Carbon monoxide pollution and neurodevelopment: A public health concern

Abstract

Although an association between air pollution and adverse systemic health effects has been known for years, the effect of pollutants on neurodevelopment has been underappreciated. Recent evidence suggests a possible link between air pollution and neurocognitive impairment and behavioral disorders in children, however, the exact nature of this relationship remains poorly understood. Infants and children are uniquely vulnerable due to the potential for exposure in both the fetal and postnatal environments during critical periods in development. Carbon monoxide (CO), a common component of indoor and outdoor air pollution, can cross the placenta to gain access to the fetal circulation and the developing brain. Thus, CO is of particular interest as a known neurotoxin and a potential public health threat. Here we review overt CO toxicity and the policies regulating CO exposure, detail the evidence suggesting a potential link between CO-associated ambient air pollution, tobacco smoke, and learning and behavioral abnormalities in children, describe the effects of subclinical CO exposure on the brain during development, and provide mechanistic insight into a potential connection between CO exposure and neurodevelopmental outcome. CO can disrupt a number of critical processes in the developing brain, providing a better understanding of how this specific neurotoxin may impair neurodevelopment. However, further investigation is needed to better define the effects of perinatal CO exposure on the immature brain. Current policies regarding CO standards were established based on evidence of cardiovascular risk in adults with pre-existing comorbidities. Thus, recent and emerging data highlighted in this review regarding CO exposure in the fetus and developing child may be important to consider when the standards and guidelines are evaluated and revised in the future.

Keywords: Air pollution; Autism; Brain; Carbon monoxide; Development; Toxicity.

Figure 1. Diffusion of carbon monoxide (CO) into tissue is dictated by the Haldane equation (Bissonnette, 1977a; Jain, 2009)

Following formation of carboxyhemoglobin (COHb), CO diffuses from the capillaries into the tissue compartments. Tissue tension of CO (pCO) is determined by COHb concentration, partial pressure of oxygen (pO₂), the affinity of hemoglobin for CO (M), and the concentration of oxyhemoglobin (O₂Hb). The Haldane equation also dictates transplacental CO diffusion.

Figure 2. Developmental processes in the brain impaired by carbon monoxide (CO)

Animal models have demonstrated that perinatal subclinical CO exposure interrupts many of the processes that are critical for normal brain development. Inhibition due to prenatal or postnatal CO exposure is indicated. Specific mechanisms remain largely unknown and are likely not due to tissue hypoxia.

Figure 3. Mechanism of carbon monoxide (CO)-mediated inhibition of developmental apoptosis

The mitochondrial pathway of apoptosis is depicted. Cytochrome c (cyt c), can bind to cardiolipin (CL) on the inner mitochondrial membrane via hydrophobic and electrostatic interactions. Cyt c has peroxidase activity and, in the presence of hydrogen peroxide (H₂O₂), peroxidizes CL to hydroperoxycardiolipin (CL-OOH). This mobilizes cyt c from the inner mitochondrial membrane and allows cyt c to be released following permeabilization of the outer mitochondrial membrane by Bax. Subsequently, cyt c forms the apoptosome along with procaspase-9 and APAF-1. Caspase-9 then becomes activated and, in turn, activates caspase-3, resulting in apoptosis. CO readily diffuses across the outer mitochondrial membrane and binds to the cyt c-CL complex. CO inhibits the peroxidase activity of cyt c, preventing CL peroxidation, cyt c mobilization, cyt c release, and subsequent caspase activation.