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Relationship: 3559
Title
Decrease, ATP production leads to Decrease, Population growth rate
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
| AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
|---|---|---|---|---|---|---|
| Binding to plastoquinone B site leading to decreased population growth rate via photosystem II inhibition | adjacent | High | High | Li Xie (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
| Sex | Evidence |
|---|---|
| Unspecific | High |
Life Stage Applicability
| Term | Evidence |
|---|---|
| All life stages | High |
Key Event Relationship Description
The decrease in ATP production reduces the cellular energy available for essential biological processes including biosynthesis, cell proliferation, reproduction, and maintenance. ATP limitation constrains anabolic metabolism and cell cycle progression, leading to reduced growth and reproductive output at the organismal level (Nicholls & Ferguson, 2013; Hardie, 2011). In multicellular organisms, sustained energetic deficiency impairs fecundity, developmental success, and survival, which collectively reduce population growth rate (Wallace, 1999). Because ATP is the universal energy currency supporting physiological performance, chronic mitochondrial dysfunction and energetic stress are mechanistically linked to decreased organismal fitness and population-level growth dynamics.
Evidence Collection Strategy
Evidence was identified through targeted literature searches linking mitochondrial dysfunction and ATP depletion to organismal fitness endpoints, including growth, reproduction, fecundity, and population. Studies were prioritized that quantified energetic impairment alongside life-history or demographic parameters to establish mechanistic continuity between cellular ATP limitation and reduced population growth rate.
Evidence Supporting this KER
ATP is the universal energy currency underpinning reproduction, survival, and development — the three vital rates that collectively determine population growth rate (r). Chronic reductions in ATP production impair fecundity and offspring viability, which propagate to population-level decline. Environmental stressors that reduce mitochondrial ATP synthesis are mechanistically linked to growth inhibition across a broad range of taxa (Song et al., 2021). Reductions in cumulative fecundity yield declines in population size over time, and fecundity is a key vital rate driving overall population trajectories (Miller & Ankley, 2004; Kramer et al., 2011). Integrating survival, fecundity, and development impacts via population growth rate analysis provides a more robust basis for ecological risk assessment than individual-level endpoints alone (Forbes & Calow, 2002).
Biological Plausibility
The biological plausibility of this KER is high. ATP, mainly produced through mitochondrial oxidative phosphorylation, fuels all energy-demanding cellular processes including biosynthesis, cell division, and reproduction (Nicholls & Ferguson, 2013). When ATP production is chronically impaired, energy allocation to growth, reproduction, and survival becomes constrained (Hardie, 2011). Reduced ATP availability suppresses cell cycle progression and protein synthesis, limiting somatic growth and fecundity (Chaube et al., 2012). Since population growth rate integrates survival, fecundity, and developmental time as vital rates, energetic deficiency at the cellular level propagates predictably to population-level decline (Forbes & Calow, 2002; Kramer et al., 2011). This mechanistic chain, from impaired oxidative phosphorylation through reduced organismal fitness to decreased population growth, is evolutionarily conserved across taxa.
Empirical Evidence
Empirical evidence for this KER is considered high.
Rationale: Empirical support for this KER draws on laboratory exposure studies using mitochondrial toxicants — including uncouplers (e.g., 2,4-dinitrophenol, pentachlorophenol, dinoterb), electron transport chain inhibitors (e.g., rotenone), photosynthesis inhibitors (e.g., diuron, atrazine), and ionising radiation — that directly reduce cellular ATP production. Evidence spans multiple endpoints (ATP content, fecundity, survival, developmental timing, algal growth rate, biomass) across ecologically relevant taxa, including Daphnia magna, fish, invertebrates, and photosynthetic organisms including microalgae and vascular plants. In photosynthetic organisms, ATP depletion can occur via disruption of chloroplastic photophosphorylation and mitochondrial oxidative phosphorylation, providing a dual mechanistic route to the same downstream population-level effect. The strength of this KER is supported by concordance across dose-response, temporal, and incidence dimensions.
