Venlafaxine induces Teratogenesis and alters SHH Gene Expression and Protein Biochemistry of Developing Gallus sp. Embryos
Abstract
The use of antidepressant drugs during pregnancy is increasing globally. SNRIs and SSRIs are most widely used for treating panic disorders. Venlafaxine is an antidepressant that inhibits serotonin and norepinephrine reuptake. Given the increasing prevalence of antidepressant use during pregnancy, Venlafaxine exposure during the early stages of development could lead to changes in protein dynamics and disrupt essential gene pathways, raising concerns about the potential teratogenic effects of antidepressant exposure during pregnancy. This study explores the developmental impact of Venlafaxine, a commonly prescribed serotonin-norepinephrine reuptake inhibitor (SNRI), on protein biochemistry and gene expression in the developing Gallus gallus domesticus embryos. Significant changes in protein profiles were observed among control and Venlafaxine-treated groups. Sonic Hedgehog (SHH) gene, a key regulator of embryonic patterning and organogenesis, specifically neural tube formation, and limb development, is known for its crucial role in embryonic development. qRT-PCR analysis of Venlafaxine-treated embryos showed changes in SHH gene expression suggesting that Venlafaxine may target SHH gene expression, and potentially alter signalling pathways crucial for normal embryogenesis. However, detailed studies are needed to understand the long-term consequences of prenatal and foetal antidepressant exposure on embryonic growth and development. These changes may lead to abnormal growth patterns or congenital defects, emphasizing the need for caution when prescribing Venlafaxine during pregnancy.
Keywords: Antidepressants, Venlafaxine, SNRI, Gallus gallus domesticus, Sonic Hedgehog (SHH), Protein Biochemistry, qRT-PCR
Keywords:
Antidepressants, Venlafaxine, SNRI, Gallus gallus domesticus, Sonic Hedgehog (SHH), Protein Biochemistry, qRT-PCRDOI
https://doi.org/10.22270/jddt.v15i1.6954References
1. Vallianatou K. Antipsychotics. Vol. 44, Medicine (United Kingdom). Elsevier Ltd; 2016. p. 748-52.
https://doi.org/10.1016/j.mpmed.2016.09.018
2. Dharmshaktu P, Tayal V, Kalra BS. Efficacy of antidepressants as analgesics: A review. Vol. 52, Journal of Clinical Pharmacology. 2012. p. 6-17. https://doi.org/10.1177/0091270010394852 PMid:21415285
3. Pal A, Roy DN. Biochemical and Molecular Mechanisms of Liver Damage-Induced by Antidepressant Drugs: an Update Review. Curr Hepatol Rep. 2017 Dec 1;16(4):271-5. https://doi.org/10.1007/s11901-017-0366-6
4. Singh KP, Tripathi N. The Scientific Temper 89 Antipsychotic Medication During Pregnancy And Possible Birth Defects. https://doi.org/10.58414/SCIENTIFICTEMPER.2011.02.1.17F
5. Ellingrod VL, Perry PJ. Runical V, REVIEW Venlafaxine: A heterocyclic antidepressant. https://academic.oup.com/ajhp/article-abstract/51/24/3033/5182262 https://doi.org/10.1093/ajhp/51.24.3033
6. Gutierrez MA, Stimmel GL, Aiso JY. Venlafaxine: A 2003 Update. 2003. https://doi.org/10.1016/S0149-2918(03)80210-2 PMid:14512125
7. Gałecki P, Mossakowska-Wójcik J, Talarowska M. The anti-inflammatory mechanism of antidepressants - SSRIs, SNRIs. Vol. 80, Progress in Neuro-Psychopharmacology and Biological Psychiatry. Elsevier Inc.; 2018. p. 291-4. https://doi.org/10.1016/j.pnpbp.2017.03.016 PMid:28342944
8. Singh PSB. Selective Serotonin-norepinephrine Re-uptake Inhibition Limits Renovas-cular-hypertension Induced Cognitive Impairment, Endothelial Dysfunction, and Oxidative Stress Injury. Curr Neurovasc Res. 2016 May 1;13(2):135-46. https://doi.org/10.2174/1567202613666160226152549 PMid:26915517
9. Pratt VM, Mcleod HL, Rubinstein WS. Venlafaxine Therapy and CYP2D6 Genotype. National Center for Biotechnology Information (US. 2015.
