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AOP: 301

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

Inhibition of Cystathionine Beta synthase leading to impaired the early development of anterior-posterior axis

Short name

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

Homocysteine, anterior-posterior axis

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Handbook Version v2.0

Graphical Representation

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Authors

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Chang Seon Ryu¹, Kichul Choe¹, Baeckkyoung Sung¹, Seungyun Baik¹, Sang Kyum Kim² and Young Jun Kim¹

¹Environmental Safety Group, Korea Institute of Science and Technology (KIST) Europe, Campus E 7.1, Saarbruecken, Germany

²College of Pharmacy, Chungnam National University, daehakro 99, daejeon, Republic of Korea

Point of Contact

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Young Jun Kim (email point of contact)

Contributors

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Young Jun Kim

Coaches

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OECD Information Table

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

This AOP was last modified on April 29, 2023 16:03

Revision dates for related pages

Page	Revision Date/Time
Inhibition of cystathionine beta-synthase	June 14, 2019 09:39
Increased Homocysteine level	June 14, 2019 09:45
Increased, Plasma HCY level	July 03, 2019 05:31
Induced, dysfunction of microcirculation	July 03, 2019 05:34
Impaired,anterior-posterior axis development	July 03, 2019 05:35
CBS inhibition leads to Homocysteine increases	June 14, 2019 09:53
Homocysteine increases leads to Plasma HCY level	July 03, 2019 05:37
Plasma HCY level leads to dysfunction of microcirculation	July 03, 2019 05:37
dysfunction of microcirculation leads to anterior-posterior axis development	July 03, 2019 05:37
Aminooxyacetic acid	June 14, 2019 09:57
S-(4-Carboxybutyl)-D,L-homocysteine; 5-(3-Amino-3-carboxypropyl)sulfanyl-pentanoic acid	June 14, 2019 09:57

Abstract

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This AOP describes an adverse outcome that results from the inhibition of homocysteine (Hcy) catabolism. Hcy is a non-proteinogenic intermediary amino acid formed by the conversion of methionine to cysteine. Hcy is metabolized via two major pathways that remethylated via two remethylation pathway methionine synthase (MS) and betaine homocysteine methyltransferase (BHMT) and transsulfuration pathway enzyme, cystathionine beta-synthase (CBS). Impairment of re-methylation inhibition and/or transsulfuration lead to increment systemic concentration as known as hyperhomocysteinemia. CBS is responsible for 50% of Hcy clearance (Noga et al. 2003), together CBS is responsible for the generation of hydrogen sulfide (H₂S) from cysteine (Carter and Morton, 2016). Hyperhomocysteinemia leads to increment in Hcy to the neuronal system. CBS gene was expressed in liver and kidney, skeletal, cardiac and nervous systems (Robert et al. 2003; Namekata et al. 2004). Genetic deficiency of CBS in fish is critical for axis development (Prabhudesai et al. 2018), but there is not enough evidence in early neuronal development impairment in fish by chemical inhibition. Aminooxyacetic acid is a widely used CBS inhibitor that can reduce Hcy clearance and H₂S formation in the brain, has not only inhibition of CBS but also cystathione gamma-lyase. So far no selective pharmacological SBS inhibitor is currently available (Asimakopoulou et al. 2013).

AOP Development Strategy

Context

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Several observations indicate the involvement of hyperhomocysteinemia in neurodegeneration. Hcy levels may play a role in neuronal death via stimulation of glutamate receptors. Homocysteine is an agonist for metabotropic glutamate receptors as well as for NMDA (N-methyl-D-aspartate, as a partial antagonist) and AMPA (amino-3-hydroxy-5-methyl-4-isoxazolepropionate)/Kainate ionotropic glutamate receptors (Lazarewicz et al. 2003; Poddar and Paul 2009). Hcy further mediated subsequent Ca2+ efflux to biphasic activation of p38 mitogen-activated protein kinase (MAPK) (poddar and Paul 2013). Second possible mechanism of Hcy toxicity is free radical species production, and downregulation of antioxidant enzymes such as superoxide dismutase and peroxidase (Moat et al. 2000; Liu et al. 2013) Hcy has also been reported to modulate the expression of pro-inflammatory molecules, C-reactive protein in vascular smooth muscle cells (Pang et al. 2014). Moreover, Hcy is able to inhibit neurogenesis in the hippocampus and subventricular zone of the murine adult brain (Wang et al. 2012; Rabaneda et al. 2008). Hyperhomocysteinemia accelerates the dopaminergic cell death, probably due to the fact that hyperhomocysteinemia could cause a severe reduction in dopamine turnover in the striatum (De Lau et al. 2005).

Acknowledgements: This research was supported by the National Research Council of Science & Technology(NST) grant by the Korea government (MSIP) (No. CAP-17-01-KIST Europe)

Strategy

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Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

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Key Events (KE)

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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

1657

Inhibition of cystathionine beta-synthase

CBS inhibition

KE	1661	Increased Homocysteine level	Homocysteine increases
KE	1665	Increased, Plasma HCY level	Plasma HCY level
KE	1666	Induced, dysfunction of microcirculation	dysfunction of microcirculation

1667

Impaired,anterior-posterior axis development

anterior-posterior axis development

Relationships Between Two Key Events (Including MIEs and AOs)

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Title	Adjacency	Evidence	Quantitative Understanding

CBS inhibition leads to Homocysteine increases	adjacent	High	Low
Homocysteine increases leads to Plasma HCY level	adjacent	High	Moderate
Plasma HCY level leads to dysfunction of microcirculation	adjacent	Moderate	Low
dysfunction of microcirculation leads to anterior-posterior axis development	adjacent	Moderate	Low

Network View

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Prototypical Stressors

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Name
Aminooxyacetic acid
S-(4-Carboxybutyl)-D,L-homocysteine; 5-(3-Amino-3-carboxypropyl)sulfanyl-pentanoic acid

Life Stage Applicability

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

Life stage	Evidence
Birth to < 1 month	High

Taxonomic Applicability

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Sex Applicability

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Sex	Evidence
Mixed	Moderate

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

This AOP is under development supported by the National Research Council of Science & Technology (NST) grant by the Korea government (MSIP) (No. CAP-17-01-KIST Europe).

