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AOP: 592

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 strand breaks and LDH activity inhibition leading to population growth rate decline via energy metabolism disrupt and apoptosis

Short name

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DBDPE leading to population growth rate decline from energy metabolism disrupts

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

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help

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

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lihua Yang

Coaches

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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 strand breaks	December 17, 2024 11:57
Inhibition of LDH activity	August 16, 2025 00:33
Increased, DNA Damage-Repair	September 16, 2017 10:17
Decreased, Glycolysis	August 16, 2025 00:33
Increased, OXPHOS	August 16, 2025 00:34
Increased, MMP	August 16, 2025 00:34
Disrupted, energy metabolism	August 16, 2025 00:35
Activation, Apoptosis signaling	August 16, 2025 00:35
Disrupted, Spermatogenesis and Sperm quality	August 16, 2025 00:36
decreased, Fertility	December 17, 2024 15:46
Decrease, Population growth rate	January 03, 2023 09:09
Increase, DNA strand breaks leads to Increased, DNA Damage-Repair	August 16, 2025 00:37
Increased, DNA Damage-Repair leads to Activation, Apoptosis signaling	August 16, 2025 00:37
Inhibition of LDH activity leads to Decreased, Glycolysis	August 16, 2025 00:38
Decreased, Glycolysis leads to Increased, OXPHOS	August 16, 2025 00:38
Increased, OXPHOS leads to Increased, MMP	August 16, 2025 00:38
Increased, MMP leads to Disrupted, energy metabolism	August 16, 2025 00:38
Disrupted, energy metabolism leads to Activation, Apoptosis signaling	August 16, 2025 00:38
Activation, Apoptosis signaling leads to Disrupted, Spermatogenesis and Sperm quality	August 16, 2025 00:39
Disrupted, Spermatogenesis and Sperm quality leads to decreased, Fertility	August 16, 2025 00:39
decreased, Fertility leads to Decrease, Population growth rate	March 26, 2021 15:24
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

This Adverse Outcome Pathway (AOP) delineates the male reproductive toxicity of decabromodiphenyl ethane (DBDPE), a widely used novel brominated flame retardant (NBFR), integrating evidence from ex vivo zebrafish spermatozoa, in vivo zebrafish models, and in vitro mouse spermatogonial (GC-1) cell studies. The AOP development addresses growing concerns over DBDPE’s environmental persistence, bioaccumulation potential, and reproductive risks, particularly given its role as a replacement for legacy BFRs with poorly characterized hazards.

The pathway initiates with two Molecular Initiating Events: 1. Increased DNA strand breaks, triggered by DBDPE-induced genotoxic stress. 2. Inhibition of lactate dehydrogenase (LDH) activity, disrupting glycolytic flux. These MIEs propagate through critical Key Events : DNA damage response activation, leading to disrupted cell cycle regulation and apoptotic signaling. Metabolic reprogramming, characterized by decreased glycolysis and increased oxidative phosphorylation (OXPHOS), Cumulative energy metabolism disruption impairs spermatogenesis and sperm quality. The cascade culminates in Adverse Outcomes: Disrupted spermatogenesis and sperm quality (reduced motility, abnormal morphology). Decreased fertility and impaired population growth in aquatic species.

Scientific evidence from integrated omics , biochemical assays, and phenotypic analyses robustly supports the AOP. DNA damage, metabolic shifts, and germ cell apoptosis were consistently observed across models at environmentally relevant concentrations. Key knowledge gaps include species extrapolation to mammals, long-term multigenerational effects, and the exact role of nuclear actin polymerization in DNA damage.

This AOP provides a mechanistic framework for screening DBDPE-like compounds and supports the development of New Approach Methodologies (NAMs) combining in vitro, ex vivo, and non-rodent models for efficient risk assessment. Its application can inform regulatory policies on NBFRs and guide biomonitoring strategies for early detection of mitochondrial hyperpolarization (MMP) as a sensitive biomarker of metabolic disruption.

