
This AOP is licensed under a Creative Commons Attribution 4.0 International License.
Aop: 465
Title
AhR activation leads to increased diabetes risk
Short name
Graphical Representation
Point of Contact
Contributors
- Arthur Author
Status
Author status | OECD status | OECD project | SAAOP status |
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Under development: Not open for comment. Do not cite |
This AOP was last modified on August 18, 2022 18:01
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Activation, AhR | March 22, 2018 14:00 |
Up Regulation, CYP1A1 | August 18, 2022 11:18 |
Oxidative Stress | July 15, 2022 09:40 |
Increase, Mitochondrial Dysfunction | February 09, 2022 11:48 |
Pancreatic beta cell dysfunction | August 18, 2022 17:55 |
Increased diabetes risk | August 18, 2022 18:32 |
Activation, AhR leads to Up Regulation, CYP1A1 | December 03, 2016 16:37 |
Up Regulation, CYP1A1 leads to Increase, Mt Dysfunction | August 18, 2022 17:06 |
Up Regulation, CYP1A1 leads to Oxidative Stress | August 08, 2022 22:45 |
Up Regulation, CYP1A1 leads to Beta cell dysfunction | August 08, 2022 22:46 |
Oxidative Stress leads to Increase, Mt Dysfunction | August 08, 2022 22:45 |
Activation, AhR leads to Increased diabetes risk | August 08, 2022 22:47 |
Increase, Mt Dysfunction leads to Beta cell dysfunction | August 08, 2022 22:45 |
Oxidative Stress leads to Beta cell dysfunction | August 15, 2022 10:56 |
Beta cell dysfunction leads to Increased diabetes risk | August 08, 2022 22:45 |
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) | February 09, 2017 14:32 |
benzo[a]pyrene | October 30, 2019 16:47 |
Polycyclic aromatic hydrocarbons (PAHs) | February 09, 2017 15:43 |
Dioxin and dioxin-like compounds | November 29, 2016 21:19 |
Bioflavonoids | April 25, 2017 04:07 |
Tryptophan derivatives | August 08, 2022 22:56 |
Abstract
Diabetes is a chronic disease that affects nearly half a billion people globally (International Diabetes Association, 2021). Type 2 diabetes is the most common type of diabetes and accounts for 90-95% of all cases (American Diabetes Association, 2021; International Diabetes Association, 2021). The recent increase in T2D incidence and prevalence cannot be explained by genetic predisposition alone, and exposure to environmental pollutants have been shown to increase diabetes risk (Henriksen et al., 1997; Lee et al., 2006, 2010; Wolf et al., 2019).
The aryl hydrocarbon receptor (AhR) is a transcription factor known to respond to a broad range of environmental cues, including exposure to persistent organic pollutants (Stejskalova et al., 2011; Stockinger et al., 2014). Strong epidemiological evidence suggests environmental pollutant exposure is associated with type 2 diabetes (Airaksinen et al., 2011; Henriksen et al., 1997; Lee et al., 2006). Serum AhR ligand activity has also been shown to be higher in individuals with T2D and is associated with insulin resistance (Roh et al., 2015). In mice, knocking out AhR led to increased insulin sensitivity and glucose tolerance compared to wildtype mice (Wang et al., 2011).
One of the many target genes of the AhR is cytochrome P4501A1 (CYP1A1), which codes for a xenobiotic metabolism enzyme. CYP1A1 is inducible and functional in human and mouse islets after exposure to pollutants (Ibrahim et al., 2020). Although CYP1A1 is important in detoxification, it is known to produce reactive oxygen species (ROS) as a by-product of its activity (Shimada & Fujii-Kuriyama, 2004). Beta cells may be especially susceptible to ROS, because they produce relatively lower levels of antioxidants (Gurgul-Convey et al., 2016). In fact, excess production of ROS is associated with mitochondrial damage and beta cell dysfunction (Li et al., 2009). INS-1E cells (pancreatic beta cell line) and rat islets acutely exposed to an oxidative stress agent (200 µM H2O2 for 10 minutes) exhibited reduced glucose-induced insulin secretion and decreased oxygen consumption 3 days post-exposure. Treated INS-1E cells also had increased mitochondrial ROS compared to untreated cells (Li et al., 2009).
