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Persistent and Dose-Dependent Neural and Metabolic Gene Expression Changes Induced by Transient Citalopram Exposure in Zebrafish

ABSTRACT: Citalopram, a common selective serotonin reuptake inhibitor (SSRI), has been increasingly detected in aquatic environments due to ineffective removal and improper disposal. Although developmental exposure to SSRIs is linked to neurotoxicity, little is known about the persistence of gene expression alterations following limited exposure periods. Zebrafish embryos were exposed from 2 to 24 hours post-fertilization (hpf) at concentrations of citalopram hydrobromide spanning surface water to therapeutic serum levels (0.03, 0.9, 50, and 250 µg/L), followed by removal of the citalopram and development until 48 hpf. Whole-embryo RNA sequencing at 48 hpf revealed a non-linear dose–response wherein the lowest dose resulted in the induction of the highest number of differentially expressed genes (DEGs). Gene set enrichment analyses (GSEA) and overrepresentation analyses (ORA) showed that 0.03 µg/L citalopram caused upregulation of metabolic and developmental pathway genes, but suppressed synaptic membrane genes, whereas 0.9 µg/L resulted in strong downregulation of key neurotransmitter receptors. At 50 µg/L, genes linked to oxidative stress (glutathione metabolism and ferroptosis) were upregulated, and at 250 µg/L, stress and apoptotic processes were increased, while glutamate receptor genes were repressed. All four citalopram doses suggested synaptic and neurotransmitter alterations, implying that persistent neurodevelopmental impacts resulted from a limited early window of exposure. These data highlight that transient, low-level SSRI exposures shape long-term embryonic gene expression.

ORGANISM(S): Danio rerio

PROVIDER: GSE308723 | GEO | 2025/12/17

REPOSITORIES: GEO

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Project description:Background: Selective serotonin reuptake inhibitors (SSRIs), used to treat prenatal maternal depression, have been associated with neurobehavioral disturbances in exposed neonates, though the underlying molecular mechanisms remain poorly understood. In utero exposure to SSRIs may have an effect on DNA methylation (DNAme) in the human placenta, which is an epigenetic mark that is established during development and is associated with gene expression. Methods: Chorionic villus samples from 64 human placentas were profiled with the Illumina MethylationEPIC BeadChip and clinical assessments of maternal mood were collected at multiple time points during pregnancy. Case distribution was 20 SSRI-exposed cases and 44 SSRI non-exposed cases. Maternal depression using a mean maternal Hamilton Depression score >8 to indicate symptomatic depressed mood (“maternally-depressed”) further classified cases into SSRI-exposed, maternally-depressed (n=14); SSRI-exposed, not maternally-depressed (n=6); SSRI non-exposed, maternally-depressed (n=20); and SSRI non-exposed, not maternally-depressed (n=24). To provide a replication cohort, Illumina 450K DNAme profiles were obtained from 34 additional cases from an independent cohort (n=17 SSRI-exposed, n=17 SSRI non-exposed). Results: No CpGs were differentially methylated at FDR < 0.05 comparing SSRI-exposed to non-exposed placentas, while adjusting for mean maternal Hamilton Depression score, nor comparing SSRI-exposed maternally-depressed to SSRI-non-exposed maternally-depressed cases. At a relaxed threshold of FDR < 0.25, five CpGs were differentially methylated (|Δβ| > 0.03) by SSRI exposure status. Four of these CpGs were covered by the 450K array and were examined in the replication cohort, but none replicated. Amongst SSRI non-exposed cases, No CpGs were differentially methylated (FDR < 0.25) comparing maternally depressed to not depressed cases. In sex-stratified analyses for SSRI-exposed versus non-exposed cases (females n=31; males n=33), three additional CpGs in females, but none in males, were differentially methylated at the relaxed FDR < 0.25 cut-off. Conclusions: We did not observe large-scale alterations of DNAme in placentas exposed to maternal SSRI treatment compared to placentas with no SSRI exposure. We also found no evidence for altered DNAme in maternal depression-exposed versus depression non-exposed placentas. This novel work in a prospectively-recruited cohort with clinician-ascertained SSRI exposure and mood assessments would benefit from future replication.

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Persistent and Dose-Dependent Neural and Metabolic Gene Expression Changes Induced by Transient Citalopram Exposure in Zebrafish

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