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 study is applicable for assessing the toxic effects of DBDPE at environmentally relevant concentrations on the reproductive systems of adult male zebrafish and mammals (mouse spermatogonial cells), particularly suitable for toxicity studies at the level of adult males and germ cells.

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	1635	Increase, DNA strand breaks	Increase, DNA strand breaks
MIE	2349	Inhibition of LDH activity	Inhibition of LDH activity

KE	1281	Increased, DNA Damage-Repair	Increased, DNA Damage-Repair
KE	2350	Decreased, Glycolysis	Decreased, Glycolysis
KE	2351	Increased, OXPHOS	Increased, OXPHOS
KE	2352	Increased, MMP	Increased, MMP
KE	2353	Disrupted, energy metabolism	Disrupted, energy metabolism
KE	2354	Activation, Apoptosis signaling	Activation, Apoptosis signaling

AO	2355	Disrupted, Spermatogenesis and Sperm quality	Disrupted, Spermatogenesis and Sperm quality
AO	406	decreased, Fertility	decreased, Fertility
AO	360	Decrease, Population growth rate	Decrease, Population growth rate

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 strand breaks leads to Increased, DNA Damage-Repair	adjacent	High	High
Increased, DNA Damage-Repair leads to Activation, Apoptosis signaling	adjacent	High	High
Inhibition of LDH activity leads to Decreased, Glycolysis	adjacent	High	High
Decreased, Glycolysis leads to Increased, OXPHOS	adjacent	High	High
Increased, OXPHOS leads to Increased, MMP	adjacent	High	High
Increased, MMP leads to Disrupted, energy metabolism	adjacent	High	High
Disrupted, energy metabolism leads to Activation, Apoptosis signaling	adjacent	Moderate	Moderate
Activation, Apoptosis signaling leads to Disrupted, Spermatogenesis and Sperm quality	adjacent	High	High
Disrupted, Spermatogenesis and Sperm quality leads to decreased, Fertility	adjacent	High	High
decreased, Fertility leads to Decrease, Population growth rate	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
Adults	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
Male	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

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

In zebrafish testes and GC-1 cells, DBDPE-induced DNA damage is accompanied by abnormal spermatogenesis and activation of cell death signals; similarly, when using oxidative phosphorylation inhibitors (such as oxamate) to mimic the effects of DBDPE, DNA damage and metabolic dysregulation were observed synergistically, indirectly supporting the necessity of DNA damage in driving downstream KEs (such as energy reprogramming). The necessity of energy metabolism reprogramming (shift from glycolysis to oxidative phosphorylation) was directly validated through LDH activity inhibition experiments—oxamate treatment reproduced the metabolic phenotype of DBDPE (mitochondrial hyperpolarization, altered ATP production pathways), and the parameters between the two were significantly correlated, indicating that metabolic reprogramming is a requisite event for DBDPE-induced reproductive toxicity.

Evidence Assessment

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

KER 1: Inhibition of Mitochondrial Complex Ⅰ leads to Altered, Redox Homeostasis

The inhibition of mitochondrial complex Ⅰ will change the redox homeostasis which indicate the change of NAD⁺ /NADH ratio. In female nude mice, treated by metformin can inhibit the mitochondrial complex Ⅰ, which further decrease the ratio(Parisotto et al., 2022). Also, in mouse and mice hepatocytes, rotenone can inhibit the complex Ⅰ and reduce the NADH/NAD state(Alshawi and Agius, 2019). What’s more, the DBDPE inhibit the complex Ⅰ and alter the NAD⁺/NADH ratio in zebrafish larvae(Yang et al., 2023).

KER 2: Altered, Redox Homeostasis leads to Disruption, Mitochondrial electron transport chain

The change of NAD⁺/NADH ratio which also indicate the alteration of redox homeostasis, will disrupt the mitochondrial electron transport chain (ETC). In human, obesity will impair the ETC further decrease NAD⁺/NADH ratio which ultimately lead to accelerate heart failure (Karamanlidis et al., 2013). Also, in the human HeLa cells, when a gene LbNOX that inducing a compartment-specific increase of the NAD/NADH ratio is added to the mitochondria, the impact of doxycycline bring to the ETC is mitigated(Titov et al., 2016). In zebrafish larvae, the larvae impact by DBDPE have decrease in NAD⁺/NADH ratio and disrupted ETC, when nicotinamide riboside (NR) was added to the culture water, the adverse effects of DBDPE was alleviated(Yang et al., 2023).

