Inhibition of Ceramide Synthase

116355-83-0

UVBUBMSSQKOIBE-ZWKVXHQASA-N

Fumonisin B1

FB1 1,2,3-Propanetricarboxylic acid, 1,1'-[(1S,2R)-1-[(2S,4R,9R,11S,12S)-12-amino-4,9,11-trihydroxy-2-methyltridecyl]-2-[(1R)-1-methylpentyl]-1,2-ethanediyl] ester, (2R,2'R)- 1,2,3-Propanetricarboxylic acid, 1,1'-[1-(12-amino-4,9,11-trihydroxy-2-methyltridecyl)-2-(1-methylpentyl)-1,2-ethanediyl] ester, [2S-[1[1R*(S*),2S*(S*),2(S*)],2R*,4S*,9S*,11R*,12R*]]-

DTXSID6020644

625-45-6

RMIODHQZRUFFFF-UHFFFAOYSA-N

Methoxyacetic acid

Acetic acid, methoxy- 2-Methoxyacetic acid ACETIC ACID, METHOXY Acide methoxyacetique acido metoxiacetico Methoxy acetic acid Methoxyessigsaure Methoxyethanoic acid NSC 7300

DTXSID1031591

461-55-2

FERIUCNNQQJTOY-UHFFFAOYSA-M

Butyrate

DTXSID8040432

58880-19-6

RTKIYFITIVXBLE-QEQCGCAPSA-N

Trichostatin A

TSA

DTXSID6037063

99-66-1

NIJJYAXOARWZEE-UHFFFAOYSA-N

Valproic acid

VPA Pentanoic acid, 2-propyl- 2-Propylpentanoic acid 2-Propylvaleriansaure 2-propylvaleric acid 4-Heptanecarboxylic acid Acetic acid, dipropyl- acide 2-propylvalerique acido 2-propilvalerico Depakine Dipropylacetic acid Ergenyl Mylproin n-Dipropylacetic acid NSC 93819 VALERIC ACID, 2-PROPYL-

DTXSID6023733

149647-78-9

WAEXFXRVDQXREF-UHFFFAOYSA-N

Suberoylanilide hydroxamic acid

vorinostat Octanediamide, N-hydroxy-N'-phenyl- SAHA

DTXSID6041133

209783-80-2

INVTYAOGFAGBOE-UHFFFAOYSA-N

MS-275

DTXSID0041068

183506-66-3

JWOGUUIOCYMBPV-GMFLJSBRSA-N

JWOGUUIOCYMBPV-LQJYRIKDSA-N

Apicidin

(3S,6S,9S,15aR)-9-[(2S)-Butan-2-yl]-6-[(1-methoxy-1H-indol-3-yl)methyl]-3-(6-oxooctyl)octahydro-2H-pyrido[1,2-a][1,4,7,10]tetraazacyclododecine-1,4,7,10(3H,12H)-tetrone Apicidin Ia

DTXSID40274182

PR:000008478

PR histone deacetylase 1

GO:0004857

GO enzyme inhibitor activity

WIKI decreased

Fumonisin B1

2022-07-14T09:19:02

Methoxyacetic acid

2018-01-21T20:38:50

Butyrate

2018-01-21T20:39:19

Trichostatin A

2018-01-21T20:39:33

Valproic acid

2018-12-20T04:35:21

Suberoylanilide hydroxamic acid

2018-12-20T04:36:36

MS-275

2018-12-20T04:37:02

Apicidin

2018-12-20T04:37:15

Rocilinostat / Ricolinostat

2021-06-23T05:53:11

10116

NCBI rat

WCS_9606

common toxicological species human

10090

NCBI mouse

Inhibition of Ceramide Synthase

Inhibition CerS

Molecular

Ceramide synthases (CerS) are enzymes that catalyze the acylation of Sphiganine (Sa) to form (dihydro-)ceramide (a precursor for ceramide and complex sphingolipds) and also the reacylation of Sphingosine (So) that is derived from the turnover of complex sphingolipids (EFSA et al., 2018; Sassa et al., 2016). Six mammalian isoforms of ceramide synthases exist (CerS1–6), which differ in their tissue distribution as well as in their specificity of the fatty acid chain length used for N-acylation (EFSA et al., 2018; Stiban et al., 2010; Tidhar and Futerman, 2013). The inhibition of CerS results in an increase of Sa, So, and, often, Sa/So ratio. Among others, two possible effects of CerS inhibition are 1) a decrease in the level of ceramides and complex sphingolipids (Riley and Merrill, 2019) and 2) an increase in the phosphorylated forms of Sa and So (Gelineau-van Waes et al., 2012).