10. Vargesson N, Fraga L. Teratogenesis. In: Encyclopedia of Life Sciences [Internet]. Wiley; 2017. p. 1-7. https://doi.org/10.1002/9780470015902.a0026056 PMid:28602455
11. Beckman DA, Brent RL. MECHANISMS OF TERA TOGENESIS [Internet]. Vol. 24, An". Rev. Pharmacol. Toxicol. 1984. https://doi.org/10.1146/annurev.pa.24.040184.002411 PMid:6203482
12. Gilbert-Barness E. Review: Teratogenic Causes of Malformations [Internet]. 2010. Available from: www.annclinlabsci.org
13. Wong EA, Uni Z. Centennial Review: The chicken yolk sac is a multifunctional organ. Vol. 100, Poultry Science. Elsevier Inc.; 2021. https://doi.org/10.1016/j.psj.2020.11.004 PMid:33518342 PMCid:PMC7936120
14. Muhammad Nihad AS, Deshpande R, Kale VP, Bhonde RR, Datar SP. Establishment of an in ovo chick embryo yolk sac membrane (YSM) assay for pilot screening of potential angiogenic and anti-angiogenic agents. Cell Biol Int. 2018 Nov 1;42(11):1474-83. https://doi.org/10.1002/cbin.11051 PMid:30136736
15. Starck JM. Morphology of the avian yolk sac. Vol. 282, Journal of Morphology. John Wiley and Sons Inc; 2021. p. 959-72. https://doi.org/10.1002/jmor.21262 PMid:32930439
16. Simpson RJ. SDS-PAGE of Proteins. Cold Spring Harb Protoc. 2006 Jun;2006(1):pdb.prot4313. https://doi.org/10.1101/pdb.prot4313 PMid:22485689
17. University of Arizona. GEISHA: Gallus Expression In Situ Hybridization Analysis. University of Arizona. https://geisha.arizona.edu. Accessed August 17, 2024.
18. Jeng KS, Chang CF, Lin SS. Sonic hedgehog signaling in organogenesis, tumors, and tumor microenvironments. International Journal of Molecular Sciences. MDPI AG; 2020;21. https://doi.org/10.3390/ijms21030758 PMid:31979397 PMCid:PMC7037908
19. Vaillant C, Monard D. SHH pathway and cerebellar development. Vol. 8, Cerebellum. 2009. p. 291-301. https://doi.org/10.1007/s12311-009-0094-8 PMid:19224309
20. Lyndon GJ, Prieto R, Wajsbrot DB, Allgulander C, Bandelow B. Efficacy of venlafaxine extended release in major depressive disorder patients: Effect of baseline anxiety symptom severity. Int Clin Psychopharmacol. 2019;34(3):110-8. https://doi.org/10.1097/YIC.0000000000000256 PMid:30870236 PMCid:PMC6445597
21. Arakawa R, Stenkrona P, Takano A, Svensson J, Andersson M, Nag S, et al. Venlafaxine ER blocks the norepinephrine transporter in the brain of patients with major depressive disorder: a PET study using [ 18 F]FMeNER-D 2. Available from: https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyz003/5288303
22. Ye W, Zhao Y, Robinson RL, Swindle RW. Treatment patterns associated with Duloxetine and Venlafaxine use for Major Depressive Disorder. BMC Psychiatry. 2011 Jan 31;11. https://doi.org/10.1186/1471-244X-11-19 PMid:21281479 PMCid:PMC3044657
23. Liebowitz MR, Gelenberg AJ, Munjack D. Venlafaxine Extended Release vs Placebo and Paroxetine in Social Anxiety Disorder.
24. Einarson A, Schachtschneider AMK, Halil R, Bollano E, Koren G. SSRI'S and other antidepressant use during pregnancy and potential neonatal adverse effects: Impact of a public health advisory and subsequent reports in the news media. BMC Pregnancy Childbirth. 2005 May 20;5. https://doi.org/10.1186/1471-2393-5-11 PMid:15907207 PMCid:PMC1156906
25. Polen KND, Rasmussen SA, Riehle-Colarusso T, Reefhuis J. Association between reported venlafaxine use in early pregnancy and birth defects, national birth defects prevention study, 1997-2007. Birth Defects Res A Clin Mol Teratol. 2013 Jan;97(1):28-35. https://doi.org/10.1002/bdra.23096 PMid:23281074 PMCid:PMC4484721
26. Wimasis Image Analysis. WimCAM: CAM Assay Analysis. Available from: https://www.wimasis.com/cam-assay. Accessed: November 12, 2024.
