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AOP: 591

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

DBDPE-induced DNA damage increase in liver leading to Non-alcoholic fatty liver disease via liver steatosis and inhibition of regeneration

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

DBDPE-induced DNA damage leading to NAFLD

The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help

Handbook Version v2.7

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

lihua Yang (email point of contact)

Contributors

Users with write access to the AOP page. Entries in this field are controlled by the Point of Contact. More help

lihua Yang

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication. More help

OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on October 23, 2025 04:44

Revision dates for related pages

Page	Revision Date/Time
Increase, DNA damage	May 08, 2019 12:28
Upregulation, growth arrest and DNA-damage-inducible beta a	August 16, 2025 00:14
Activation, MAPK	August 16, 2025 00:15
Activation, FOXO	September 16, 2017 10:17
Decrease, Proliferating Cell Nuclear Antigen	August 16, 2025 00:16
Cell cycle, disrupted	June 30, 2021 02:56
Decrease, Cell proliferation	December 07, 2020 06:55
Accumulation, Triglyceride	March 26, 2024 13:09
Increase, Lipid degradation	August 16, 2025 00:26
Increase, Liver steatosis	February 11, 2026 05:41
Inhibition, Liver regeneration	August 16, 2025 00:27
Non-alcoholic fatty liver disease	June 27, 2022 23:18
Increase, DNA Damage leads to Upregulation, gadd45ba	August 16, 2025 00:27
Upregulation, gadd45ba leads to Activation, MAPK	August 16, 2025 00:27
Upregulation, gadd45ba leads to Downregulation, PCNA	August 16, 2025 00:28
Downregulation, PCNA leads to Cell cycle, disrupted	August 16, 2025 00:28
Cell cycle, disrupted leads to Decrease, Cell proliferation	October 08, 2024 04:53
Decrease, Cell proliferation leads to Inhibition, Liver regeneration	August 16, 2025 00:29
Inhibition, Liver regeneration leads to Non-alcoholic fatty liver disease	August 16, 2025 00:29
Activation, MAPK leads to Activation, FOXO	August 16, 2025 00:30
Activation, MAPK leads to Accumulation, Triglyceride	August 16, 2025 00:30
Accumulation, Triglyceride leads to Increase, Liver steatosis	March 27, 2024 10:09
Activation, FOXO leads to Increase, Lipid degradation	August 16, 2025 00:30
Increase, Lipid degradation leads to Increase, Liver steatosis	August 16, 2025 00:31
Increase, Liver steatosis leads to Non-alcoholic fatty liver disease	August 16, 2025 00:31
1,1'-Ethane-1,2-diylbis(pentabromobenzene)	December 29, 2024 21:12

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Decabromodiphenyl ethane (DBDPE), a widely used industrial substitute for polybrominated diphenyl ethers (PBDEs), acts as a significant environmental stressor. Exposure of zebrafish (Danio rerio) larvae to high concentrations of DBDPE (100 nM) causes an increase in DNA damage. This damage serves as the molecular initiating event (MIE), triggering a cascade of downstream effects.

The elevated DNA damage induces gadd45ba upregulation by p53 (Liebermann et al., 2008), which in turn activates the MAPK signaling pathway; Furthermore a positive feedback loop may further amplify this signal and subsequently activate the FoxO pathway (Li et al., 2023; Liebermann et al., 2008; Takekawa et al., 1998; Yang et al., 2009). Within this cascade, gadd45ba also binds directly to Proliferating Cell Nuclear Antigen (PCNA) which decreases its level (Chen et al., 1995). The resulting downregulation of PCNA disrupts the cell cycle (Li et al., 2023; Strzalka et al., 2011; Xu et al., 2016), leading to inhibited cell proliferation and further impaired liver regeneration (Li et al., 2023; Salehi et al., 2013).

In addition to affecting cell proliferation, the activated MAPK, which in turn activates the FoxO pathway (Essers et al., 2004; Exil et al., 2014) also disrupt lipid metabolism. MAPK signaling upregulates dgat1a causing triglyceride (TG) accumulation (Li et al., 2023, 2025). The FoxO pathway contributes by mediating the expression of related enzyme and genes, which promotes lipid degradation (Chakrabarti et al., 2009; Zhou et al., 2024). Together, the accumulation of TG and altered lipophagy result in hepatic steatosis (Zechner et al., 2017).

