Developmental Neurotoxicity: Evaluation of Testing Procedures with Methylazoxymethanol and Methylmercury

Testing procedures for identification of potential developmentalneurotoxicants were evaluated using two prototypical developmentalneurotoxicants, methylazoxymethanol (MAM) and methylmercury(MeHg). Evaluation of offspring of LongEvans rats incorporatedassessments of developmental toxicity, neurochemistry, histology,and behavior, with most testing being completed near weaning.A number of endpoints in the testing strategy were sensitiveto the effects of prenatal exposure to MAM [30 mg/kg on GestationDay (GD) 15]: (1) MAM caused reduced neonatal body weights butdid not effect viability or postnatal survivorship; (2) measurementof total and regional brain weight and histological analysisshowed that a number of regions, the cortex and hippocampusin particular, were affected by MAM exposure; (3) an assay forglial fibrillary acidic protein (GFAP) showed that the concentrationof this protein was significantly increased in the cortex andhippocampus of treated offspring; (4) a T-maze delayed-alternationprocedure indicated that MAM-treated pups were slower in theacquisition phase of the task relative to control pups; (5)motor activity testing revealed hyperactivity in treated offspringthat persisted into adulthood; and (6) acoustic startle proceduresrevealed reduced startle amplitudes in preweanlings. Few endpointswere significantly affected by prenatal MeHg exposure (1, 2,or 4 mg/kg on GD 6–15). High fetal and neonatal mortalityand lower neonatal body weights were detected at the highestdose of MeHg. Although minimal effects of MeHg may reflect arelative insensitivity of the test species and/or the test methods,the combined results from both chemicals suggest that some proceduresnot currently required in the developmental neurotoxicity guidelinemay be useful in hazard identification, and further evaluationwith other chemicals, species, strains, and/or exposure paradigmsmay be warranted.     

Developmental Exposure to Aroclor 1254 Produces Low-Frequency Alterations in Adult Rat Brainstem Auditory Evoked Responses

Developmental exposure of Long—Evans rats to 0, 1, 4,or 8 mg/kg/day Aroclor 1254 (A1254) from Gestational Day 6 throughPostnatal Day 21 produces an elevated behavioral threshold fora 1-kHz tone. Brahistem auditory evoked responses (BAERs) wereassessed in a subset of these animals (about 1 year old) usingfiltered clicks at 1 (65 and 80 dB SPL), 4 (60 and 80 dB SPL),16 (40 and 80 dB SPL), and 32 (40 and 80 dB SPL) kHz. Aroclor1254 decreased BAER amplitudes at 1 and 4 kHz, but not at 16or 32 kHz. A dose-related decrease in the baseline-to-peak P_1Aamplitude was observed for the 1-kHz (80-dB) stimulus. Dosesof 1, 4, or 8 mg/kg/day A1254 decreased the peak-to-peak amplitudeof both P_1AN₁ and P_1BN₁ for a 1-kHz (80-dB) stimulus. Dosesof 4 and 8 mg/kg/day A1254 decreased the peak-to-peak amplitudeof N₁P₂ and P₂N₂ for a 4-kHz (60-dB) or 1-kHz (80-dB) stimulus.At 8 mg/kg/day, A1254 also increased the latency of peak P₄at 1 kHz (65 dB). The decreases in peak P_1A amplitudes are consistentwith a dysfunction of the cochlea and/or auditory nerve. Together,the data confirm that developmental exposure of rats to A1254produces a permanent low- to mid-frequency auditory dysfunctionand suggest a cochlear and/or auditory nerve site of action.