KER3: Disruption, Mitochondrial electron transport chain leads to Decrease, Mitochondrial ATP production

KER4: Decrease, Mitochondrial ATP production leads to Disruption, Glucolipid metabolism

The decrease of mitochondrial ATP contents or synthesis can disrupt glucolipid metabolism. In male SD rats, DBDPE can decrease ATP synthesis which induce disruption in glycolipid metabolism(Gao et al., 2022). Methionine and choline deficient diet in rats can induce nonalcoholic steatohepatitis and reduce ATP content result in dysregulated hepatic glycolipid metabolism(Vendemiale et al., 2001). Streptozotocin induced type 1 diabetic mice also reduced their ATP contents then make glycolipid metabolism dysregulated(Wang et al., 2014).

KER5: Disruption, Glucolipid metabolism leads to impaired, Larval development

The disruption in glycolipid metabolism can cause impaired in larval growth or development. In zebrafish larvae, procymidone can influence the lipid metabolism then cause developmental toxicity. Also, under co-exposure of neonicotinoid pesticide acetamiprid and cadmium will induce harmful effects on glycolipid metabolism which result in inhibitory effect on the growth of larvae. In silkworm, Overexpression of BmFoxO can induce disruption in glycolipid metabolism then affect growth.

KER6: Decrease, Mitochondrial ATP production leads to Disruption, Neurotransmitter release

Synapses are the primary sites of ATP consumption in the brain. The decrease in mitochondrial ATP production would likely impair neurotransmitter release at the synapse(Harris et al., 2012).

KER7: Disruption, Neurotransmitter release leads to Abnormal, Behavior

Disruption of neurotransmitter release will lead to behavior change. In zebrafish, 6PPD and zinc chloride both can altered neurotransmitter result in abnormal behavior, and DBDPE can elevate multiple neurotransmitters in larvae resulting in hyperactivity. What’s more, in rats, HIV antiretroviral drug Efavirenz can Altered neurotransmitters glutamate and GABA then lead to anxiety-like and depression-like behavior.

KER8: Abnormal, Behavior leads to impaired, Larval development

Abnormal behavior, such as impaired prey recognition caused by chlorpyrifos (CHP) exposure, can hinder larval feeding and ultimately impact their development(Langer-Jaesrich et al., 2010).

KER11: Increased Mortality leads to Decrease, Population growth rate

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

A. Alshawi and L. Agius. (2019), “Low metformin causes a more oxidized mitochondrial NADH/NAD redox state in hepatocytes and inhibits gluconeogenesis by a redox-independent mechanism,” The Journal of Biological Chemistry, Vol. 294/8, pp. 2839–2853, https://doi.org/10.1074/jbc.RA118.006670.

G. I. T. Cavalcante et al. (2017), “HIV antiretroviral drug Efavirenz induces anxiety-like and depression-like behavior in rats: evaluation of neurotransmitter alterations in the striatum,” European Journal of Pharmacology, Vol. 799, pp. 7–15, https://doi.org/10.1016/j.ejphar.2017.02.009.

L. Gao et al. (2022), “Fat mass and obesity-associated gene (FTO) hypermethylation induced by decabromodiphenyl ethane causing cardiac dysfunction via glucolipid metabolism disorder,” Ecotoxicology and Environmental Safety, Vol. 237, p. 113534, https://doi.org/10.1016/j.ecoenv.2022.113534.

J. J. Harris, R. Jolivet and D. Attwell. (2012), “Synaptic energy use and supply,” Neuron, Vol. 75/5, pp. 762–777, https://doi.org/10.1016/j.neuron.2012.08.019.

