The cell–cell and cell–matrix interactions mediated by the adhesion molecules on the cell surface are vital to neural development and plasticity. The neural cell adhesion molecule (NCAM), a member of the immunoglobulin superfamily, promotes cell-to-cell adhesion in the nervous system through a homophilic, Ca2+-independent binding mechanism. NCAM-mediated cell adhesion is involved in the regulation of neural cell migration, neurite outgrowth and fasciculation, and synaptic formation. Polysialic acid (PSA), found as a component of neural tissue, is a linear homopolymer containing sialic acid residues in -2,8-linkage. Polysialylation of the NCAM decreases the homophilic binding of NCAM thereby attenuating cell adhesion. The attachment of PSA to NCAM gives rise to additional mechanisms in modulating cell adhesion. The polysialylation of NCAM is modulated in the developmental stage and is site-specific during the development. Endoneuraminidase N, which specifically cleaves PSA without compromising the cell viability, has been utilized to explore the modulatory effects of PSA upon cell migration. PAS on the NCAM contributes to the motility of migratory cells. The expression levels of NCAM and polysialylated NCAM are critical for neural plasticity, which is dependent on either cell migration and sprouting or the synaptic activity.

Neuropsychological functioning has frequently been found to be the most sensitive endpoint in studies of the developmental neurotoxicity of chemicals, such as lead and methylmercury. This chapter discusses considerations in incorporating neuropsychological assessments into such studies. These include factors that bear on the decision about the age(s) at which children should be assessed and the tests to include in the assessment battery. In general, these decisions depend on the primary purpose in conducting the study, the state of knowledge about the neurotoxicity of the chemical of interest, the training of the neuropsychological assessors, the cultural setting, and the time available for assessment. It is critical that the quality control information for the neuropsychological assessments be utilized in a study as detailed as that presented for the analytical measurements of relevant biomarkers. As no neuropsychological test assesses the integrity of a single brain region, caution is warranted in drawing inferences about the underlying brain–behavior relationships.

Since the first description of myelin by Virchow as neuroglia or nerve glue, many breakthroughs have been made that have changed the perception of myelin from a static insulating structure to a dynamic multilamellar structure serving several functions in the nervous system. Myelination in the central nervous system and peripheral nervous system is accomplished by oligodendrocytes and Schwann cells, respectively, involving complex interaction between axon and glia through a network of transcription and neurotrophic factors. Transgenic mouse models have revealed the role of these specialized cells in not only initiating and maintaining the functional integrity of the myelin sheath but also in the function and survival of underlying axons. This information reveals new possibilities for treatment of neuropsychiatric diseases with myelin abnormalities. This chapter presents an overview of myelin structure and function and its communication with axons it ensheaths. The chapter also describes the current understanding of axoglial communications and the role of glial cells in myelin disorders.

The developing brain is a self-organizing system that incorporates environmental influences into its structure and function. Morphologic features of the developing brain are emergent properties of dynamic interactions, and the differentiation of particular brain regions depends on the whole. System biology holds promise for revealing the dynamics of brain morphogenesis and its vulnerability and resilience to toxic insult. With an increased emphasis on systems, the focus of developmental neurotoxicology shifts from reductionist to holistic approaches. The dynamics of morphogenesis provides a structural context for linkages across biological levels, linkages that are critical to a holistic approach. We briefly explore three examples of emergent properties of brain morphogenesis: sensory pathways, neurovascular coupling, and engrams. We then present preliminary observations from our assessments of the zebrafish brain. Finally, we speculate on how morphology may help inform holistic models of the developing brain that have the potential to simulate developmental neurotoxicity.

Cadmium (Cd2+) is a heavy metal that occurs naturally in the earth’s crust and artificially through industrial processes. It has been widely established that Cd2+ adversely affects various bodily systems and organs, in particular, the kidneys; however, the harmful effects of Cd2+ on the developing nervous system have garnered substantial attention more recently. Numerous animal studies have demonstrated that Cd2+ accumulates in the developing brain, induces oxidative stress, and alters neurotransmitter and electrophysiological activity. They have also shown that Cd2+ impairs the activity of enzymes responsible for healthy cellular functioning in various brain regions. These neurochemical changes are often accompanied by unfavorable neurobehavioral outcomes. In recent human studies, prenatal and postnatal Cd2+ exposure has been found to predict poorer outcomes on measures of behavior, cognition, and development during childhood and adolescence. Overall, Cd2+ appears to pose a significant risk to the developing nervous system and measures should be taken to limit exposures to it, particularly early in life.