EFSA, Knutsen, H.K., Barregård, L., Bignami, M., Brüschweiler, B., Ceccatelli, S., Cottrill, B., Dinovi, M., Edler, L., Grasl-Kraupp, B., Hogstrand, C., Hoogenboom, L. (Ron), Nebbia, C.S., Petersen, A., Rose, M., Roudot, A.C., Schwerdtle, T., Vleminckx, C., Vollmer, G., Wallace, H., Dall’Asta, C., Gutleb, A.C., Humpf, H.U., Galli, C., Metzler, M., Oswald, I.P., Parent-Massin, D., Binaglia, M., Steinkellner, H., Alexander, J., 2018. Appropriateness to set a group health-based guidance value for fumonisins and their modified forms. EFSA J. 16. https://doi.org/10.2903/j.efsa.2018.5172 Gelineau-van Waes, J., Rainey, M.A., Maddox, J.R., Voss, K.A., Sachs, A.J., Gardner, N.M., Wilberding, J.D., Riley, R.T., 2012. Increased sphingoid base-1-phosphates and failure of neural tube closure after exposure to fumonisin or FTY720. Birth Defects Res. Part A - Clin. Mol. Teratol. 94, 790–803. https://doi.org/10.1002/bdra.23074 Riley, R.T., Merrill, A.H., 2019. Ceramide synthase inhibition by fumonisins: A perfect storm of perturbed sphingolipid metabolism, signaling, and disease. J. Lipid Res. 60, 1183–1189. https://doi.org/10.1194/jlr.S093815 Sassa, T., Hirayama, T., Kihara, A., 2016. Enzyme activities of the ceramide synthases CERS2-6 are regulated by phosphorylation in the C-terminal region. J. Biol. Chem. 291, 7477–7487. https://doi.org/10.1074/jbc.M115.695858 Stiban, J., Tidhar, R., Futerman, A.H., 2010. Ceramide synthases: Roles in cell physiology and signaling. Adv. Exp. Med. Biol. 688, 60–71. https://doi.org/10.1007/978-1-4419-6741-1_4 Tidhar, R., Futerman, A.H., 2013. The complexity of sphingolipid biosynthesis in the endoplasmic reticulum. Biochim. Biophys. Acta - Mol. Cell Res. 1833, 2511–2518. https://doi.org/10.1016/j.bbamcr.2013.04.010 AOPWiki 2022-07-14T09:20:48

2022-07-19T06:16:05

Reduced complex sphingolipids

Cellular

Complex sphingolipids are derived from ceramide and have a rather large structural diversity. They inlude, for example, sphingomyelin (SM) and glycosphingolipids such as gangliosides (GM), and are essential constituents or eukaryotic membranes (Kolter and Sandhoff, 2006). Considering their biologically relevant role as components of the cell membrane and thus basal functioning of cells, a decrease in sphingolipids may result in a variety of adverse effecfts. For example, sphinoglipids have been assigned a role in the pathogenesis of various metabolic diseases (sphingolipidoses), myocardial infarction, hypertension and diabetis mellitus (Borodzicz et al., 2015; Kolter and Sandhoff, 2006).

