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© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Introduction: Children with fetal alcohol spectrum disorders (FASD) exhibit behavioral and affective dysregulation, including hyperactivity and depression. The mechanisms are not known, but they could conceivably be due to postnatal social or environmental factors. However, we postulate that, more likely, the affective dysregulation is associated with the effects of EtOH exposure on the development of fetal serotonergic (5-HT) and/or dopaminergic (DA) pathways, i.e., pathways that in postnatal life are believed to regulate mood. Many women who use alcohol (ethanol, EtOH) during pregnancy suffer from depression and take selective serotonin reuptake inhibitors (SSRIs), which might influence these monoaminergic pathways in the fetus. Alternatively, monoaminergic pathway abnormalities might reflect a direct effect of EtOH on the fetal brain. To distinguish between these possibilities, we measured their expressions in fetal brains and in fetal brain-derived exosomes (FB-Es) isolated from the mothers’ blood. We hypothesized that maternal use of EtOH and/or SSRIs during pregnancy would be associated with impaired fetal neural development, detectable as abnormal levels of monoaminergic and apoptotic biomarkers in FB-Es. Methods: Fetal brain tissues and maternal blood were collected at 9–23 weeks of pregnancy. EtOH groups were compared with unexposed controls matched for gestational age (GA). The expression of 84 genes associated with the DA and 5-HT pathways was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) on microarrays. FB-Es also were assayed for serotonin transporter protein (SERT) and brain-derived neurotrophic factor (BDNF) by enzyme-linked immunosorbent assay (ELISA). Results: Six EtOH-exposed human fetal brain samples were compared to SSRI- or polydrug-exposed samples and to unexposed controls. EtOH exposure was associated with significant upregulation of DA receptor D3 and 5-HT receptor HTR2C, while HTR3A was downregulated. Monoamine oxidase A (MAOA), MAOB, the serine/threonine kinase AKT3, and caspase-3 were upregulated, while mitogen-activated protein kinase 1 (MAPK1) and AKT2 were downregulated. ETOH was associated with significant upregulation of the DA transporter gene, while SERT was downregulated. There were significant correlations between EtOH exposure and (a) caspase-3 activation, (b) reduced SERT protein levels, and (c) reduced BDNF levels. SSRI exposure independently increased caspase-3 activity and downregulated SERT and BDNF. Early exposure to EtOH and SSRI together was associated synergistically with a significant upregulation of caspase-3 and a significant downregulation of SERT and BDNF. Reduced SERT and BDNF levels were strongly correlated with a reduction in eye diameter, a somatic manifestation of FASD. Conclusions: Maternal use of EtOH and SSRI during pregnancy each was associated with changes in fetal brain monoamine pathways, consistent with potential mechanisms for the affective dysregulation associated with FASD.

Details

Title
Biomarkers of Affective Dysregulation Associated with In Utero Exposure to EtOH
Author
Darbinian, Nune 1 ; Merabova, Nana 2 ; Tatevosian, Gabriel 1 ; Morrison, Mary 3   VIAFID ORCID Logo  ; Darbinyan, Armine 4 ; Zhao, Huaqing 5 ; Goetzl, Laura 6 ; Selzer, Michael Edgar 7 

 Center for Neural Repair and Rehabilitation (Shriners Hospitals Pediatric Research Center), Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; [email protected] (N.M.); [email protected] (G.T.) 
 Center for Neural Repair and Rehabilitation (Shriners Hospitals Pediatric Research Center), Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; [email protected] (N.M.); [email protected] (G.T.); Medical College of Wisconsin-Prevea Health, Green Bay, WI 54304, USA 
 Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; [email protected]; Department of Psychiatry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA 
 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA; [email protected] 
 Center for Biostatistics and Epidemiology, Department of Biomedical Education and Data Science, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; [email protected] 
 Department of Obstetrics & Gynecology, University of Texas, Houston, TX 77030, USA; [email protected] 
 Center for Neural Repair and Rehabilitation (Shriners Hospitals Pediatric Research Center), Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; [email protected] (N.M.); [email protected] (G.T.); Department of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA 
First page
2
Publication year
2024
Publication date
2024
Publisher
MDPI AG
e-ISSN
20734409
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2912522818
Copyright
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.