Dose-response concordance:
The most direct within-study dose-response evidence comes from Nestler et al. (2012), who simultaneously measured EC50 values for both ATP content (upstream KE) and growth inhibition (downstream KE) in Chlamydomonas reinhardtii exposed to paraquat. The 24 h EC50 for ATP content (0.16 µM) was approximately 2.6-fold lower than the growth EC50 (0.41 µM), demonstrating that ATP depletion occurs at lower concentrations than growth inhibition. In gamma irradiation studies of D. magna, ATP content was significantly reduced at dose rates of ≥10 mGy h⁻¹ after 8 days of exposure, and cumulative fecundity was significantly reduced at ≥31 mGy h⁻¹ across a 21-day reproductive period, establishing a dose-ordered progression from the upstream ATP KE to the downstream reproductive and population-level KE (Song et al., 2020; Gilbin et al., 2008).
Temporal concordance:
Nestler et al. (2012) provide the strongest within-study temporal evidence, measuring both ATP content and growth inhibition at 2, 6, and 24 h in C. reinhardtii exposed to paraquat. At 0.33 µM, significant ATP content inhibition was detectable at 6 h (LOEC = 0.33 µM) with no concurrent effect on growth, which only became significant at 24 h at the same concentration, a clear temporal lag confirming that ATP depletion precedes growth inhibition. By 24 h, ATP inhibition was nearly complete while growth was inhibited to only aournd 60% of control, consistent with the biological latency required for cellular energy depletion to propagate through cell division cycles and manifest as growth rate reduction.
Incidence concordance:
in D. magna, chronic exposure to ibuprofen — a pharmaceutical with known mitochondrial membrane effects — significantly suppressed fecundity and population growth rate (PGR) during a 10-day exposure period; following transfer to clean water, individuals exhibited compensatory 'catch-up' reproduction and recovered PGR to values comparable to controls (1.15–1.28 day⁻¹), demonstrating that population growth rate depression is reversible upon removal of the energetic stressor (Heckmann et al., 2008).
Uncertainties and Inconsistencies
Several uncertainties and inconsistencies qualify the confidence in this KER. First, compensatory metabolic mechanisms, notably upregulation of glycolysis during chronic low-dose exposures, can partially sustain ATP levels despite mitochondrial impairment, potentially decoupling the upstream and downstream KEs (Jose et al., 2011; OECD, 2022). Second, inconsistent observations have been reported where ATP levels increased rather than decreased following exposure to certain uncouplers (Kuruvilla et al., 2003), and where the adverse outcome (growth inhibition) responded more sensitively than the upstream KE (ATP depletion), contradicting the expected causal ordering (Nestler et al., 2012; OECD, 2022). Third, non-optimal sampling time points in empirical studies may obscure true temporal relationships between KEs. Finally, the population growth rate integrates multiple vital rates simultaneously, making it difficult to attribute its decline exclusively to ATP limitation when co-occurring stressors affect survival or development through non-energetic pathways (Forbes & Calow, 2002).
Known modulating factors
| Modulating Factor (MF) | MF Specification | Effect(s) on the KER | Reference(s) |
|---|---|---|---|
| Metabolic compensation | Upregulation of glycolysis, metabolic reprogramming | Buffers moderate ATP depletion, delaying reductions in growth and reproduction | Hardie, 2011 |
| Life-history strategy | r-selected vs. K-selected species | r-selected species may show rapid reproductive decline; K-selected species may prioritize survival over reproduction | Forbes & Calow, 2002 |
| Energy allocation trade-offs | Reallocation from reproduction to maintenance | Reduced fecundity despite maintained survival, modifying impact on intrinsic rate of increase (r) | Forbes & Calow, 2002 |
| Density dependence | Population density effects on survival and reproduction | Compensatory survival or reproduction at low density may mask ATP-driven declines in population growth | Kramer et al., 2011 |
| Developmental stage | Larval/juvenile vs. adult | Early life stages with high energetic demand may exhibit stronger growth impairment | Wallace, 1999 |
| Environmental stressors | Temperature, food limitation, hypoxia | Co-stressors amplify energetic deficit and accelerate demographic decline | Kramer et al., 2011 |
| Photosynthetic capacity (autotrophs) | Light availability and carbon fixation | In plants/algae, chloroplast ATP production may partially buffer mitochondrial ATP loss | Raghavendra & Padmasree, 2003 |
Quantitative Understanding of the Linkage
The quantitative understanding of this KER is considered high. A threshold of 85–90% ATP depletion relative to baseline has been proposed as a critical point determining whether cells undergo proliferation arrest or death, though this threshold varies across species and biological systems (Nieminen et al., 1994; OECD, 2022). At the algal level, Nestler et al. (2012) derived EC50 values for both ATP content (0.16 µM) and growth inhibition (0.41 µM) from the same experimental system in C. reinhardtii exposed to paraquat at 24 h, providing an empirical response-response ratio of approximately 2.6-fold between the upstream and downstream KEs. A Bayesian regression and network modelling approach has been applied to quantify causal response-response relationships between ATP depletion and growth inhibition using Lemna minor exposure data, demonstrating proof-of-concept for predicting the adverse outcome from upstream KE measurements (Moe et al., 2021). At the population level, matrix population models and DEBtox-based approaches exist for quantitatively linking individual vital rates to population growth rate in D. magna (Song et al., 2020).