Borodzicz, S., Czarzasta, K., Kuch, M., Cudnoch-Jedrzejewska, A., 2015. Sphingolipids in cardiovascular diseases and metabolic disorders. Lipids Health Dis. 14, 1–8. https://doi.org/10.1186/s12944-015-0053-y Kolter, T., Sandhoff, K., 2006. Sphingolipid metabolism diseases. Biochim. Biophys. Acta - Biomembr. 1758, 2057–2079. https://doi.org/10.1016/j.bbamem.2006.05.027 AOPWiki 2022-07-14T09:22:04

2022-07-19T06:29:16

Affected folate transporter

Cellular

AOPWiki 2022-07-14T09:23:03

2022-07-14T09:23:03

decreased folate uptake

decrease folate

Cellular

AOPWiki 2022-07-14T09:23:47

2022-07-14T09:23:47

Increased sphingolipid-1-phosphate

Increased S1-P

Cellular

AOPWiki 2022-07-19T05:43:52

2022-07-19T05:43:52

Histone deacetylase inhibition

Molecular

Nucleosomes consist of eight core histones, two of each histone H2A, H2B, H3, and H4 [Damaskos et al., 2017]. DNA strands (about 200 bp) wind around the core histones, which can be modified on their N-terminal ends. One possible modification is the acetylation of lysine residues, which decreases the binding strength between DNA and the core histone. Histone deacetylases (HDACs) hydrolyze the acetyl residues [Damaskos et al., 2017]. HDACs remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Thus, the inhibition of HDAC blocks this action and can result in hyperacetylation of histones associated mostly with increases in transcriptional activation. Histone deacetylase inhibitor (HDI) inhibits HDAC, causing increased acetylation of the histones and thereby facilitating binding of transcription factors [Taunton et al., 1996]. It is known that eukaryotic HDAC isoforms are classified into four classes: class I HDACs (isoforms 1, 2, 3, 8), class II HDACs (isoforms 4, 5, 6, 7, 9, 10), class III HDACs (the sirtuins), and HDAC11 [Gregoretti et al., 2004; Weichert, 2009; Barneda-Zahonero and Parra, 2012]. HDACs 1, 2, and 3 are ubiquitously expressed, whereas HDAC8 is predominantly expressed in cells with smooth muscle/myoepithelial differentiation [Weichert, 2009]. HDAC6 is not observed to be expressed in lymphocytes, stromal cells, and vascular endothelial cells [Weichert, 2009]. Class III HDACs, sirtuins, are widely expressed and localized in different cellular compartments [Barneda-Zahonero and Parra, 2012]. SirT1 is highly expressed in testis, thymus, and multiple types of germ cells [Bell et al., 2014]. HDAC11 expression is enriched in the kidney, brain, testis, heart, and skeletal muscle [Barneda-Zahonero and Parra, 2012]. The members of classes 1, 2, and 4 are dependent on a zinc ion and a water molecule at their active sites, for their deacetylase function. The Sirtuins of class 3 depend on NAD+ and are considered impervious to most known HDAC inhibitors [Drummond et al., 2005]. Several structurally distinct groups of compounds have been found to inhibit HDACs of class 1, 2, and 4, among others short-chain fatty acids (e.g. butyrate and VPA), hydroxamic acids (e.g. TSA and SAHA), and epoxyketones (e.g. Trapoxin) [Drummond et al., 2005]. The hydroxamic acids seem to exert their inhibitory action by mimicking the acetyl-lysine target of HDACs, chelating the zinc ion in the active site, and displacing the water molecule [Finnin et al., 1999]. Several high-resolution crystal structures support this mode of inhibition [Decroos et al., 2015; Luckhurst et al., 2016]. The mode of inhibition of epoxyketones seems to function in the formation of a stable transition state analog with the zinc ion in the active site [Porter and Christianson, 2017]. The inhibitory actions of the short-chain fatty acids are less well defined, but it has been speculated that VPA blocks access to the binding pocket [Göttlicher et al., 2001]. It has been shown that VPA exerts similar gene regulatory effects to TSA, on a panel of migration-related transcripts in neural crest cells [Dreser et al., 2015], supporting a mode of action similar to hydroxamic-acid type HDAC inhibitors. Some in silico methods including molecular modeling, virtual screening, and molecular dynamics are used to find the common HDAC inhibitor structures [Huang et al., 2016; Yanuar et al. 2016].

