Abstract
Adverse outcome pathways (AOPs) are pragmatic tools in human health hazard characterization and risk assessment. As such, one of the main goals of AOP development is to provide a clear, progressive, and linear mechanistic representation of pertinent toxicological key events (KEs) occurring along the different levels of biological organization. Here, we present an AOP framework that depicts how exposure to organohalogens can lead to mitochondrial disease. Organohalogens are disinfectant by-products (DBPs) found in our drinking water. Chloroform, trichloroacetic acid, and trichlorophenol were selected to represent specific types of organohalogens for the development of this AOP. Although each of these compounds contains chlorine atoms, they differ in aromaticity and solubility, which have a significant impact on their potency. This AOP consists of two main pathways, both of which are triggered by the molecular initiating event (MIE) of excessive reactive oxygen species generation. Pathway 1 details the downstream consequences of oxidative stress, which include mitochondrial DNA damage, protein aggregation, and depolarization of the mitochondrial membrane. Pathway 2 shows the KEs that result from inadequate supply of glutathione, including calcium dysregulation and ATP depletion. Pathways 1 and 2 converge at a common KE: opening of the mitochondrial membrane transition pore (mPTP). This leads to the release of cytochrome c, caspase activation, apoptosis, and mitochondrial disease. This AOP was developed according to the Organisation for Economic Co-operation and Development guidance, including critical consideration of the Bradford Hill criteria for Weight of Evidence assessment and key questions for evaluating confidence. The presented AOP is expected to serve as the basis for designing new toxicological tests as well as the characterization of novel biomarkers for disinfectant by-product exposure and adverse health effects.
Highlights
In the early 1960s, researchers identified mitochondrial disease as a serious clinical condition and have since increased their efforts to identify its etiology [1]
Based on well-established knowledge of mitochondrial function, the biological plausibility between increased reactive oxygen species (ROS) production and mitochondrial disease is strong. This is often associated with mitochondrial electron transport chain disruption or complex I inhibition [60,61,62]
An Adverse outcome pathways (AOPs) was created to best characterize the pathway-based analysis of organohalogen exposure that results in dysfunction of the mitochondrial electron transport chain in humans (Figure 1)
Summary
In the early 1960s, researchers identified mitochondrial disease as a serious clinical condition and have since increased their efforts to identify its etiology [1]. Mitochondrial failure leads to cell injury, closely followed by cellular demise [2]. When multiple cells expire through this pathway, the most common adverse outcome (AO) is organ failure [3,4,5,6]. Mitochondrial dysfunction can occur in nearly any organ system of the human body and cause a variety of adverse health conditions, ranging from mild (i.e., nausea or mild cognitive impairment) to severe (heart failure or Parkinson’s Disease) [7,8,9]. The most common symptoms of mitochondrial dysfunction include loss of muscle coordination, muscle weakness, developmental delays, learning disabilities, heart disease, diabetes, gastrointestinal disorders, liver disease, kidney disease, and neurological problems [10,11,12,13,14]
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