S06: Basics in developmental neuropathology

Abstract

Introduction “Developmental neuropathology” includes the morphological diagnostics of specific tissue lesions that occur during the process of nervous system development and maturation. Some malformations may be easily detected by macroscopic inspection of the brain others may be more discrete and need a more sophisticated approach including histopathological examinations by light microscopy and a quantitative analysis of the size of specific brain areas or numbers of neurons. The public concern In the last two decades, the public and scientific community has become increasingly alarmed about the rise of unexplained mental disorders in human infants. Research has suggested that some of the disorders with no genetic background can be attributed to exposure of xenobiotics during the early development of the nervous system. In utero and postnatal exposure to toxic agents, such as ethanol, lead or methylmercury, is known to be responsible for brain-related disorders in children. Parkinson disease, schizophrenia and autism as significant neurological disorders are catch items linked to environmental impacts on the brain development, and there have been controversial discussions on whether some pesticides may be a risk factor in this respect. As a distinct morphological correlate is present in most cases of a true impact on neurodevelopment, aberration can be detected by developmental neuropathology structure analysis that may be therefore the crucial tool for developmental neurotoxicity hazard identification also in experimental models. The experimental model The Developmental Neurotoxicity (DNT) Study was introduced by the US EPA as Health Effect Test guideline OPPTS 870.6300 1 in 1991 but studies were increasingly required from 1998 on for teratogens, psychoactive drugs, hormonally active compounds, peptides and amino acids, organophosphates and carbamates. Beside the US EPA, also the OECD has published a final draft Guideline 426: Developmental Neurotoxicity Study. 2 The DNT study is designed to address the developing nervous system specifically. Dams are treated from gestational day (GD) 6 on up to postnatal day (PD) 21. Developmental neuropathology (qualitative and quantitative analysis) is a central part of the study design and performed in pups and young adults at least after two time-points, one latest at PD 21 directly after end of exposure and on PD 62. PD 21 will already give information about impacts on the process of neuro- and gliogenesis, impacts on neuronal migration, and the postnatal period of the “brain growth spurt” and myelination gliosis. Examination at PD 62 will further characterize lesions as permanent or transient and may give hints for impacts on the neuronal network maturation (synaptogensis). The presentation will give examples for specific developmental neuropathology lesions and a rationale for including and interpretation of the quantitative analysis of major brain areas.