The measurement of HDAC inhibition monitors changes in histone acetylation. HDAC inhibition can be detected directly by the measurement of HDAC activity using commercially available colorimetric or fluorimetric kits or indirectly by the increase of histone acetylation as the detection of global histone acetylation changes by Western blot or mass spectrometry (MS)-based proteomics methods or as detection of site-specific histone acetylation changes using chromatin immunoprecipitation (ChIP) or ChIP-on-Chip. The measurement methods include the immunological detection of histone acetylation with anti-acetylated histone antibodies [Richon et al., 2004]. The histones are isolated from pellets of cells treated with HDIs, followed by acid-urea-triton gel electrophoresis, western blotting, and immunohistochemistry [Richon et al., 2003]. The HDAC activity is measured directly with ultra-high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UHPLC-ESI-MS/MS) by calculating the ratio of deacetylated peptide and acetylated peptide [Zwick et al., 2016]. HDAC inhibition can be predicted by perturbations in gene expression patterns as well; an 81-gene transcriptomic biomarker of HDAC inhibition, called TGx-HDACi, has shown to accurately predict HDAC inhibition after 4 hour exposures to HDI in TK6 human lymphoblastoid cells [Cho et al., 2021].

The inhibition of HDAC by HDIs is well conserved between species from lower organisms to mammals. <ul> <li>HDAC inhibition restores the rate of resorption of subretinal blebs in hyperglycemia in brown Norway rat and HDAC activity was inhibited with HDIs in human ARPE19 cells [Desjardins et al., 2016].</li> <li>Treatment of HDIs inducing HDAC inhibition showed anti-tumor effects in human non-small cell lung cancer cells [Ansari et al., 2016; Miyanaga et al., 2008].</li> <li>HDAC acetylation level was increased by HDIs in the MRL-lpr/lpr murine model of lupus splenocytes [Mishra et al., 2003].</li> <li>SAHA increased histone acetylation in the brain and spleen of mice [Hockly et al., 2003].</li> <li>MAA inhibits HDAC activity in HeLa cells and spleens from C57BL/6 mice [Jansen et al., 2004].</li> <li>It is also reported that MAA inhibits HDAC activity in testis cytosolic and nuclear extract of juvenile rats (27 days old) [Wade et al., 2008].</li> <li>VPA and TSA inhibit HDAC enzymatic activity in the mouse embryo and human HeLa cell nuclear extract [Di Renzo et al., 2007].</li> <li>The treatment with HDAC inhibitors, phenylbutyrate (PB) (2 mM) and TSA (200 nM), inhibits HDAC in adjuvant arthritis synovial cells derived from rats, causing higher acetylated histone [Chung et al., 2003].</li> </ul>

