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Toxicological mechanisms of hepatocyte apoptosis through the PARP1 dependent cell death pathway
Point of Contact
- Fei Li
- Brendan Ferreri-Hanberry
|Handbook Version||OECD status||OECD project|
This AOP was last modified on April 29, 2023 13:02
|Activation, PARP1||July 18, 2022 05:23|
|Releasing, Apoptosis-Inducing Factor (AIF)||July 18, 2022 05:25|
|N/A, Mitochondrial dysfunction 1||March 07, 2022 07:12|
|Increase, DNA damage||May 08, 2019 12:28|
|Apoptotic cell death||November 02, 2020 07:11|
|ROS formation||September 16, 2017 10:17|
|PARP1 leads to N/A, Mitochondrial dysfunction 1||July 28, 2022 03:36|
The changes of PARP1 activity were considered as the molecular initial event. The activated PARP1 affected the downstream key events, such as the damage of mitochondrial structure and function, apoptotic factors AIF release and ROS production and DNA damage. These key events finally induced cell death through PARP1 dependent pathway. Mitochondrial PARP1 was a vital target to illuminate the early mechanism of apoptosis induced by typical organophosphate ester.
AOP Development Strategy
Triphenyl phosphate (TPP), as a typical aryl organophosphate ester, has drew much attention to its adverse effects (Du et al., 2016; Mendelsohn et al., 2016; Su et al., 2014; Zhang et al., 2016). It was also considered as a mitochondrial toxicant that could alter mitochondrial function and disorder mitochondria metabolism to exert severe cytotoxicity (Bowen et al., 2020). Further research is necessary to explore how TPP affects mitochondrial PARP1 activation in the early stage to cause cell death pathway.
In this study, the cell viability assay aimed to determine the effective dose of TPP on L02 cells. Docking analysis was performed to explore the structural characteristics and interaction between TPP and PARP1. The activity of PARP1 enzyme in mitochondria was determined to confirm the effects of TPP on PARP1. In addition, mitochondrial membrane potential (MMP), apoptotic induction factor (AIF) and reactive oxygen species (ROS) production, DNA damage, cell apoptosis, and PJ34 hydrochloride (PARP1 inhibitor) assay were conducted to further reveal the underlying toxicological effect.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|KE||2031||Releasing, Apoptosis-Inducing Factor (AIF)||AIF release|
|KE||177||N/A, Mitochondrial dysfunction 1||N/A, Mitochondrial dysfunction 1|
|KE||1194||Increase, DNA damage||Increase, DNA Damage|
|AO||1817||Apoptotic cell death||Apoptotic cell death|
Relationships Between Two Key Events (Including MIEs and AOs)
|PARP1 leads to N/A, Mitochondrial dysfunction 1||adjacent||Moderate||Moderate|