One-point quantification of metabolite concentrations in the sample was calculated using the intensity ratio of endogenous metabolite to the internal standard and multiplied with the concentration of the internal standard (Marques et al., 2022).
"],"repository":["MetaboLights"],"study_status":["Public"],"ptm_modification":[""],"instrument_platform":["Direct infusion MS - positive"],"direct_infusion_protocol":["Untargeted metabolomic profiling was performed using the direct infusion probe (DIP) for ESI-MS (Marques et al., 2022). Please refer to the cited publication for further information about the methodology.
"],"publication":["Lysophosphatidylcholines are elevated after selective serotonin reuptake inhibitor exposure during neural differentiation and correlate with early neurodevelopmental symptoms. 10.1101/2025.05.30.25328657."],"submitter_name":["Abishek Arora"],"submitter_affiliation":["Karolinska Institutet"],"organism_part":["iPSC derived cell line","blank"],"technology_type":["mass spectrometry assay"],"disease":[""],"extraction_protocol":["The cell culture plates were stored at -80 °C prior to lysing with the electrospray solvent containing 9:1 methanol:water, with 0.1% formic acid and 28 internal standards. To enable comparisons, all cell samples were normalised to total cell counts per sample.
"],"organism":["blank","Homo sapiens"],"data_transformation_protocol":["The resulting data was extracted using 30 s data per sample and sorted in MZmine 2 (Pluskal et al., 2010).
"],"study_factor":["Cell line","Differentiation time","Sex","Exposure","Concentration"],"submitter_email":["abishek.arora@ki.se"],"metabolights_link":["https://www.ebi.ac.uk/metabolights/MTBLS12645"],"sample_collection_protocol":["Untargeted metabolomic profiling was performed using the direct infusion probe (DIP) for ESI-MS (Marques et al., 2022) on snap-frozen cells at day 5 (N=120) and day 28 (N=120) of SSRI exposures during neural differentiation of NES cells, with 2 biological replicates having 3 technical replicates each for the treated and untreated groups in all 4 cell lines: CTRLMale, CTRLFemale, ASDHNRNPU and ASDCASK. For the day 5 samples, the cells were exposed to 3.0 µM of fluoxetine hydrochloride (FH), citalopram hydrobromide (CH) and paroxetine hydrochloride (PH), and 1.5 µM of sertraline hydrochloride (SH), as per the previously determined concentrations based on the cytotoxicity assays. For the day 28 samples, the cells were exposed to a standardised dose of 1.5 µM to enable direct comparison of long-term exposure related metabolomic effects induced by each SSRI.
"],"omics_type":["Metabolomics"],"study_design":["Paroxetine","stem cell","Fluoxetine","untargeted metabolites","Sertraline","Citalopram"],"curator_keywords":["Paroxetine","stem cell","Fluoxetine","untargeted metabolites","Sertraline","Citalopram"],"mass_spectrometry_protocol":["The samples were analysed on a QExactive Orbitrap instrument (Thermo Scientific) at mass resolving power of 140,000 (m/∆m) using untargeted full scanning between 70 and 1000 Da in positive mode.