The development of hepatic steatosis (Dyson et al., 2014), coupled with an impaired capacity for liver regeneration (Fazia et al., 2018), ultimately leads to non-alcoholic fatty liver disease (NAFLD). This pathology represents the final adverse outcome of the pathway.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

This AOP is developed for zebrafish embryos exposed up to 120 hpf at the larval stage and 4 month old transgenic female zebrafish or wild-type female zebrafish. It provides novel insight into the toxic mechanisms of DBDPE as well as other emerging pollutants.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components. Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help

Key Events (KE)

A measurable event within a specific biological level of organisation. More help

Adverse Outcomes (AO)

An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Type	Event ID	Title	Short name

MIE

1194

Increase, DNA damage

Increase, DNA Damage

KE	2344	Upregulation, growth arrest and DNA-damage-inducible beta a	Upregulation, gadd45ba
KE	2345	Activation, MAPK	Activation, MAPK
KE	1293	Activation, FOXO	Activation, FOXO
KE	2346	Decrease, Proliferating Cell Nuclear Antigen	Downregulation, PCNA
KE	1505	Cell cycle, disrupted	Cell cycle, disrupted
KE	1821	Decrease, Cell proliferation	Decrease, Cell proliferation
KE	291	Accumulation, Triglyceride	Accumulation, Triglyceride
KE	2347	Increase, Lipid degradation	Increase, Lipid degradation
KE	459	Increase, Liver steatosis	Increase, Liver steatosis
KE	2348	Inhibition, Liver regeneration	Inhibition, Liver regeneration

2019

Non-alcoholic fatty liver disease

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Title	Adjacency	Evidence	Quantitative Understanding

Increase, DNA Damage leads to Upregulation, gadd45ba	adjacent	High	Moderate
Upregulation, gadd45ba leads to Activation, MAPK	adjacent	High	High
Upregulation, gadd45ba leads to Downregulation, PCNA	adjacent	Moderate	Moderate
Downregulation, PCNA leads to Cell cycle, disrupted	adjacent	High	High
Cell cycle, disrupted leads to Decrease, Cell proliferation	adjacent	Not Specified	Not Specified
Decrease, Cell proliferation leads to Inhibition, Liver regeneration	adjacent	High	High
Inhibition, Liver regeneration leads to Non-alcoholic fatty liver disease	adjacent	Moderate	Moderate
Activation, MAPK leads to Activation, FOXO	adjacent	High	High
Activation, MAPK leads to Accumulation, Triglyceride	adjacent	High	High
Accumulation, Triglyceride leads to Increase, Liver steatosis	adjacent	High	High
Activation, FOXO leads to Increase, Lipid degradation	adjacent	High	High
Increase, Lipid degradation leads to Increase, Liver steatosis	adjacent	High	High
Increase, Liver steatosis leads to Non-alcoholic fatty liver disease	adjacent	High	High

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Name
1,1'-Ethane-1,2-diylbis(pentabromobenzene)

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
Larvae	High
Adult	High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Term	Scientific Term	Evidence	Link
zebrafish	Danio rerio	High	NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Sex	Evidence
Female	High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

The research is conducted on zebrafish embryos up to 120 hpf, transitioning from the embryo to larval stage and 4 month old transgenic female zebrafish or wild-type female zebrafish..

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

KER1 Increase, DNA damage lead to Upregulation, gadd45ba

gadd45ba which is growth arrest and DNA-damage-inducible beta a, will be upregulated when the DNA is impaired to repair the DNA (Liebermann et al., 2008).

KER2 Upregulation, gadd45ba lead to Activation, MAPK(Han et al., 2020)

In vivo, many experiments and evidence have shown that the GADD45 can mediated MAPK signal pathway (Li et al., 2023; Liebermann et al., 2008; Takekawa et al., 1998; Yang et al., 2009). When the stressor activate the Gadd45 upregulated by p53, it will bind to the MTK1 and activate the downstream p38/JNK. Further, the p53 will be upregulated by p38, which will form a positive feedback loop between Gadd45ba and MAPK signaling pathway (Han et al., 2020).

KER3 Upregulation, gadd45ba lead to Decrease, PCNA

The Gabb45 have the ability to directly bind to the PCNA which will disrupt its function in cell cycles(Chen et al., 1995).

KER4 Decrease, PCNA lead to Cell cycle, disrupted

PCNA which is Proliferating Cell Nuclear Antigen, have crucial role in cell cycle that is tightly linked to cell proliferation(Strzalka et al., 2011). The Decrease of PCNA will disrupt the cell cycle progression(Li et al., 2023; Xu et al., 2016).

KER5 Cell cycle, disrupted lead to Decrease, Cell proliferation

KER6 Decrease, Cell proliferation lead to Inhibition, Liver regeneration

The liver regenerates through cell proliferation, but this regenerative capacity is impaired when the process is inhibited by stressors(Li et al., 2023; Salehi et al., 2013).

KER7 Inhibition, Liver regeneration lead to Non-alcoholic fatty liver disease

The failure of liver regeneration will accelerate the disease progression in fatty liver, which may lead to the Non-alcoholic fatty liver disease(Fazia et al., 2018).

KER8 Activation, MAPK lead to Activation, FOXO

The MAPK and FoxO signaling pathways have many multiple regulatory mechanisms, remarkably, when p38 inhibited by inhibitor in exposed to Mn, the FoxO level also reduced(Exil et al., 2014). What’s more, c-Jun N-terminal Kinase (JNK) in MAPK family activated by cell stress can increase Foxo transcription (Essers et al., 2004).