To do		Expected duration
Building the AOP frame	Development of KEs	3 month
Building the AOP frame	Production of experimental data	18 month
Overall assessment of the AOP	Biological domain of applicability	3 month
	Essentiality of all KEs	3 month
	Evidence supporting all KERs	5 month
	Quantitative WoE considerations	5 month
	Quantitative understanding for each KER	6 month

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

FIsh

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

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

Quantitative Understanding

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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

This AOP is designed to detect changes of Hcy concentration in early developmental condition including fish larvae by chemical inhibition of CBS. Accumulation of neuronal damage in fish is the should be measured together in in vivo experiment for clarifing the adverse outcome. In addition, screening of selective potential chemical inhibitor of CBS will be performed in in vitro cell-based assay in different species.

References

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

Abbott MH, Folstein SE, Abbey H, Pyeritz RE. (1987) Psychiatric manifestations of homocystinuria due to cystathionine beta-synthase deficiency: prevalence, natural history, and relationship to neurologic impairment and vitamin B6-responsiveness. Am J Med Genet. 1987 Apr; 26(4):959-69.

SJ Lee, SH Park, JF Chung, WR Choi, and HK Huh(2017) Homocysteine-induced peripheral microcirculation dysfunction in zebrafish and its attenuation by L-arginine. Oncotarget. 2017 Aug 29; 8(35): 58264–58271.

Noga AA, Stead LM, Zhao Y, Brosnan ME, Brosnan JT, Vance DE (2003) Plasma homocysteine is regulated by phospholipid methylation. J. Biol. Chem. 278, 5952–5955.

Carter RN, Morton NM. (2016) Cysteine and hydrogen sulphide in the regulation of metabolism: insights from genetics and pharmacology J Pathol. 238(2):321-32.

Lazarewicz JW1, Ziembowicz A, Matyja E, Stafiej A, Zieminska E (2003) Homocysteine-evoked 45Ca release in the rabbit hippocampus is mediated by both NMDA and group I metabotropic glutamate receptors: in vivo microdialysis study. Neurochem Res. 28(2):259-69.

Poddar R, Paul S. (2009) Homocysteine-NMDA receptor-mediated activation of extracellular signal-regulated kinase leads to neuronal cell death. J Neurochem. 110(3):1095-106

Pang X, Liu J, Zhao J, Mao J, Zhang X, Feng L (2014) Homocysteine induces the expression of C-reactive protein via NMDAr-ROS-MAPK-NF-KB signal pathway in rat vascular smooth muscle cells. Atherosclerosis. 236:73–81

De Lau LM, Koudstaal PJ, van Meurs JB, Uitterlinden AG, Hofman A, Breteler MM (2005) Methylenterahydrofolate reductase C677T genotype and PD. Annu. Neurol. 57:927–930.

Liu HH, Shih TS, Huang HR, Huang SC, Lee LH, Huang YC. (2013) Plasma homocysteine is associated with increased oxidative stress and antioxidant enzyme activity in welders. ScientificWorldJournal. 370487.

Moat SJ, Bonham JR, Cragg RA, Powers HJ.(2000) Elevated plasma homocysteine elicits an increase in antioxidant enzyme activity. Free Radic Res. 2000 Feb;32(2):171-9.

Wang J, Bai X, Chen Y, Zhao Y, Liu X. (2012) Homocysteine induces apoptosis of rat hippocampal neurons by inhibiting 14-3-3ε expression and activating calcineurin. PLoS One. 7(11):e48247.

Rabaneda LG1, Carrasco M, López-Toledano MA, Murillo-Carretero M, Ruiz FA, Estrada C, Castro C. (2008) Homocysteine inhibits proliferation of neuronal precursors in the mouse adult brain by impairing the basic fibroblast growth factor signaling cascade and reducing extracellular regulated kinase 1/2-dependent cyclin E expression. FASEB J. 22(11):3823-35.

Prabhudesai et al. (2018) Cystathionine β-Synthase Is Necessary for Axis Development in Vivo. Front Cell Dev Biol. 2018 Feb 16;6:14

Asimakopoulou A, Panopoulos P, Chasapis CT, Coletta C, Zhou Z, Cirino G, Giannis A, Szabo C, Spyroulias GA, Papapetropoulos A. (2013) Selectivity of commonly used pharmacological inhibitors for cystathionine β synthase (CBS) and cystathionine γ lyase (CSE). Br J Pharmacol. 169(4):922-32.

J Histochem Cytochem. 2003 Mar;51(3):363-71. Expression of the cystathionine beta synthase (CBS) gene during mouse development and immunolocalization in adult brain. Robert K1, Vialard F, Thiery E, Toyama K, Sinet PM, Janel N, London J.

J Biol Chem. 2004 Dec 17;279(51):52961-9. Epub 2004 Oct 4. Abnormal lipid metabolism in cystathionine beta-synthase-deficient mice, an animal model for hyperhomocysteinemia. Namekata K1, Enokido Y, Ishii I, Nagai Y, Harada T, Kimura H.