Vulnerability to, and mechanisms of, neurotoxic exposures vary throughout the lifespan. Accordingly, to evaluate the risks posed by various neurotoxicants to humans, it is critical to model the effects of exposure at various stages of development. During the last 20 years, great utility has been made of nonhuman primates (NHPs) in the evaluation of the effects of in utero, perinatal, juvenile, and adolescent exposures to toxic substances. The relevance of this work has been demonstrated through the use of translational cognitive test batteries that can be used in humans and nonhumans alike. These instruments facilitate the transfer of preclinical findings to the clinical environment, and allow for the changes observed in the preclinical setting to be correlated with more traditional clinical metrics such as IQ. Here we review recent NHP work that has focused on the assessment of cognition throughout development, and its use as an endpoint in the evaluation of developmental neurotoxic effects.

The behavioral repertoire of nonhuman primates is highly evolved and includes advanced problem-solving capabilities, complex social relationships, and sensory acuity equal or superior to humans. For some potential neurotoxicants, nonhuman primate models have provided valuable data that are helpful in identifying the likely effects of developmental exposures on human infants and children. The ability to identify subtle effects of neurotoxicant exposure is highly dependent on the selection of measurement tools that can identify meaningful individual differences in performance. This chapter provides brief descriptions of assessment measures that have been developed for young monkeys, both infants and adolescents, to investigate emerging cognitive skills, sensory functioning, and social behaviors. Examples of how these tests have been used in previous research investigating the developmental effects of neurotoxicants are provided to illustrate the contribution of this research to our knowledge regarding important environmental determinants of behavior.

Health risk assessment for developmental neurotoxicants often requires the analysis and use of data collected in nonhuman mammalian species exposed to high doses, at different developmental stages, via exposure routes and scenarios different from anticipated human exposures. In such cases, the challenge of extrapolating from one test or exposure condition and dose level to another can be resolved on the basis of target tissue dose (e.g., area under the brain concentration vs. time curve and maximal brain concentration). Physiologically based pharmacokinetic (PBPK) models are scientifically sound tools that facilitate the simulation of target tissue dose for a number of developmental neurotoxicants (e.g., dioxins, polychlorinated biphenyls, organochlorine pesticides, metals, and organometallics). The construction and evaluation of PBPK models to account for prenatal and postnatal exposures is described in this chapter along with examples of their application in the risk assessment of methylmercury, atrazine, chlorpyriphos, and ethanol. The use of PBPK models in the risk assessment for developmental neurotoxicants will not only enhance the credibility of the process, but also provide a dynamic way of integrating new observations on the mode of action, biomonitoring, and high throughput screening assays as they emerge for diverse sets of developmental neurotoxicants.

Many studies using laboratory animals have demonstrated that exposure to general anesthesia during critical periods of development can be harmful to the immature brain. In particular, preclinical studies have shown that developmental exposure to general anesthetics results in widespread neuronal cell death, as well as long-term deficits in cognitive function. Nevertheless, the ability of general anesthetics to produce similar effects in humans has not been proven. Although many retrospective observational studies in humans have shown an association between developmental exposure to anesthesia and adverse neurobehavioral outcomes, other studies have not. To clarify this relationship, continuing clinical investigations are underway. Likewise, preclinical studies are continuing to explore the potential mechanisms of action responsible for anesthetic-induced neurotoxicity, as well as to identify effective prevention and treatment strategies. This research aims to shed further light upon the phenomenon, allowing for the development of ameliorative or preventative strategies leading to best practice guidance for the protection of public health.

Developmental neurotoxicity (DNT) testing of industrial chemicals is an increasingly perceived societal need in light of strong increases in neurodevelopmental disorders including autism. The current testing approach for DNT in vivo does not satisfy these needs because despite enormous costs and animal use, there appears to be limited predictivity for its health effects in humans. The Center for Alternatives to Animal Testing (CAAT) in the United States and Europe along with its partners has steered a process of developing in vitro strategies for DNT, which is summarized here. This process has prioritized models, cellular key events, reference compounds, and others. This shaped a 3DNT approach, which aims to employ three-dimensional (3D) microphysiological models such as an induced pluripotent stem cells–derived mini-brain model from our laboratory. These complex models have to be complemented with, favorably 3D, models of homogenous cell models for pathway identification; an example of a 3D dopaminergic neurons (LUHMES) model is given. The human mini-brain model offers opportunities beyond studying developmental effects. It is also undergoing further amendments such as the addition of microglia and a blood–brain barrier. A major recent breakthrough showed that the model could be frozen for stockpiling and transport. This enables us to make the model readily available via commercial vendors. For this purpose, a Johns Hopkins spin-off biotech company, Organome LLC, was formed.