Acetaminophen's Role in Autism and ADHD: A Mitochondrial Perspective

Abstract

One in 36 children were identified with autism in 2020, a 22% increase from 2018 and a 98% increase from 2010. Simultaneously, attention-deficit/hyperactivity disorder (ADHD) diagnoses increased 36% from 2003 to 2016-2019. Despite this surge, their etiologies remain largely unknown. However, numerous studies document higher incidences of mitochondrial abnormalities in affected individuals. Additionally, acetaminophen has been implicated in these disorders in longitudinal studies and murine models. This paper is a compilation of literature aiming to explore a theoretical framework for acetaminophen-induced mitochondrial damage in utero. It focuses on a toxic metabolite of acetaminophen, N-acetyl-p-benzoquinone imine (NAPQ1), and its role in neuroinflammation. Based on our findings, we recommend further research studying fetal mitochondria after maternal acetaminophen usage.

Keywords: N-acetyl-p-benzoquinone imine (NAPQI); acetaminophen; attention-deficit/hyperactivity disorder (ADHD); autism spectrum disorder (ASD); mitochondrial dysfunction; neuroinflammation; oxidative stress; prenatal exposure.

Figure 1

Acetaminophen metabolism and NAPQI-mediated mitochondrial effects leading to neurodevelopmental outcomes. Most acetaminophen is detoxified via sulfation and glucuronidation to form non-toxic metabolites (black arrows). A smaller fraction (5–10%) is metabolized by cytochrome P450 to NAPQI, which is normally neutralized by glutathione and converted to non-toxic conjugates (green arrows). During pregnancy, however, reduced glutathione levels increase vulnerability to NAPQI, which can result in mitochondrial oxidative stress, elevated ROS production, disruption of electron transport chain complexes I, III, and IV, and mitochondrial DNA damage (red arrow ending in red box). These effects on mitochondria contribute to neuroinflammation, epigenetic priming of microglia, impaired astrocyte-neuron lactate shuttling (relevant to ADHD), and neurodevelopmental disruptions that may manifest as ASD and ADHD symptoms (red arrow ending in a purple box). The image was generated by using BioRender.com.