Abstract
Neurodevelopment is uniquely sensitive to toxic insults and there are concerns that environmental chemicals are contributing to widespread subclinical developmental neurotoxicity (DNT). Increased DNT evaluation is needed due to the lack of such information for most chemicals in common use, but in vivo studies recommended in regulatory guidelines are not practical for the large-scale screening of potential DNT chemicals. It is widely acknowledged that developmental neurotoxicity is a consequence of disruptions to basic processes in neurodevelopment and that testing strategies using human cell-based in vitro systems that mimic these processes could aid in prioritizing chemicals with DNT potential. Myelination is a fundamental process in neurodevelopment that should be included in a DNT testing strategy, but there are very few in vitro models of myelination. Thus, there is a need to establish an in vitro myelination assay for DNT. Here, we summarize the routes of myelin toxicity and the known models to study this particular endpoint.
Highlights
Role of Environmental Factors in an Epidemic of Adverse Neurodevelopmental OutcomesOne in every six children in the United States, or about ten million children, were diagnosed with a developmental disorder from 2006 to 2008, according to the latest report by the Centers for Disease Control and Prevention (CDC) National Center on Birth Defects and Developmental Disabilities (NCBDDD) [1]
The CDC Autism and Developmental Disabilities Monitoring (ADDM) Network estimates that one in 54 children has been identified with autism spectrum disorder (ASD) [8], and the NCBDDD of the CDC reports that 9.4% (6.1 million) of children in the United States were diagnosed with attention deficit/hyperactivity disorder (ADHD) in 2016 [9]
The sheaths are formed by multiple alternating protein–lipid layers with a characteristic composition different from other cellular membranes [93]. It consists of 70–85% lipids and 20–30% proteins, such as myelin basic protein (MBP), proteolipid protein (PLP), 2 3 -cyclic-nucleotide 3 -phospodiesterase (CNP), myelin-associated glycoprotein (MAG), and myelin oligodendrocyte glycoprotein (MOG) [93,94,95,96]
Summary
Role of Environmental Factors in an Epidemic of Adverse Neurodevelopmental Outcomes. One in every six children in the United States, or about ten million children, were diagnosed with a developmental disorder from 2006 to 2008, according to the latest report by the Centers for Disease Control and Prevention (CDC) National Center on Birth Defects and Developmental Disabilities (NCBDDD) [1]. It has been estimated that about 3% of developmental defects are directly attributable to maternal exposure to chemical or physical agents in the environment, and approximately 25% are due to gene–environment interactions in genetically predisposed individuals (NRC 2000) These rough approximations are reported to likely underestimate the magnitude of the environmental influence on neurodevelopment [21]. There are concerns that environmental chemicals are contributing to a subclinical pandemic of neurodevelopmental toxicity, with reductions in cognitive function characterized by a slight decrease in intelligence quotient (IQ) These diseases might even be more prevalent than neurodevelopmental disorders with clinically observable behavioral phenotypes (such as ASD and ADHD) [11]. Given the potential societal implications of reduced cognitive function resulting from childhood exposures, the environmental influence on neurodevelopment is a major public health concern, because children are a uniquely susceptible population [11]
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