Prenatal paroxetine dysregulates monoamine homeostasis and affects placental hemodynamics in the rat fetoplacental unit

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F25%3A10505094" target="_blank" >RIV/00216208:11160/25:10505094 - isvavai.cz</a>

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=EC64Ddrh.c" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=EC64Ddrh.c</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.biopha.2025.118680" target="_blank" >10.1016/j.biopha.2025.118680</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Prenatal paroxetine dysregulates monoamine homeostasis and affects placental hemodynamics in the rat fetoplacental unit

Popis výsledku v původním jazyce

Antidepressant use during pregnancy is increasingly common, with selective serotonin reuptake inhibitors (SSRIs) widely prescribed for maternal depression. However, growing evidence links prenatal SSRI exposure to adverse outcomes, including impaired placental functions, disrupted fetal development, and long-term neurobehavioral risks. Monoamines such as serotonin, dopamine, and norepinephrine are critical regulators of placental vascular tone, fetal programming, and neurodevelopment, making them highly susceptible to pharmacological disruption. Here, we investigated the effects of prenatal paroxetine on monoamine regulation, metabolite profiles, and fetoplacental hemodynamics in a pregnant rat model. Paroxetine was administered orally at two doses, 15 mg/kg (n = 10) or 50 mg/kg (n = 7) and compared to controls (n = 6). Gene expression of monoamine-related transporters and enzymes was quantified in placenta and fetal brain by qRT-PCR. Placental and fetal brain metabolomes were assessed via LC-MS, and Doppler ultrasound was used to evaluate uterine and fetal vascular parameters. At 15 mg/kg, paroxetine reduced fetal (2.03 +- 1.10 g vs. 2.27 +- 0.92 g) and placental weights (0.35 +- 0.08 g vs. 0.46 +- 0.05 g), downregulated placental expression of serotonin, dopamine, and norepinephrine transporters, disrupted tryptophan metabolism, and increased vascular resistance in umbilical arteries (2.10 +- 0.21 vs. 1.85 +- 0.05). Surprisingly, the 50 mg/kg dose attenuated many of these effects, suggesting non-linear pharmacological response, potentially due to transporter saturation and/or receptor desensitization. Importantly, gene expression and hemodynamic effects were consistent across sexes. These findings provide novel mechanistic insights into the impact of SSRIs on placental function and fetal development, underscoring the complexity of their pharmacokinetics and pharmacodynamics during pregnancy and emphasizing the need for careful dose consideration during pregnancy.

Název v anglickém jazyce

Prenatal paroxetine dysregulates monoamine homeostasis and affects placental hemodynamics in the rat fetoplacental unit

Popis výsledku anglicky

Antidepressant use during pregnancy is increasingly common, with selective serotonin reuptake inhibitors (SSRIs) widely prescribed for maternal depression. However, growing evidence links prenatal SSRI exposure to adverse outcomes, including impaired placental functions, disrupted fetal development, and long-term neurobehavioral risks. Monoamines such as serotonin, dopamine, and norepinephrine are critical regulators of placental vascular tone, fetal programming, and neurodevelopment, making them highly susceptible to pharmacological disruption. Here, we investigated the effects of prenatal paroxetine on monoamine regulation, metabolite profiles, and fetoplacental hemodynamics in a pregnant rat model. Paroxetine was administered orally at two doses, 15 mg/kg (n = 10) or 50 mg/kg (n = 7) and compared to controls (n = 6). Gene expression of monoamine-related transporters and enzymes was quantified in placenta and fetal brain by qRT-PCR. Placental and fetal brain metabolomes were assessed via LC-MS, and Doppler ultrasound was used to evaluate uterine and fetal vascular parameters. At 15 mg/kg, paroxetine reduced fetal (2.03 +- 1.10 g vs. 2.27 +- 0.92 g) and placental weights (0.35 +- 0.08 g vs. 0.46 +- 0.05 g), downregulated placental expression of serotonin, dopamine, and norepinephrine transporters, disrupted tryptophan metabolism, and increased vascular resistance in umbilical arteries (2.10 +- 0.21 vs. 1.85 +- 0.05). Surprisingly, the 50 mg/kg dose attenuated many of these effects, suggesting non-linear pharmacological response, potentially due to transporter saturation and/or receptor desensitization. Importantly, gene expression and hemodynamic effects were consistent across sexes. These findings provide novel mechanistic insights into the impact of SSRIs on placental function and fetal development, underscoring the complexity of their pharmacokinetics and pharmacodynamics during pregnancy and emphasizing the need for careful dose consideration during pregnancy.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biomedicine &amp; Pharmacotherapy

ISSN

0753-3322

e-ISSN

1950-6007

Svazek periodika

192

Číslo periodika v rámci svazku

November

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

11

Strana od-do

118680

Kód UT WoS článku

999

EID výsledku v databázi Scopus

2-s2.0-105020878919