UBERON:0000062

UBERON organ

CL:0000000

CL cell

High Unspecific

Moderate

All life stages

High High High

Ansari, J. et al. (2016), "Epigenetics in non-small cell lung cancer: from basics to therapeutics", Transl Lung Cancer Res 5:155-171 Barneda-Zahonero, B. and Parra, M. (2012), "Histone deacetylases and cancer", Mol Oncol 6:579-589 Bell, E.L. et al. (2014), "SirT1 is required in the male germ cell for differentiation and fecundity in mice", Development 141:3495-3504 Cho, E. et al. (2021), "Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells", Arch Toxicol 95:1631–1645 Chung, Y.L. et al. (2003), "A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis", Mol Ther 8:707-717 Damaskos, C. et al. (2016), "Histone deacetylase inhibitors: a novel therapeutic weapon against medullary thyroid cancer?", Anticancer Res 36:5019-5024 Damaskos, C. et al. (2017), "Histone deacetylase inhibitors: an attractive therapeutic strategy against breast cancer", Anticancer Research 37:35-46 Decroos, C. et al. (2015), "Biochemical and structural characterization of HDAC8 mutants associated with cornelia de lange syndrome spectrum disorders", Biochemistry 54:6501–6513 Desjardins, D. et al. (2016), "Histone deacetylase inhibition restores retinal pigment epithelium function in hyperglycemia", PLoS ONE 11:e0162596 Di Renzo, F. et al. (2007), "Boric acid inhibits embryonic histone deacetylases: A suggested mechanism to explain boric acid-related teratogenicity", Toxicol and Appl Pharmacol 220:178-185 Dreser, N. et al. (2015), "Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling", Neurotoxicology 50:56–70 Drummond, D.C. et al. (2005), "Clinical development of histone deacetylase inhibitors as anticancer agents", Annu Rev Pharmacol Toxicol 45:495–528 Finnin, M.S. et al. (1999), "Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors", Nature 401:188–193 Göttlicher, M. et al. (2001), "Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells", EMBO J 20:6969–6978 Gregoretti, I.V. et al. (2004), "Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis", J Mol Biol 338:17–31 Hockly, E. et al. (2003), "Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease", Proc Nat Acad Sci 100:2041-2046 Hu, E. et al. (2003), "Identification of novel isoform-selective inhibitors within class I histone deacetylases", J Pharmacol Exp Ther 307:720-728 Huang, Y.X. et al. (2016), "Virtual screening and experimental validation of novel histone deacetylase inhibitors", BMC Pharmacol Toxicol 17(1):32 Jansen, M.S. et al. (2014), "Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition", Proc Natl Acad Sci USA 101(18):7199-7204 Luckhurst, C.A. et al. (2016), "Potent, Selective, and CNS-Penetrant Tetrasubstituted Cyclopropane Class IIa Histone Deacetylase (HDAC) Inhibitors", ACS Med Chem Lett 7:34–39 Mishra, N. et al. (2003), "Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse", J Clin Invest 111:539-552 Miyanaga, A. et al. (2008), "Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model", Mol Cancer Ther 7:1923-1930 Ooi, J.Y.Y., et al. (2015), “HDAC inhibition attenuates cardiac hypertrophy by acetylation and deacetylation of target genes”, Epigenetics 10:418-430 Park M.J. and Sohrabi F. (2016), “The histone deacetylase inhibitor, sodium butyrate, exhibits neuroprotective effects for ischemic stroke in middle-aged female rats”, J Neuroinflammation 13:300 Porter, N.J., and Christianson, D.W. (2017), "Binding of the microbial cyclic tetrapeptide trapoxin A to the Class I histone deacetylase HDAC8", ACS Chem Biol 12:2281–2286 Richon, V.M. et al. (2003), "Histone deacetylase inhibitors: assays to assess effectiveness in vitro and in vivo", Methods Enzymol. 376:199-205 Ropero, S. and Esteller, M. (2007), "The role of histone deacetylases (HDACs) in human cancer", Mol Oncol 1:19-25 Sekhavat, A. et al. (2007), "Competitive inhibition of histone deacetylase activity by trichostatin A and butyrate", Biochemistry and Cell Biology 85:751-758 Taunton, J. et al. (1996), "A mammalian histone deacetylase related to the Yeast transcriptional regulator Rpd3p", Science 272:408-411 Villar-Garea, A. and Esteller, M. (2004), "Histone deacetylase inhibitors: understanding a new wave of anticancer agents", Int J Cancer 112:171-178 Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831 Wagner F.F. et al. (2015), “Kinetically selective inhibitors of histone deacetylase 2 (HDAC2) as cognition enhances”, Chem Sci 6:804 Weichert, W. (2009) "HDAC expression and clinical prognosis in human malignancies", Cancer Letters 280:168-176 Yanuar, A. et al. (2016), "In silico approach to finding new active compounds from histone deacetylase (HDAC) family", Curr Pharm Des 22:3488-3497 Zwick, V. et al. (2016), "Cell-based multi-substrate assay coupled to UHPLC-ESI-MS/MS for a quick identification of class-specific HDAC inhibitors", J Enzyme Inhib Med Chem 31:209-214 AOPWiki 2018-01-21T20:07:19

2022-07-14T16:18:05

Neural tube defects

Tissue

Wrongly differentiated cells may not be able to perform the process of neural tube closure.

In vitro assays that follow rosettes formation In vivo animal models

AOPWiki 2018-12-20T08:31:33

2018-12-20T08:40:30

<upstream-id>41f4d705-06ee-455b-bddf-acf3f2a6b3f5</upstream-id> <downstream-id>0e92febd-3bba-48c7-87d6-23d3d2b54dad</downstream-id>

Ceramide synthases (CerS) inhibition primarily results in accumulation of sphingoid bases and a decrease in levels of ceramides, which are the precursors of complex sphingolipids (for review, see Futerman and Hannun, 2004; Mullen et al., 2011). It is therefore highly plausible that the inhibition of ceramide synthase would result in a decrease in levels of complex sphingolipids.

