Serotonin and serotonin reuptake inhibitors alter placental aromatase

Thibeault, Andrée-Anne Hudon; Santos, Yossef López de los; Doucet, Nicolas; Sanderson, J. Thomas; Vaillancourt, Cathy

doi:10.1016/j.jsbmb.2019.105470

Cited by 13 publications

(8 citation statements)

References 78 publications

(108 reference statements)

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“…Prenatal SSRI exposure also tends to be associated with lower fetal-placental weight ratios and fetal vascular malperfusion, indicative of less efficient fetal blood flow to or from the placenta (22). Both of these factors indicate less efficient placental function in association with prenatal SSRI exposure, which may be related to downstream neonatal cognitive outcomes (22); SSRI exposure on the placenta has been previously reported to affect syncytializaton and extravillous trophoblast function, and to affect placental 5-HT levels (23–25). Taken together, the effect of SSRI exposure on pregnancy outcomes suggests an interplay between the placenta and SSRI pharmacobiology, which could occur by a variety of mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy

Inkster

Konwar

Peñaherrera

et al. 2022

Preprint

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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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Section: Introductionmentioning

confidence: 99%

Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy

Inkster

Konwar

Peñaherrera

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Both of these factors indicate less efficient placental function in association with prenatal SSRI exposure, which may be related to downstream neonatal cognitive outcomes 14 . Exposure to maternal SSRI treatment has previously been reported to affect syncytializaton of placental trophoblasts and extravillous trophoblast function, and to affect placental serotonin levels [15][16][17] . Taken together, the effect of SSRI exposure on pregnancy outcomes suggests an interplay between the placenta and SSRI pharmacobiology, which could occur by a variety of mechanisms.…”

mentioning

confidence: 99%

Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy

Inkster

Konwar

Peñaherrera

et al. 2022

Sci Rep

Self Cite

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Selective serotonin reuptake inhibitors (SSRIs) for treatment of prenatal maternal depression have been associated with neonatal neurobehavioral disturbances, though the molecular mechanisms remain poorly understood. In utero exposure to SSRIs may affect DNA methylation (DNAme) in the human placenta, an epigenetic mark that is established during development and is associated with gene expression. Chorionic villus samples from 64 human placentas were profiled with the Illumina MethylationEPIC BeadChip; clinical assessments of maternal mood and SSRI treatment records were collected at multiple time points during pregnancy. Case distribution was 20 SSRI-exposed cases and 44 SSRI non-exposed cases. Maternal depression was defined using a mean maternal Hamilton Depression score > 8 to indicate symptomatic depressed mood (“maternally-depressed”), and we 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). For replication, Illumina 450K DNAme profiles were obtained from 34 additional cases from an independent cohort (n = 17 SSRI-exposed, n = 17 SSRI non-exposed). No CpGs were differentially methylated at FDR < 0.05 comparing SSRI-exposed to non-exposed placentas, in a model adjusted for mean maternal Hamilton Depression score, or in a model restricted to maternally-depressed cases with and without SSRI exposure. However, at a relaxed threshold of FDR < 0.25, five CpGs were differentially methylated (|Δβ| > 0.03) by SSRI exposure status. Four were covered by the replication cohort measured by the 450K array, but none replicated. 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. We did not observe large-scale alterations of DNAme in placentas exposed to maternal SSRI treatment, as 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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“…One more role assigned to the HTR2A receptor in the human placenta relates to the regulation of placental estrogen production. Specifically, studies in human primary trophoblasts ( 106 ) as well as trophoblast-like cell lines (BeWo, JEG-3) ( 107 ) have shown that serotonin induces the expression and activity of aromatase CYP19, a key enzyme in placental estrogen synthesis, via activation of the HTR2A receptor. The observed increase in aromatase activity was induced by HTR2A-mediated stimulation of the protein kinase C pathway ( 107 ) and possibly the JAK2/STAT3 pathway ( 104 ).…”

Section: Serotonin System and Its Components In The Human Placentamentioning

confidence: 99%

“…Furthermore, studies in animals and humans suggest an interaction between sex hormones and the serotonin system. For example, estrogens modulate the synthesis, uptake and catabolism of serotonin ( 147 ), while changes in serotonin signaling have been reported to affect estrogen production ( 106 , 148 ). Overall, the influence of fetal sex needs to be considered in future studies of the function, regulation, and pathology-related changes of the serotonin system in the human placenta.…”

Section: Outlook - Future Perspectivesmentioning

confidence: 99%

Serotonin system in the human placenta – the knowns and unknowns

et al. 2022

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The biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) is a chemical messenger widely distributed in the brain and various other organs. Its homeostasis is maintained by the coordinated activity of a variety of proteins, including enzymes of serotonin metabolism, transmembrane transporters of serotonin, and serotonin receptors. The serotonin system has been identified also in the placenta in rodent models as a key component of placental physiology. However, serotonin pathways in the human placenta are far from well understood. Their alterations may have long-lasting consequences for the fetus that can manifest later in life. In this review, we summarize information on the location of the components of the serotonin system in the human placenta, their regulation, function, and alterations in pathological pregnancies. We highlight current controversies and discuss important topics for future research.

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Serotonin and serotonin reuptake inhibitors alter placental aromatase

Cited by 13 publications

References 78 publications

Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy

Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy

Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy

Serotonin system in the human placenta – the knowns and unknowns

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