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Cost-effective neurotoxicity testing with high discriminative power: examples in rats after pre- or peri-natal exposure too methylazoxy methanol or methylmercury.

Authors
DeGroot-D; Israel-J; Moerkens-M; Gloudemans-A; Hartgring-S; VanDeHorst-L; Otto-M; Lammers-J; Bos-Kuipers-M; Waalkens-I; O'Callaghan-J; Kaufman-W; Sorensen-S; Pakkenberg-B; Gundersen-HJ
Source
Toxicol Lett 2007 Oct; 172(Suppl 1):S182-S183
NIOSHTIC No.
20032880
Abstract
A tiered morphological approach (brain size --> microscopic slide reading --> 2D linear morphometry --> 3D stereology) was used in a regulatory developmental neurotoxicity (DNT) study (EPA OPPTS 870.6300) with rats to demonstrate that prenatal exposure to methylazoxy methanol (MAM; doses up to 7.5 mg/(kg day); PN13ĘC15) causes substantial effects on brain morphology, as shown by 2D and 3D morphometry/ stereology. During microscopic slide reading the effects went unrecognized (DeGroot et al., 2005a,b). Likewise, significant effects of perinatal exposure to methyl mercury (MeHg; doses up to 1 mg/(kg day); GD6-PD10) were demonstrated, however, by 3D stereology only. Especially total cell numbers and brain region volume showed high discriminative power. So, it was concluded that stereology offers the best opportunity to detect early morphological changes in the developing brain and adverse effects of drugs, chemicals or food components thereon. However, counting cells is a time consuming job. Instead, volume estimates can be determined fast as long as the investigated region can clearly be defined and borders demarcated. Hereto, we developed a "novel" mini-atlas of the rat brain defined as 10 major regions. Together with multi-brain embedding/ sectioning/sampling, the renewed and reversed tiered approach (brain size --> 3D stereology --> 2D linear morphometry --> microscopic slide reading) proved to be sensitive and efficient. The estimates of brain region volumes appeared to be sensitive first-tier indicators to pinpoint the focus for toxicity and to narrow-down the workload. We could demonstrate that stereology is now within reach of cost-effective regulatory DNT testing.
Keywords
Chemical-hypersensitivity; Skin-absorption; Exposure-levels; Exposure-methods; Central-nervous-system-disorders; Neurotoxins; Neurotoxicology; Prenatal-exposure; Laboratory-animals; Animal-studies
CODEN
TOLED5
CAS No.
7439-97-6
Publication Date
20071007
Document Type
Journal Article
Fiscal Year
2008
NTIS Accession No.
NTIS Price
ISSN
0378-4274
NIOSH Division
HELD
Source Name
Toxicology Letters
State
WV
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