Several studies report decrease in glycosphingolipids and SM after CerS inhibition, using mostly FB1 as an inhibitor of CerS (for example, Babenko and Kharchenko, 2015; Merrill et al., 1993; Stevens and Tang, 1997).

it remains to be determined whether there are differences between different complex glycosphingolipids (e.g., sphingomyelin, gangliosides, etc.) - are some more impacted and/or more essential for the downstream events than the others?

metabolism on insulin-induced glucose uptake and glycogen synthesis in liver cells of old rats. Biochem. 80, 104–112. https://doi.org/10.1134/S0006297915010125 Futerman, A.H., Hannun, Y.A., 2004. The complex life of simple sphingolipids. EMBO Rep. 5, 777–782. https://doi.org/10.1038/sj.embor.7400208 Merrill, A.H., Van Echten, G., Wang, E., Sandhoff, K., 1993. Fumonisin B1 inhibits sphingosine (sphinganine) N-acyltransferase and de novo sphingolipid biosynthesis in cultured neurons in situ. J. Biol. Chem. 268, 27299–27306. https://doi.org/10.1016/s0021-9258(19)74249-5 Mullen, T.D., Jenkins, R.W., Clarke, C.J., Bielawski, J., Hannun, Y.A., Obeid, L.M., 2011. Ceramide synthase-dependent ceramide generation and programmed cell death: Involvement of salvage pathway in regulating postmitochondrial events. J. Biol. Chem. 286, 15929–15942. https://doi.org/10.1074/jbc.M111.230870 Stevens, V.L., Tang, J., 1997. Fumonisin B1-induced sphingolipid depletion inhibits vitamin uptake via the glycosylphosphatidylinositol-anchored folate receptor. J. Biol. Chem. 272, 18020–18025. https://doi.org/10.1074/jbc.272.29.18020 AOPWiki 2022-07-19T05:45:38

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Folate transporter Folbp1 is a GPI-anchored protein, and sphingolipids were shown to be involved in endocytic trafficking of GPI-anchored proteins (Chatterjee et al., 2001). Marasas and colleagues proposed that a depletion of sphingolipids (due to the inhibition of ceramide synthases) could alter membrane microdomains enriched in cholesterol and sphingolipids, also called lipid rafts, thereby affecting the folate transporter Folbp1 trafficking and folate amounts available in maternal blood as well as in embryonic tissues (Gelineau-Van Waes et al., 2005; Marasas et al., 2004). <div> <div>   </div> </div>

Chatterjee, S., Smith, E.R., Hanada, K., Stevens, V.L., Mayor, S., 2001. GPI anchoring leads to sphingolipid-dependent retention of endocytosed proteins in the recycling endosomal compartment. EMBO J. 20, 1583–1592. https://doi.org/10.1093/emboj/20.7.1583 Gelineau-Van Waes, J., Starr, L., Maddox, J., Aleman, F., Voss, K.A., Wilberding, J., Riley, R.T., 2005. Maternal fumonisin exposure and risk for neural tube defects: Mechanisms in an in vivo mouse model. Birth Defects Res. Part A - Clin. Mol. Teratol. 73, 487–497. https://doi.org/10.1002/bdra.20148 Marasas, W.F.O., Riley, R.T., Hendricks, K.A., Stevens, V.L., Sadler, T.W., Gelineau-van Waes, J., Missmer, S.A., Cabrera, J., Torres, O., Gelderblom, W.C.A., Allegood, J., Martínez, C., Maddox, J., Miller, J.D., Starr, L., Sullards, M.C., Roman, A.V., Voss, K.A., Wang, E., Merrill, A.H., 2004. Fumonisins Disrupt Sphingolipid Metabolism, Folate Transport, and Neural Tube Development in Embryo Culture and In Vivo: A Potential Risk Factor for Human Neural Tube Defects among Populations Consuming Fumonisin-Contaminated Maize. J. Nutr. 134, 711–716. https://doi.org/10.1093/jn/134.4.711 AOPWiki 2022-07-19T05:46:00

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Ceramide synthase inhibition leading to neural tube defects

