Developmental neurotoxicity testing with methylmercury and methylazoxymethanol.
de Groot-DMG; van Dael-MFP; Hartgring-SAY; Pelgrim-MPT; Waanders-NM; Pakkenberg-B; Kaufmann-WSH; Bos-Kuijpers-MHM; O'Callaghan-JP; Lammers-JHCM; Waalkens-Berendsen-DH; Gundersen-HJG
Neurotoxicology 2004 Jun; 25(4):708-709
A Developmental Neurotoxicity Test (EPA, OPPTS 6300 and 8600) was carried out with methylmercury chloride (MeHg) and methylazoxymethanol actetate (MAM) in rats (5 dose levels each including vehicle control) to study existing and new neuropathology endpoints for potential use in regulatory Developmental Neurotoxicity Testing (American Chemistry Council RfP 01-01; Ref. no. 1847). MeHg caused significant maternal (body weight) and developmental toxicity (number of pups delivered, number of stillborn pups, pup weight and hydronephrosis at necropsy) in the 1 mg MeHg group. MAM caused significant and dose-related maternal toxicity (mainly body weight) in the 2.5, 5 and 1.5 mg MAM groups and developmental toxicity (pup weight and motor activity) in the 7.5 mg MAM group. Effects of MAM on time patterns of motor activity during development were observed, suggesting a developmental neurotoxic effect of MAM. Various macroscopical brain size measures indicate significant effects of MAM (5 end 7.5 mg) but not of MeHg. Linear measures of morphormetry showed a dose-related reduction in size of certain brain regions (hypoplasia), significant even in the 2.5 mg MAM dose group. Effects of MeHg were not observed. Estimation of neuron numbers in hippocampus (MAM) and cerebellum (MeHg) by stereological means is on-going to evaluate absolute neuron numbers as new neuropathology endpoint for potential use in regulatory Developmental Neurotoxicity Testing.
Neurotoxicology; Neurotoxic-effects; Laboratory-animals; Animal-studies; Animals; Dose-response; Dosimetry