Response-response Relationship
A monotonic positive response-response relationship between ATP depletion and population growth rate reduction is generally assumed (OECD, 2022). Nestler et al. (2012) quantified a 2.6-fold ratio between ATP content EC50 (0.16 µM) and growth EC50 (0.41 µM) for paraquat in C. reinhardtii at 24 h. Bayesian regression modelling of Lemna minor data further demonstrated forward prediction of growth inhibition from upstream ATP depletion measurements (Moe et al., 2021).
Time-scale
The time-scale of this KER spans from hours to weeks depending on the organism and stressor type. At the cellular level, ATP depletion is detectable within minutes to hours of exposure — in C. reinhardtii exposed to paraquat, significant ATP inhibition was measurable at 6 hours (Nestler et al., 2012). Downstream growth rate inhibition requires 24–72 hours in algae, reflecting the lag needed for cellular energy depletion to propagate through cell division cycles. In D. magna, ATP depletion was detectable at day 8, while fecundity reductions manifested by day 15, and full population growth rate decline accumulated across the 21-day reproductive period (Song et al., 2020). In multigenerational studies, population growth rate continues to deteriorate progressively across successive generations (F0–F2) under sustained ATP limitation, extending the relevant time-scale to weeks-to-months (Parisot et al., 2015). Overall, the time-scale of this KER is inherently organism-specific, ranging from hours (unicellular algae) to weeks (crustaceans), consistent with differences in generation time and metabolic rate across taxa.
Known Feedforward/Feedback loops influencing this KER
Upon ATP depletion, AMPK is activated, triggering a negative feedback loop that suppresses anabolic biosynthesis and cell proliferation while partially restoring ATP via catabolic upregulation and mitochondrial biogenesis (Hardie, 2011; Herzig & Shaw, 2018). Under chronic depletion, sustained AMPK activation overwhelms compensation, directly reinforcing growth inhibition and amplifying the downstream KE.
Domain of Applicability
Taxonomic applicability: This KER applies broadly across all aerobic organisms dependent on mitochondrial oxidative phosphorylation and/or chloroplastic photophosphorylation for ATP production, including microalgae, vascular plants, aquatic invertebrates, fish, and terrestrial organisms.
Sex applicability: Not sex-specific. ATP production via oxidative phosphorylation is a fundamental cellular process operating similarly across sexes.
Life-stage applicability: Applicable across all actively growing and reproducing life stages, including juvenile, adult, and reproductive phases.
Chemical domain: Relevant to all chemicals that reduce cellular ATP production, including mitochondrial uncouplers (e.g., 2,4-dinitrophenol, pentachlorophenol, dinoterb), electron transport chain inhibitors (e.g., rotenone, antimycin A), PSII inhibitors in photosynthetic organisms (e.g., diuron, atrazine), PSI inhibitors (e.g., paraquat), and ionising radiation. Also applicable to non-chemical stressors that impair mitochondrial or photosynthetic ATP synthesis, including hypoxia, temperature extremes, and UV radiation.
References
Chaube, R., et al. (2012). AMP-activated protein kinase and energy balance in fish. General and Comparative Endocrinology, 176, 366–374.
