Dear Editor:
Brown and Rais1 offer an interesting case report of the autistic son of a mother with a “multisystem litany of symptoms and diseases... typical for a patient with a mitochondrial disease,” including vasovagal syncope (a sudden, systemic hypotension), dysautonomia (dysfunction of the autonomic nervous system), adrenal insufficiency, central sleep apnea, paroxysmal atrial fibrillation, hypothyroidism, and early onset cataracts [see Innov Clin Neurosci. 2015;12(9-10):29-32]. The authors postured that the underpinning heritability of autism spectrum disorders (ASD) may be through undiagnosed maternal mitochondrial disease. Inasmuch as the aforementioned symptoms may be associated with mitochondrial dysfunction, it should also be recognized that many of these symptoms, including mitochondrial disease itself, can arise from maternal exposure to certain air pollutants previously implicated in the etiopathogenesis of ASD.
The author of this letter has previously been the first to suggest that gestational exposure to the increasing air pollutant (and mild medical anesthetic and analgesic) nitrous oxide (N2O) may be the dominating influence in the pathological development of an ASD phenotype, as well as other neurodevelopmental disorders.2 Nitric oxide (NO) is a gaseous biological messenger in vertebrates, perhaps most widely appreciated for its role as a potent systemic vasodilator. Elevated serum NO levels in ASD may arise from the compensatory formation of central oxidative stress markers attributable to N2O-mediated neuronal cholinergic inhibition.2 Nisoli and Carruba3 discuss the role that excess NO may have in mitochondrial dysfunction, including binding to cytochrome oxidase c (complex III) and inhibiting cell respiration. It is interesting that ASD has been associated with deficiencies in the mitochondrial respiratory chain, especially complexes III and IV.4 Moreover, NO has been implicated in cataract formation,5 adrenal insufficiency,6 parasympathetic dominance7 (with enhanced vagal tone thought to play a role in atrial fibrillation8). The author has also highlighted a potential role of N2O exposure and induction of hypothyroxinemia.9 Others have pointed to an increase in obstructive sleep events in man may be attributable to N2O inhalation.10
What these many studies suggest is that Brown and Rais1 may be well-served by reevaluating the singular importance placed upon mitochondrial disease in ASD. The aforementioned evidence avails a potential important confounder to this hypothesis and suggests that, in accord with the emerging literature on the link between ASD risk and air pollution, chronic exposure to increasing environmental N2O may elicit a litany of physiological effects in man, including mitochondrial dysfunction and attendant comorbidities, while simultaneously instituting a fetal neuro-reprogramming during gestation that is wholly consistent with ASD.
With regard,
Keith Fluegge
Institute of Health and Environmental Research, Cleveland, Ohio
Footnotes
Funding/financial disclosures.: The author has no conflicts of interest relevant to the content of this letter. Similar manuscripts related to this hypothesis may be under review, in press, or published elsewhere, although the specific content contained in this letter is original and not in review or previously published. This letter is intended for journal publication.
References.
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