Developmental neurotoxicity: evaluation of testing procedures with methylazoxymethanol and methylmercury.
Testing procedures for identification of potential developmental neurotoxicants were evaluated using two prototypical developmental neurotoxicants, methylazoxymethanol (MAM) and methylmercury (MeHg). Evaluation of offspring of Long-Evans rats incorporated assessments of developmental toxicity, neurochemistry, histology, and behavior, with most testing being completed near weaning. A number of endpoints in the testing strategy were sensitive to the effects of prenatal exposure to MAM [30 mg/kg on Gestation Day (GD) 15]: (1) MAM caused reduced neonatal body weights but did not effect viability or postnatal survivorship; (2) measurement of total and regional brain weight and histological analysis showed that a number of regions, the cortex and hippocampus in particular, were affected by MAM exposure; (3) an assay for glial fibrillary acidic protein (GFAP) showed that the concentration of this protein was significantly increased in the cortex and hippocampus of treated offspring; (4) a T-maze delayed-alternation procedure indicated that MAM-treated pups were slower in the acquisition phase of the task relative to control pups; (5) motor activity testing revealed hyperactivity in treated offspring that persisted into adulthood; and (6) acoustic startle procedures revealed reduced startle amplitudes in preweanlings. Few endpoints were significantly affected by prenatal MeHg exposure (1, 2, or 4 mg/kg on GD 6-15). High fetal and neonatal mortality and lower neonatal body weights were detected at the highest dose of MeHg. Although minimal effects of MeHg may reflect a relative insensitivity of the test species and/or the test methods, the combined results from both chemicals suggest that some procedures not currently required in the developmental neurotoxicity guideline may be useful in hazard identification, and further evaluation with other chemicals, species, strains, and/or exposure paradigms may be warranted.
Neurotoxicology Division, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
E S
ES
Goldey
J P
JP
O'Callaghan
M E
ME
Stanton
S
S
Barone
K M
KM
Crofton
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006309:Hearing / Q000187:drug effects; D008297:Male; D008746:Methylazoxymethanol Acetate / Q000031:analogs & derivatives* / Q000633:toxicity; D008767:Methylmercury Compounds / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D013216:Reflex, Startle / Q000187:drug effects
D000477:Alkylating Agents; D005904:Glial Fibrillary Acidic Protein; D008767:Methylmercury Compounds; D008746:Methylazoxymethanol Acetate; C030667:methylazoxymethanol