AOP Development Strategy
Context
This AOP was developed to show how environmental pollutant exposure can increase diabetes risk via the AhR pathway.
Strategy
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
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MIE | 18 | Activation, AhR | Activation, AhR |
KE | 80 | Up Regulation, CYP1A1 | Up Regulation, CYP1A1 |
KE | 1392 | Oxidative Stress | Oxidative Stress |
KE | 1968 | Increase, Mitochondrial Dysfunction | Increase, Mt Dysfunction |
KE | 2037 | Pancreatic beta cell dysfunction | Beta cell dysfunction |
AO | 2038 | Increased diabetes risk | Increased diabetes risk |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
Activation, AhR leads to Up Regulation, CYP1A1 | adjacent | Moderate | Moderate |
Up Regulation, CYP1A1 leads to Oxidative Stress | adjacent | Moderate | Low |
Oxidative Stress leads to Increase, Mt Dysfunction | adjacent | Moderate | Low |
Increase, Mt Dysfunction leads to Beta cell dysfunction | adjacent | Moderate | Low |
Beta cell dysfunction leads to Increased diabetes risk | adjacent | Moderate | Moderate |
Up Regulation, CYP1A1 leads to Increase, Mt Dysfunction | non-adjacent | Moderate | Low |
Up Regulation, CYP1A1 leads to Beta cell dysfunction | non-adjacent | Low | Low |
Activation, AhR leads to Increased diabetes risk | non-adjacent | Moderate | Low |
Oxidative Stress leads to Beta cell dysfunction | non-adjacent | Moderate | Low |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
All life stages | Low |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Mixed | High |
Overall Assessment of the AOP
The empirical evidence for the overall AOP is low, but biological plausibility is moderate.
Domain of Applicability
This AOP is applicable to all animals susceptible to diabetes, including humans and non-human primates, rodents, and some birds (Niaz et al., 2018; Walker et al., 2021). Diabetes onset can occur across all life stages (International Diabetes Association, 2021).
Essentiality of the Key Events
Cyp1 knockout studies in mice suggest Cyp1a1 is essential to mitochondrial injury caused by AhR pathway activation. Wildtype mice exposed to β-Naphthoflavone, an AhR agonist, had reduced hepatic mitochondrial oxygen consumption rate (OCR) compared to Cyp1a1/1a2 double knockout (DKO) mice and Cyp1a1/1a2/1b1 triple knockout (TKO) mice (Anandasadagopan et al., 2017). Another group of researchers looked at the effects of benzo[a]pyrene (BaP) and TCDD on pancreatic mitochondrial function and found similar results (Ghosh et al., 2018). Compared to wildtype mice, DKO and TKO mice were protected from BaP-induced mitochondrial dysfunction (Ghosh et al., 2018). Interestingly, mice with only Cyp1b1 knocked out were not protected against BaP-induced mitochondrial dysfunction, but DKO and TKO mice had similar protection (Ghosh et al., 2018). They also showed that in mouse pancreatic tissue, BaP induced Cyp1a1 and Cyp1b1, but not Cyp1a2 (Ghosh et al., 2018). This suggests that the observed phenotype is mainly driven by Cyp1a1.
Evidence Assessment
Evidence for each KER is low to moderate (Table 1). Overall, the biological plausibility of the AOP is moderate, but the empirical evidence is low.
Known Modulating Factors
Quantitative Understanding
The quantitative understanding for the overall AOP is low.
Considerations for Potential Applications of the AOP (optional)
References
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Anandasadagopan, S. K., Singh, N. M., Raza, H., Bansal, S., Selvaraj, V., Singh, S., Chowdhury, A. R., Leu, N. A., & Avadhani, N. G. (2017). β-naphthoflavone-induced mitochondrial respiratory damage in Cyp1 knockout mouse and in cell culture systems: Attenuation by resveratrol treatment. Oxidative Medicine and Cellular Longevity, 2017. https://doi.org/10.1155/2017/5213186
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