstrated that each tier in the approach contributed to refinement of the search for the predilection areas of MAM and MeHg. The discriminative strength of the endpoints increased along with each step of the tiered approach, while their use as apical test decreased. We believe that the use of this tiered approach increases the probability to pinpoint the location and extent of developmental brain lesions. Based on the opinion that quantification of morphological changes during development of the brain is essential, the tiered approach would perfectly fit into the regulatory Developmental Neurotoxicity test protocol. Therefore, we developed an efficient and cost-effective histology protocol that uses thick systematically cut sections as the starting material for all steps of the tiered approach. The embedding and sectioning procedures by itself are reduced to 1/3rd of their original workload. In addition, a sampling design to study total volumes of 10 major predefined brain regions relevant from a toxicological point of view is introduced as apical stereological endpoint. From this endpoint, further refinement is achieved through 2D linear morphometry. The protocol appears to be efficient and time and money saving.
Neuropathology; Neurotoxicity; Laboratory-animals; Animals; Animal-studies; Morphology; Prenatal-exposure; Brain-disorders; Neurotoxicology; Neurotoxic-effects
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The Toxicologist. Society of Toxicology 45th Annual Meeting and ToxExpo, March 5-9, 2006, San Diego, California