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Summary Human in vitro models of brain neurophysiology are needed to investigate molecular and cellular mechanisms associated with neurological disorders and neurotoxicity. We have developed a reproducible iPSC-derived human 3D brain microphysiological system (BMPS), comprised of differentiated mature neurons and glial cells (astrocytes and oligodendrocytes) that reproduce neuronal-glial interactions and connectivity. BMPS mature over eight weeks and show the critical elements of neuronal function: synaptogenesis and neuron-to-neuron (e.g., spontaneous electric field potentials) and neuronal-glial interactions (e.g., myelination), which mimic the microenvironment of the central nervous system, rarely seen in vitro before. The BMPS shows 40% overall myelination after 8 weeks of differentiation. Myelin was observed by immunohistochemistry and confirmed by confocal microscopy 3D reconstruction and electron microscopy. These findings are of particular relevance since myelin is crucial for proper neuronal function and development. The ability to assess oligodendroglial function and mechanisms associated with myelination in this BMPS model provide an excellent tool for future studies of neurological disorders such as multiple sclerosis and other demyelinating diseases. The BMPS provides a suitable and reliable model to investigate neuron-neuroglia function as well as pathogenic mechanisms in neurotoxicology.

The Baltimore Memory Study is a cohort study of the multilevel determinants of cognitive decline in 50-70-year-old randomly selected residents of specific city neighborhoods. Prior studies have demonstrated that cognitive function differs by race/ethnicity, with lower scores in minorities than in whites, but the underlying basis for these differences is not understood. Studies have differed in the rigor with which they evaluated and controlled for such important confounding variables as socioeconomic status (SES), health-related behaviors, comorbid illnesses, and factors in the physical environment. The goal of this study was to describe differences in neurobehavioral test scores by race/ethnicity, before and after control for a four-dimensional measure of SES and health-related behaviors and health conditions, in a cross-sectional analysis of first visit data. Random samples of households in the study area were selected until enrollment goals were reached. Among the 2,351 persons on whom eligibility was determined, 60.8% were scheduled for an enrollment visit; of these, 1,140 (81.3%) were enrolled and tested. These study participants were 34.3% male and 65.7% female and were from 65 Baltimore, Maryland, neighborhoods. After adjustment for age, sex, and testing technician, there were large and statistically significant differences in neurobehavioral test scores by race/ethnicity, with African-American scores lower than those for whites, for both men and women. After adjustment for individual SES (educational status, household income, household assets, and occupational status), the average difference declined by 25.8%. After additional adjustment for SES, health-related behaviors and health conditions, and blood lead, the average difference declined another 10%, but large differences persisted; African Americans had test scores that averaged 0.43 standard deviation lower than those for whites across all neurobehavioral tests. These differences were present in all cognitive domains, including tests that would not be characterized as susceptible to differential item functioning by race/ethnicity, suggesting that the results are not due to race/ethnicity-associated measurement error.

(divalent metal transporter 1) is a hydrogen-coupled divalent metal transporter with a substrate preference for iron, although the protein when expressed in frog oocytes transports a broad range of metals, including the toxic metals cadmium and lead. Wild-type Caco-2 cells displayed saturable transport of lead and iron that was stimulated by acid. Cadmium and manganese inhibited transport of iron, but zinc and lead did not. The involvement of DMT1 in the transport of toxic metals was examined by establishing clonal DMT1 knockdown and control Caco-2 cell lines. Knockdown cell lines displayed much lower levels of DMT1 mRNA and a smaller Vmax for iron uptake compared with control cell lines. One clone was further characterized and found to display an ϳ50% reduction in uptake of iron across a pH range from 5.5 to 7.4. Uptake for cadmium also decreased 50% across the same pH range, but uptake for lead did not. These results show that DMT1 is important in iron and cadmium transport in Caco-2 cells but that lead enters these cells through an independent hydrogen-driven mechanism.