CerS leads to NTDs

Lola Bajard

Lola Bajard1, Annick D. van den Brand2, Jochem Louisse3, Marcel J.B. Mengelers2, Alberto Mantovani4 1RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic 2Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands 3Wageningen Food Safety Research (WFSR), Wageningen, The Netherlands 4Istituto Superiore di Sanità (ISS), Rome, Italy

BY-SA

2.0

<a name="_Hlk106889805">Defects in neural tube formation during early embryogenesis are congenital malformations that may lead to morbidity or lethality </a>(Finnell et al., 2021; Isaković et al., 2022). The etiology of  neural tube defects (NTDs) is not fully understood, but many studies highlight the role of environmental factors, in addition to genetic risks (Finnell et al., 2021; Isaković et al., 2022). Higher incidence of NTDs was observed in regions where higher frequency of fumonisin FB1 in maize was also reported (Hendricks, 1999; Marasas et al., 2004; Moore et al., 1997). This circumstantial evidence suggests possible associations between FB1 exposure and NTDs, that are further supported by a case-control study in human and several animal studies (Gelineau-Van Waes et al., 2005; Marasas et al., 2004; Missmer et al., 2006; Voss et al., 2014). FB1 is a well established inhibitor of the ceramide synthase (CerS) (Wang et al., 1991), a central enzyme in sphingolipid metabolism. This AOP has therefore been developped to depict the key events leading from CerS inhibition and perturbations in sphingolipid metabolism to NTDs (van den Brand et al., 2022). It is largely based on the mode of action description in the EFSA Scientific opinion on fumonisins (EFSA et al., 2018) and proposes two routes. The first route involves effects on folate uptake - the role of folate in preventing NTDs is known and very well supported by many studies (Wahbeh and Manyama, 2021). The other route involves the inhibition of histone deacethylase (HDAC) - the key events leading from HDAC inhibition to NTDs are described in the AOP 275.

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High

<table cellspacing="0" class="MsoTable15List6Colorful" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:none; border-top:1px solid black; vertical-align:top; width:47px"> Type </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:none; border-top:1px solid black; vertical-align:top; width:151px"> Title </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:none; border-top:1px solid black; vertical-align:top; width:114px"> Essentiality </td> <td style="background-color:#f2f2f2; border-bottom:1px solid black; border-left:none; border-right:none; border-top:1px solid black; vertical-align:top; width:301px"> Evidence </td> </tr> <tr> <td style="background-color:#d0cece; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:47px"> MIE </td> <td style="background-color:#d0cece; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:151px"> Inhibition of ceramide synthases (Cers) </td> <td style="background-color:#d0cece; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:114px">   </td> <td style="background-color:#d0cece; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:301px">   </td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:47px"> KE </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:151px"> Reduced complex sphingolipids   </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:114px"> Moderate </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:301px"> Ganglioside supplementation rescues FB1-induced decrease in folate concentrations and increased incidence of exencephaly, in one mouse strain (LM/Bc). </td> </tr> <tr> <td style="background-color:#ededed; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:47px"> KE </td> <td style="background-color:#ededed; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:151px"> Increase sphingolipid-1-phosphatase   </td> <td style="background-color:#ededed; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:114px">   </td> <td style="background-color:#ededed; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:301px">   </td> </tr> <tr> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:47px"> KE </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:151px"> Affected folate transporter Folbp1   </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:114px">   </td> <td style="border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:301px">   </td> </tr> <tr> <td style="background-color:#e7e6e6; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:47px"> KE </td> <td style="background-color:#e7e6e6; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:151px"> Inhibition of histone deacetylase (HDAC) </td> <td style="background-color:#e7e6e6; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:114px">   </td> <td style="background-color:#e7e6e6; border-bottom:none; border-left:none; border-right:none; border-top:none; vertical-align:top; width:301px">   </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; vertical-align:top; width:47px"> KE </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; vertical-align:top; width:151px"> Decreased folate uptake </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; vertical-align:top; width:114px"> Moderate </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:none; border-top:none; vertical-align:top; width:301px"> Folate supplementation partially rescues FB1-induced NTDs in mice (Gelineau-van Waes, 2005) and mouse embryo culture, but not at the lowest FB1 dose (2uM) (Sadler, 2002) </td> </tr> </tbody> </table>

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AOPWiki 2022-05-02T07:15:38

2023-04-29T16:03:06