"],"metabolite_name":["FA 22:0","PE 42:9","FA 22:4","FA 22:3","PE 42:5","PE 46:1","PE 42:6","PE 42:7","PE 46:3","PE 42:8","Glucose","PE 42:4","PC e 40:5","PC e 40:4","Histidine","PE 30:1","LPC 18:2","PE 38:5","LPC 14:0","PE 38:4","PE 38:3","PE 38:2","Threonine","LPC 18:0","LPC 18:1","PE 38:7","PE 38:6","Methionine","PE 34:1","PC 28:0","PE 34:0","PC 28:1","PC e 40:7","PE 34:5","PE 38:1","PC e 40:6","PE 34:4","PC e 40:9","PE 34:3","PC e 40:8","PE 34:2","PC e 32:0","PC e 32:2","PC e 32:1","Lysine","PC 30:2","PC 30:3","PC 30:0","PC 30:1","PC e 38:6","PC 34:2","PC e 38:5","PC 34:3","PC e 38:8","PC 34:0","PC e 38:7","PC 34:1","PC 38:2","C16 Carnitine","PC e 34:5","PC 38:3","PE 42:11","PC e 38:4","PC 34:4","PC e 38:3","PC 38:1","PC 34:5","PC e 34:2","PC 38:6","Glycine","PC e 34:1","PC 38:7","PC e 34:4","PC 38:4","PC e 34:3","PC 38:5","PC e 40:10","Arginine","C4 Carnitine","FA 18:1","FA 18:0","FA 18:3","FA 18:2","Alanine","FA 10:0","Phenylalanine","PC 42:5","PC 42:6","PC 42:4","FA 14:0","Tryptophan","PC 42:9","PC 42:7","PC 42:8","PC e 26:0","Leucine/Isoleucine","PE 40:2","Valine","FA 22:6","Asparagine","FA 22:5","FA 20:0","C2 Carnitine","FA 20:2","FA 20:1","PE 44:7","FA 20:4","PE 44:8","FA 20:3","PE 44:9","FA 20:5","PE 40:7","PE 40:8","PE 40:9","Aspartic Acid","PE 40:3","PE 40:4","PE 40:5","PE 40:6","PE 44:10","PC e 42:10","Tyrosine","PE 36:6","PE 36:5","PE 36:4","PC 26:0","LPC 16:0","LPC 16:1","PE 32:2","PE 32:1","PE 32:0","PE 36:3","PC e 46:0","PE 36:2","PE 36:1","PC e 42:6","PE 36:0","Carnitine","Glutamic Acid","PC e 30:1","PC e 34:0","PC e 30:0","GABA","C3 Carnitine","PC 32:0","PC 32:1","LPC 20:3","PC 44:10","LPC 20:4","PC 32:4","PC e 36:7","PC 36:1","Serine","PC 32:2","PC 32:3","Proline","PC e 36:4","PC 36:4","PC e 36:3","PC 36:5","PC e 36:6","PC 36:2","PC e 36:5","PC 36:3","LPC 20:1","LPC 20:2","PC e 36:2","PC 36:6","PC e 36:1","PC 36:7","FA 16:1","FA 16:0","PC 40:3","PC 40:4","PC 40:2","PC 40:7","PC 40:8","FA 12:0","PC 40:5","PC 44:1","PC 40:6","PC e 28:0","PC 44:7","PC 44:8","PC 44:6","PC 44:9","C18:1 Carnitine","C5 Carnitine","Glutamine"],"additional_accession":[]},"is_claimable":false,"name":"Elevated lysophosphatidylcholines during SSRI-induced neural differentiation correlate with early neurodevelopmental symptoms","description":"Background: Selective serotonin reuptake inhibitors (SSRIs) are often prescribed during pregnancy. Yet, epidemiological studies link in-utero SSRI exposure with neurodevelopmental disorders, such as autism and ADHD. The potential molecular mechanisms by which SSRIs impact early neurodevelopment are not fully understood.
Methods: We exposed neuroepithelial stem cells derived from four human induced pluripotent stem cells lines to fluoxetine, citalopram, sertraline, and paroxetine. We then assessed cellular viability, reactive oxygen species (ROS) levels, mitochondrial function using adenosine triphosphate (ATP) assays, and performed high-throughput metabolomics at two timepoints: proliferation and neural differentiation stages. The key metabolic findings were validated in the in-vitro model and in a complementary population-based cohort, the Barwon Infant Study, consisting of 1074 mother-child pairs with analysed cord-blood metabolomes.
Findings: Sertraline and paroxetine significantly decreased ROS and ATP levels, indicating mitochondrial alteration. Metabolomic profiling revealed consistent elevation of three lysophosphatidylcholines (LPCs 16:0, 18:0, 18:1) across all SSRIs except citalopram. We further observed elevated LPC levels in the cord blood of infants prenatally exposed to SSRIs, with a dose-dependent correlation to autism and ADHD-related symptoms at age two. Furthermore, the three LPCs modulated ROS and ATP levels in the neural cells.
Interpretation: These findings provide insights into SSRI-induced molecular changes, highlight candidate metabolites that may warrant further investigation as indicators of SSRI exposure, and emphasise the need for exploring prenatal SSRI exposure effects and neurodevelopmental outcomes.
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