Forbes, V.E., & Calow, P. (2002). Population growth rate as a basis for ecological risk assessment of toxic chemicals. Philosophical Transactions of the Royal Society B, 357, 1299–1306.
Hardie, D.G. (2011). AMP-activated protein kinase: An energy sensor that regulates all aspects of cell function. Genes & Development, 25(18), 1895–1908.
Heckmann, L.H., Callaghan, A., Hooper, H.L., Connon, R., Hutchinson, T.H., Maund, S.J., & Sibly, R.M. (2008). Reproduction recovery of the crustacean Daphnia magna after chronic exposure to ibuprofen. Ecotoxicology, 17(3), 175–182.
Herzig, S., & Shaw, R.J. (2018). AMPK: guardian of metabolism and mitochondrial homeostasis. Nature Reviews Molecular Cell Biology, 19(2), 121–135.
Jose, C., Bellance, N., & Rossignol, R. (2011). Choosing between glycolysis and oxidative phosphorylation: a tumor's dilemma? Biochimica et Biophysica Acta, 1807(6), 552–561.
Kramer, V.J., Etterson, M.A., Hecker, M., Murphy, C.A., Roesijadi, G., Spade, D.J., Spromberg, J.A., Wang, M., & Ankley, G.T. (2011). Adverse outcome pathways and ecological risk assessment: Bridging to population-level effects. Environmental Toxicology and Chemistry, 30(1), 64–76.
Kuruvilla, S., et al. (2003). Mechanistic and toxicokinetic data reduce uncertainty in the extrapolation of in vitro toxicity data. Toxicological Sciences, 76(1), 138–152.
Miller, D.H., & Ankley, G.T. (2004). Modeling impacts on populations: fathead minnow exposure to 17β-trenbolone as a case study. Ecotoxicology and Environmental Safety, 59, 1–9.
Moe, S.J., et al. (2021). Quantification of an adverse outcome pathway network by Bayesian regression and Bayesian network modeling. Integrated Environmental Assessment and Management, 17, 147–164.
Nestler, H., Groh, K.J., Schönenberger, R., Behra, R., Schirmer, K., Eggen, R.I.L., & Suter, M.J.F. (2012). Multiple-endpoint assay provides a detailed mechanistic view of responses to herbicide exposure in Chlamydomonas reinhardtii. Aquatic Toxicology, 110–111, 214–224.
Nicholls, D.G., & Ferguson, S.J. (2013). Bioenergetics 4. Academic Press.
Nieminen, A.L., Saylor, A.K., Tesfai, S.A., Herman, B., & Lemasters, J.J. (1994). Contribution of the mitochondrial permeability transition to lethal injury after exposure of hepatocytes to t-butylhydroperoxide. Biochemical Journal, 307, 99–106.
OECD (2022). Uncoupling of Oxidative Phosphorylation Leading to Growth Inhibition via Decreased Cell Proliferation. OECD Series on Adverse Outcome Pathways. OECD Publishing, Paris.
Parisot, F., Bourdineaud, J.P., Plaire, D., Adam-Guillermin, C., & Alonzo, F. (2015). DNA alterations and effects on growth and reproduction in Daphnia magna during chronic exposure to gamma radiation over three successive generations. Aquatic Toxicology, 163, 27–36.
Raghavendra, A.S., & Padmasree, K. (2003). Beneficial interactions of mitochondrial metabolism with photosynthetic carbon assimilation. Trends in Plant Science, 8(11), 546–553.
Song, Y., et al. (2020). Integrative assessment of low-dose gamma radiation effects on Daphnia magna reproduction: Toxicity pathway assembly and AOP development. Science of the Total Environment, 705, 135912.
Song, Y., et al. (2021). Uncoupling of oxidative phosphorylation leading to growth inhibition via decreased cell proliferation. Environmental Toxicology and Chemistry, 40(12).
Wallace, D.C. (1999). Mitochondrial diseases in man and mouse. Science, 283(5407), 1482–1488.
Wallace, D.C. (2012). Mitochondria and cancer. Nature Reviews Cancer, 12(10), 685–698.