KER9 Activation, MAPK lead to Accumulation, Triglyceride

The p38 in MAPK can regulate the TG biosynthesis through DGAT1 and PLINs, which will results in accumulation of TG in the cell(Li et al., 2023, 2025).

KER10 Activation, FOXO lead to Increase, Lipid degradation

FoxO signaling pathways have been proved to have the ability to promotes lipolysis and lipophagy which are processes of lipid degradation. In 3T3-L1 adipocyte, knockdown of FoxO1 will decrease the rate-limiting lipolytic enzyme which slow down the lipolysis(Chakrabarti et al., 2009; Zechner et al., 2017). Also, under the inhibitor of foxo1 in zebrafish liver show the lipid accumulation (Zhou et al., 2024).

KER11 Accumulation, Triglyceride lead to Increased, Liver Steatosis

KER12 Increase, Lipid degradation lead to Increased, Liver Steatosis

Lipid degradation will enhanced free fatty acid release from adipose tissues, which will contribute to the development of hepatic steatosis (Zechner et al., 2017).

KER14 Increased, Liver Steatosis lead to Non-Alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis (>5% of hepatocytes) in the absence of significant alcohol use (Dyson et al., 2014).

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Modulating Factor (MF)	Influence or Outcome	KER(s) involved

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

Chakrabarti P, Kandror K V, 2009. FoxO1 Controls Insulin-dependent Adipose Triglyceride Lipase (ATGL) Expression and Lipolysis in Adipocytes[J]. The Journal of Biological Chemistry, 284(20): 13296-13300.

Chen I T, Smith M L, O’Connor P M, et al., 1995. Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA[J]. Oncogene, 11(10): 1931-1937.

Dyson J K, Anstee Q M, McPherson S, 2014. Non-alcoholic fatty liver disease: a practical approach to diagnosis and staging[J]. Frontline Gastroenterology, 5(3): 211-218.

Essers M A G, Weijzen S, de Vries-Smits A M M, et al., 2004. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK[J]. The EMBO journal, 23(24): 4802-4812.

Exil V, Ping L, Yu Y, et al., 2014. Activation of MAPK and FoxO by manganese (Mn) in rat neonatal primary astrocyte cultures[J]. PloS One, 9(5): e94753.

Fazia M A D, Servillo G, 2018. Foie gras and liver regeneration: a fat dilemma[J]. Cell Stress, 2(7): 162-175.

Han S, Wang Y, Ma J, et al., 2020. Sulforaphene inhibits esophageal cancer progression via suppressing SCD and CDH3 expression, and activating the GADD45B-MAP2K3-p38-p53 feedback loop[J]. Cell Death & Disease, 11(8): 713.

Li F, Song G, Wang X, et al., 2023. Evidence for Adverse Effects on Liver Development and Regeneration in Zebrafish by Decabromodiphenyl Ethane[J]. Environmental Science & Technology, 57(48): 19419-19429.

Li N, Saitou M, Atilla-Gokcumen G E, 2025. The Role of p38 MAPK in Triacylglycerol Accumulation during Apoptosis[J].

Liebermann D A, Hoffman B, 2008. Gadd45 in stress signaling[J]. Journal of Molecular Signaling, 3: 15.

Salehi S, Brereton H C, Arno M J, et al., 2013. Human liver regeneration is characterized by the coordinated expression of distinct microRNA governing cell cycle fate[J]. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 13(5): 1282-1295.

Strzalka W, Ziemienowicz A, 2011. Proliferating cell nuclear antigen (PCNA): a key factor in DNA replication and cell cycle regulation[J]. Annals of Botany, 107(7): 1127-1140.

Takekawa M, Saito H, 1998. A Family of Stress-Inducible GADD45-like Proteins Mediate Activation of the Stress-Responsive MTK1/MEKK4 MAPKKK[J]. Cell, 95(4): 521-530.

Xu Y, Chen B, Zheng S, et al., 2016. IgG silencing induces apoptosis and suppresses proliferation, migration and invasion in LNCaP prostate cancer cells[J]. Cellular & Molecular Biology Letters, 21: 27.

Yang Z, Song L, Huang C, 2009. Gadd45 Proteins as Critical Signal Transducers Linking NF-κB to MAPK Cascades[J]. Current cancer drug targets, 9(8): 915-930.

Zechner R, Madeo F, Kratky D, 2017. Cytosolic lipolysis and lipophagy: two sides of the same coin[J]. Nature Reviews Molecular Cell Biology, 18(11): 671-684.

Zhou Y, Li F, Fu K, et al., 2024. Bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate Enhances foxo1-Mediated Lipophagy to Remodel Lipid Metabolism in Zebrafish Liver[J]. Environmental Science & Technology, 58(10): 4581-4593.