Elsevier

NeuroToxicology

Volume 28, Issue 5, September 2007, Pages 931-937
NeuroToxicology

Extrapolating brain development from experimental species to humans

https://doi.org/10.1016/j.neuro.2007.01.014Get rights and content

Abstract

To better understand the neurotoxic effects of diverse hazards on the developing human nervous system, researchers and clinicians rely on data collected from a number of model species that develop and mature at varying rates. We review the methods commonly used to extrapolate the timing of brain development from experimental mammalian species to humans, including morphological comparisons, “rules of thumb” and “event-based” analyses. Most are unavoidably limited in range or detail, many are necessarily restricted to rat/human comparisons, and few can identify brain regions that develop at different rates. We suggest this issue is best addressed using “neuroinformatics”, an analysis that combines neuroscience, evolutionary science, statistical modeling and computer science. A current use of this approach relates numeric values assigned to 10 mammalian species and hundreds of empirically derived developing neural events, including specific evolutionary advances in primates. The result is an accessible, online resource (http://www.translatingtime.net/) that can be used to equate dates in the neurodevelopmental literature across laboratory species to humans, predict neurodevelopmental events for which data are lacking in humans, and help to develop clinically relevant experimental models.

Introduction

Neurotoxicologists, developmental researchers, and pediatric clinicians use animal models to gather information about brain development and its disruptions, cellular or molecular mechanisms underlying neurotoxic effects, and potential interventions that cannot be studied directly in humans, but must be optimally timed for maximum safety and effectiveness. How best to relate data obtained from the nervous systems of diverse experimental species to humans is one of the most important challenges facing both basic and applied research (Fig. 1).

Not only must we be able to extrapolate from non-humans to humans for efficient biomedical research, we must also integrate data across experimental species. A specific animal model might be chosen for any conjunction of widely varying reasons. Accessibility of embryos, cost of acquiring or maintaining animals, availability of genomic analyses or probes, and/or close similarity to human physiology might factor in the design of a laboratory experiment. The result is a variety of data obtained in species born at a wide range of developmental stages and maturing at different rates, but with little explicit agreement or common understanding on how to relate them to humans. For example, how might we best study the effects of toxicants on the crucial first-generated cortical cells (subplate cells) when initial studies describing these cells were done in macaques (Kostovic and Rakic, 1980), later studies used cats (Chun and Shatz, 1989, Ghosh et al., 1990), rats (Bayer and Altman, 1990) and hamsters (Miller et al., 1993, Woo and Finlay, 1996), and future studies are likely to be accomplished in mice?

Section snippets

Model species

Although horses, elk and lions were at one time “model species” for medical research (Logan, 2002), modern science has settled on some standard species. The chart in Fig. 2 depicts a distribution used in neurodevelopmental research in articles published 2005–2006 in nine model mammals. The base of knowledge developed for each species itself quickly becomes a factor in the choice of which species to use, particularly if there is no convenient way to closely compare results between species.

Each

Morphology based comparisons

Morphological comparisons are accomplished through a painstakingly detailed linking of the appearance of gross anatomical features in the embryos of different species.

Rules of thumb

Researchers searching for uncomplicated conversions attempt to apply “rules of thumb” (concepts similar to dog years) to neural development. It is estimated that the rat brain at postnatal days (PN) 1-10 equates to the third trimester in humans, or that rat neurodevelopment at PN 7 is equivalent to that of the human brain at birth (Andrews and Fitzgerald, 1997, Dobbing and Sands, 1979). It is interesting to note that many of the studies upon which these approximations are based are decades old (

Evolutionary event-based comparisons

A recent review summarizes some major neural events that occur across development of the human central nervous system (de Graaf-Peters and Hadders-Algra, 2006). Included are general timing windows for onset and offset of cell proliferation, synapse formation, and development of neurotransmitter systems, beginning with the fifth week of gestation. Although the authors make no attempt to directly translate development across species, this study is an example of the manner with which the

Usefulness of the neuroinformatics approach

The web-based database is designed to easily produce comparisons of interest without the necessity of determining how values of interest fit into the multiple regression equation. For example, we can easily predict that in humans, the peak of neurogenesis of the first neurons destined for the cortex (subplate) occurs at approximately PC 54. The timing of this event can then be translated to hamsters (PC 10.6), mice (PC 10.9), rats (PC 12.2), cats (PC 23.9) and macaques (PC 43).

The model adjusts

Exceptions and limitations

Our neuroinformatics approach permits identification of developmental events that do not fit the model, including some that mathematical adjustments cannot correct. Two such events are birth and weaning (Clancy et al., 2000, Finlay and Darlington, 1995). Both occur at widely varying stages of brain development (Dobbing and Sands, 1979), further indicating that variability in cross-species studies based on either event might be expected. Another event that does not fit the model is a coordinated

Acknowledgements

Supported by NIH Grant # P20 RR-16460 from the IDeA Networks of Biomedical Research Excellence (INBRE) Program of the National Center for Research Resources and NIH Grant # U10 HD-500009 from the National Institute for Child Health and Human Development. The authors wish to thank James Hyde, James Fulmer and Brandon Kersh for photography expertise and figure production. Special thanks are extended to Jim, Elizabeth and Fiona Murray for the human infant photographs in Fig. 1.

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