TY - JOUR
T1 - Antidepressant Paroxetine Exerts Developmental Neurotoxicity in an iPSC-Derived 3D Human Brain Model
AU - Zhong, Xiali
AU - Harris, Georgina
AU - Smirnova, Lena
AU - Zufferey, Valentin
AU - Sá, Rita de Cássia da Silveira e.
AU - Baldino Russo, Fabiele
AU - Baleeiro Beltrao Braga, Patricia Cristina
AU - Chesnut, Megan
AU - Zurich, Marie Gabrielle
AU - Hogberg, Helena T.
AU - Hartung, Thomas
AU - Pamies, David
N1 - Funding Information:
The iPS2C1 line was developed with support from the National Institute of Mental Health (NIMH; MH099427) and kindly provided by Dr. Herbert Lachman (Albert Einstein College of Medicine). The study was supported by funding from the European Commission Horizon 2020 research and innovation program (grant No. 487 681002).
Funding Information:
Funding. The iPS2C1 line was developed with support from the National Institute of Mental Health (NIMH; MH099427) and kindly provided by Dr. Herbert Lachman (Albert Einstein College of Medicine). The study was supported by funding from the European Commission Horizon 2020 research and innovation program (grant No. 487 681002).
Publisher Copyright:
© Copyright © 2020 Zhong, Harris, Smirnova, Zufferey, Sá, Baldino Russo, Baleeiro Beltrao Braga, Chesnut, Zurich, Hogberg, Hartung and Pamies.
PY - 2020/2/21
Y1 - 2020/2/21
N2 - Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat depression during pregnancy. Various concerns have been raised about the possible effects of these drugs on fetal development. Current developmental neurotoxicity (DNT) testing conducted in rodents is expensive, time-consuming, and does not necessarily represent human pathophysiology. A human, in vitro testing battery to cover key events of brain development, could potentially overcome these challenges. In this study, we assess the DNT of paroxetine—a widely used SSRI which has shown contradictory evidence regarding effects on human brain development using a versatile, organotypic human induced pluripotent stem cell (iPSC)-derived brain model (BrainSpheres). At therapeutic blood concentrations, which lie between 20 and 60 ng/ml, Paroxetine led to an 80% decrease in the expression of synaptic markers, a 60% decrease in neurite outgrowth and a 40–75% decrease in the overall oligodendrocyte cell population, compared to controls. These results were consistently shown in two different iPSC lines and indicate that relevant therapeutic concentrations of Paroxetine induce brain cell development abnormalities which could lead to adverse effects.
AB - Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat depression during pregnancy. Various concerns have been raised about the possible effects of these drugs on fetal development. Current developmental neurotoxicity (DNT) testing conducted in rodents is expensive, time-consuming, and does not necessarily represent human pathophysiology. A human, in vitro testing battery to cover key events of brain development, could potentially overcome these challenges. In this study, we assess the DNT of paroxetine—a widely used SSRI which has shown contradictory evidence regarding effects on human brain development using a versatile, organotypic human induced pluripotent stem cell (iPSC)-derived brain model (BrainSpheres). At therapeutic blood concentrations, which lie between 20 and 60 ng/ml, Paroxetine led to an 80% decrease in the expression of synaptic markers, a 60% decrease in neurite outgrowth and a 40–75% decrease in the overall oligodendrocyte cell population, compared to controls. These results were consistently shown in two different iPSC lines and indicate that relevant therapeutic concentrations of Paroxetine induce brain cell development abnormalities which could lead to adverse effects.
KW - 3D
KW - SSRI
KW - developmental neurotoxicity
KW - iPSC
KW - neurotoxicity
KW - organoid
KW - paroxetine
UR - http://www.scopus.com/inward/record.url?scp=85081205771&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85081205771&partnerID=8YFLogxK
U2 - 10.3389/fncel.2020.00025
DO - 10.3389/fncel.2020.00025
M3 - Article
C2 - 32153365
AN - SCOPUS:85081205771
SN - 1662-5102
VL - 14
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
M1 - 25
ER -