The contributions of neonatal inhalation of copper to air pollution-induced neurodevelopmental outcomes in mice.

Exposures to ambient ultrafine particle (UFP) air pollution (AP) during the early postnatal period in mice (equivalent to human third trimester brain development) produce male-biased changes in brain structure, including ventriculomegaly, reduced brain myelination, alterations in neurotransmitters and glial activation, as well as impulsive-like behavioral characteristics, all of which are also features characteristic of male-biased neurodevelopmental disorders (NDDs). The purpose of this study was to ascertain the extent to which inhaled Cu, a common contaminant of AP that is also dysregulated across multiple NDDs, might contribute to these phenotypes. For this purpose, C57BL/6J mice were exposed from postnatal days 4-7 and 10-13 for 4 hr/day to inhaled copper oxide (CuxOy) nanoparticles at an environmentally relevant concentration averaging 171.9 ng/m3. Changes in brain metal homeostasis and neurotransmitter levels were determined following termination of exposure (postnatal day 14), while behavioral changes were assessed in adulthood. CuxOy inhalation modified cortical metal homeostasis and produced male-biased disruption of striatal neurotransmitters, with marked increases in dopaminergic function, as well as excitatory/inhibitory imbalance and reductions in serotonergic function. Impulsive-like behaviors in a fixed ratio (FR) waiting-for-reward schedule and a fixed interval (FI) schedule of food reward occurred in both sexes, but more prominently in males, effects which could not be attributed to altered locomotor activity or short-term memory. Inhaled Cu as from AP exposures, at environmentally relevant levels experienced during development, may contribute to impaired brain function, as shown by its ability to disrupt brain metal homeostasis and striatal neurotransmission. In addition, its ability to evoke impulsive-like behavior, particularly in male offspring, may be related to striatal dopaminergic dysfunction that is known to mediate such behaviors. As such, regulation of air Cu levels may be protective of public health.

Maternal Iron Deficiency and Environmental Lead (Pb) Exposure Alter the Predictive Value of Blood Pb Levels on Brain Pb Burden in the Offspring in a Dietary Mouse Model: An Important Consideration for Cumulative Risk in Development.

Maternal iron deficiency (ID) and environmental lead (Pb) exposure are co-occurring insults that both affect the neurodevelopment of offspring. Few studies have investigated how ID affects brain-region-specific Pb accumulations using human-relevant Pb concentrations. Furthermore, how these Pb exposures impact blood and brain Fe levels remains unclear. Importantly, we also wanted to determine whether the use of blood Pb levels as a surrogate for the brain Pb burden is affected by underlying iron status. We exposed virgin Swiss Webster female mice to one of six conditions differing by iron diet and Pb water concentration (0 ppm, 19 ppm, or 50 ppm lead acetate) and used Inductively Coupled Plasma Mass Spectrometry to measure the maternal and offspring circulating, stored, and brain Pb levels. We found that maternal ID rendered the offspring iron-deficient anemic and led to a region-specific depletion of brain Fe that was exacerbated by Pb in a dose-specific manner. The postnatal iron deficiency anemia also exacerbated cortical and hippocampal Pb accumulation. Interestingly, BPb levels only correlated with the brain Pb burden in ID pups but not in IN offspring. We conclude that ID significantly increases the brain Pb burden and that BPb levels alone are insufficient as a clinical surrogate to make extrapolations on the brain Pb burden.

Gestational iron deficiency affects the ratio between interneuron subtypes in the postnatal cerebral cortex in mice.

Gestational iron deficiency (gID) is highly prevalent and associated with an increased risk of intellectual and developmental disabilities in affected individuals that are often defined by a disrupted balance of excitation and inhibition (E/I) in the brain. Using a nutritional mouse model of gID, we previously demonstrated a shift in the E/I balance towards increased inhibition in the brains of gID offspring that was refractory to postnatal iron supplementation. We thus tested whether gID affects embryonic progenitor cells that are fated towards inhibitory interneurons. We quantified relevant cell populations during embryonic inhibitory neuron specification and found an increase in the proliferation of Nkx2.1+ interneuron progenitors in the embryonic medial ganglionic eminence at E14 that was associated with increased Shh signaling in gID animals at E12. When we quantified the number of mature inhibitory interneurons that are known to originate from the MGE, we found a persistent disruption of differentiated interneuron subtypes in early adulthood. Our data identify a cellular target that links gID with a disruption of cortical interneurons which play a major role in the establishment of the E/I balance.