G. Hu et al. (2023), “Combined toxicity of acetamiprid and cadmium to larval zebrafish (Danio rerio) based on metabolomic analysis,” The Science of the Total Environment, Vol. 867, p. 161539, https://doi.org/10.1016/j.scitotenv.2023.161539.

J. Ji et al. (2022), “Multiview behavior and neurotransmitter analysis of zebrafish dyskinesia induced by 6PPD and its metabolites,” The Science of the Total Environment, Vol. 838/Pt 2, p. 156013, https://doi.org/10.1016/j.scitotenv.2022.156013.

G. Karamanlidis et al. (2013), “Mitochondrial Complex I Deficiency Increases Protein Acetylation and Accelerates Heart Failure,” Cell Metabolism, Vol. 18/2, pp. 239–250, https://doi.org/10.1016/j.cmet.2013.07.002.

M. Langer-Jaesrich et al. (2010), “Impairment of trophic interactions between zebrafish (Danio rerio) and midge larvae (Chironomus riparius) by chlorpyrifos,” Ecotoxicology, Vol. 19/7, pp. 1294–1301, https://doi.org/10.1007/s10646-010-0516-x.

Z. Lu et al. (2019), “Overexpression of BmFoxO inhibited larval growth and promoted glucose synthesis and lipolysis in silkworm,” Molecular genetics and genomics: MGG, Vol. 294/6, pp. 1375–1383, https://doi.org/10.1007/s00438-019-01550-2.

M. Parisotto et al. (2022), “The NAMPT Inhibitor FK866 Increases Metformin Sensitivity in Pancreatic Cancer Cells,” Cancers, Vol. 14/22, p. 5597, https://doi.org/10.3390/cancers14225597.

Y. Sun et al. (2023), “Multi- and Transgenerational Developmental Impairments Are Induced by Decabromodiphenyl Ethane (DBDPE) in Zebrafish Larvae,” Environmental Science & Technology, Vol. 57/7, pp. 2887–2897, American Chemical Society, https://doi.org/10.1021/acs.est.3c00032.

D. V. Titov et al. (2016), “Complementation of mitochondrial electron transport chain by manipulation of the NAD+/NADH ratio,” Science, Vol. 352/6282, pp. 231–235, American Association for the Advancement of Science, https://doi.org/10.1126/science.aad4017.

R. Vartak, C. A.-M. Porras and Y. Bai. (2013), “Respiratory supercomplexes: structure, function and assembly,” Protein & Cell, Vol. 4/8, pp. 582–590, https://doi.org/10.1007/s13238-013-3032-y.

G. Vendemiale et al. (2001), “Mitochondrial oxidative injury and energy metabolism alteration in rat fatty liver: Effect of the nutritional status,” Hepatology, Vol. 33/4, pp. 808–815, https://doi.org/10.1053/jhep.2001.23060.

C. Wang et al. (2014), “Hepatic Overexpression of ATP Synthase β Subunit Activates PI3K/Akt Pathway to Ameliorate Hyperglycemia of Diabetic Mice,” Diabetes, Vol. 63/3, pp. 947–959, https://doi.org/10.2337/db13-1096.

A. Wu et al. (2021), “Developmental toxicity of procymidone to larval zebrafish based on physiological and transcriptomic analysis,” Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, Vol. 248, p. 109081, https://doi.org/10.1016/j.cbpc.2021.109081.

L. Yang et al. (2023), “Mitochondrial Dysfunction Was Involved in Decabromodiphenyl Ethane-Induced Glucolipid Metabolism Disorders and Neurotoxicity in Zebrafish Larvae,” Environmental Science & Technology, Vol. 57/30, pp. 11043–11055, American Chemical Society, https://doi.org/10.1021/acs.est.3c03552.

F. Yu et al. (2022), “Zinc alters behavioral phenotypes, neurotransmitter signatures, and immune homeostasis in male zebrafish (Danio rerio),” The Science of the Total Environment, Vol. 828, p. 154099, https://doi.org/10.1016/j.scitotenv.2022.154099.