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Plasma apelin‐13, attention‐deficit hyperactivity disorder, and environmental exposure to nitrous oxide

B ILGIÇ ET AL. conducted an exploratory study to assess the role of apelin-13 in children with attention-deficit hyperactivity disorder (ADHD). The authors report that mean plasma apelin-13 levels were significantly higher in male ADHD children compared to control children; however, no differences were noted between the groups among the entire subject cohort or in females. The authors, therefore, concluded that there is a sex-specific association between plasma apelin-13 and ADHD. The author of this correspondence has been the first to suggest via novel empirical investigation that the principal etiologic factor in the development of human neurodevelopmental disorders may be chronic exposure to the environmental air pollutant and greenhouse gas, nitrous oxide (N2O). 2–5 N2O is an oxide of nitrogen that exists predominantly in the environment as an agricultural air pollutant derived from soil-management practices. The compound has been shown to affect many neural substrates, including its targeting of the kappa-opioid receptor (KOR) system, an opioid receptor subtype implicated in decision-making and impulsivity, and central release of its endogenous ligand, dynorphin. Li et al. have also shown for the first time that the apelin receptor (APJ) and KOR, two members of the family A of Gprotein-coupled receptors, form a heterodimer that increases PKC activity. Moreover, the pro-depressant characteristics of central administration of apelin-13 may be mediated at least in part by KOR in mice. Although these data are indicative of a close relation between APJ and KOR, the functional significance of this receptor heterodimerization (i.e., receptor expression, pattern of desensitization, signal transduction) is unclear and requires further investigation. Additionally, the sex differences noted by Bilgiç et al. in AP-13 levels may be related to the role of KOR in regulating vasopressin and oxytocin release and in the sex differences in the pro-depressant effects of KOR activation. The N2O-mediated ADHD impairment hypothesis is consistent with not only evidence indicating an adverse effect of air pollution in neuropsychological development but also the significantly higher plasma levels of AP-13. Further study is therefore warranted on the role of APJ and KOR in the pathogenesis of ADHD.