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

Abstract

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 (Cu_xO_y) 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. Cu_xO_y 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.

Keywords: Air pollution; Copper; Dopamine; Metal dyshomeostasis; Neurodevelopmental disorders; Ultrafine particulate matter.