Comparing old and new endpoints to assess developmental neurotoxicity: A model study in rats with methylmercury

Over the past years we performed several developmental neurotoxicity studies using a variety of modern technologies to evaluate both conventional and new endpoints for toxicity testing. These studies were an integrated part of Extended One Generation Toxicology Studies [OECD draft EOGRTS], which included also assessment of the developing immune system. Here, we present findings obtained for the developing nervous system in a model study with methylmercury (MeHg). MeHg (1.25, 0.25, 0.5, 1.0, 1.5, 2.0 mg/kg BW) was administered to female nulliparous rats by daily gavage from day 6 of pregnancy to day 10 of lactation. A delayed neural development was demonstrated with all innovative endpoints when studied in female offspring (0 and 1.5 mg groups) shortly after weaning (PN 22) and at young adult age (PN 70), i.e.: stereologic neuropathology (decreased neuron numbers), gene expression changes, in vivo microPET imaging ([18F] FDG uptake) and ex vivo-in vitro synaptic activity in brain slices. The effects all pointed at major impact of MeHg on neural structure shortly after weaning and (persistent) deficits in neural functioning at adulthood. Strikingly, no effects were found on conventional endpoints of neuropathology (microscopic slide reading) and behavior (physical, sensory and sexual landmarks; motor activity; Functional Operational Battery measures, auditory startle response or learning and memory tasks) unless advanced statistics were applied. Our findings indicate that the proposed innovations offer powerful means to warrant safe testing of developmental neurotoxicity saving animals, time and costs.