27. Kielkopf CL, Bauer W, Urbatsch IL. Bradford assay for determining protein concentration. Cold Spring Harb Protoc. 2020 Apr 1;2020(4):136-8. https://doi.org/10.1101/pdb.prot102269 PMid:32238597
28. Al-Tubuly AA. 32 SDS-PAGE and Western Blotting.
29. IDT Primer Quest Tool Integrated DNA Technologies. PrimerQuest Tool. Available from: https://www.idtdna.com/pages/tools/primerquest. Accessed: October 02, 2024.
30. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 2001;25(4):402-8. https://doi.org/10.1006/meth.2001.1262 PMid:11846609
31. Weber BK, Pringle R, Osborx M. [1] MOLECULAR WEIGHT DETERMINATIONS ON SDS GELS 3 [1] Measurement of Molecular Weights by Electrophoresis on SDS-Acrylamide Gel. https://doi.org/10.1016/S0076-6879(72)26003-7 PMid:4680711
32. Oliveira AC, Fascineli ML, Oliveira PM de, Gelfuso GM, Villacis RAR, Grisolia CK. Multi-level toxicity assessment of the antidepressant venlafaxine in embryos/ larvae and adults of zebrafish (Danio rerio). Genet Mol Biol. 2023;46(3). https://doi.org/10.1590/1678-4685-gmb-2022-0377 PMid:37695571 PMCid:PMC10494572
33. Thompson WA, Arnold VI, Vijayan MM. Venlafaxine in Embryos Stimulates Neurogenesis and Disrupts Larval Behavior in Zebrafish. Environ Sci Technol. 2017 Nov 7;51(21):12889-97. https://doi.org/10.1021/acs.est.7b04099 PMid:29019661
34. Parrott JL, Metcalfe CD. Assessing the effects of the antidepressant venlafaxine to fathead minnows exposed to environmentally relevant concentrations over a full life cycle. Environmental Pollution. 2017;229:403-11. https://doi.org/10.1016/j.envpol.2017.06.009 PMid:28622660
35. Rodrigues P, Guimarães L, Carvalho AP, Oliva-Teles L. Carbamazepine, venlafaxine, tramadol, and their main metabolites: Toxicological effects on zebrafish embryos and larvae. J Hazard Mater. 2023 Apr 15;448. https://doi.org/10.1016/j.jhazmat.2023.130909 Mid:36860067
36. Vollmar P, Haghikia A, Dermietzel R, Faustmann PM. Venlafaxine exhibits an anti-inflammatory effect in an inflammatory co-culture model. International Journal of Neuropsychopharmacology. 2008 Feb;11(1):111-7. https://doi.org/10.1017/S1461145707007729 PMid:17445357
37. European Molecular Biology Laboratory. STITCH: Search Tool for Interactions of Chemicals. STITCH. http://stitch.embl.de/. Accessed December 01, 2024.
38. Cacabelos R, Torrellas C, López-Muñoz F. Pharmacogenomics of Antidepressant Drugs. In: Melatonin, Neuroprotective Agents and Antidepressant Therapy. Springer India; 2016. p. 545-609. https://doi.org/10.1007/978-81-322-2803-5_35
39. Ahmed AT, Biernacka JM, Jenkins G, Rush AJ, Shinozaki G, Veldic M, et al. Pharmacokinetic-Pharmacodynamic interaction associated with venlafaxine-XR remission in patients with major depressive disorder with history of citalopram / escitalopram treatment failure. J Affect Disord. 2019 Mar 1;246:62-8. https://doi.org/10.1016/j.jad.2018.12.021 PMid:30578947 PMCid:PMC6501809
40. Proft F, Kopf J, Olmes D, Hempel S, Schmidt B, Riederer P, et al. SLC6A2 and SLC6A4 Variants interact with Venlafaxine Serum Concentrations to Influence Therapy Outcome. Pharmacopsychiatry. 2014 Nov 1;47(7):245-50. https://doi.org/10.1055/s-0034-1390412 PMid:25295552
41. Lisowski P, Juszczak GR, Goscik J, Stankiewicz AM, Wieczorek M, Zwierzchowski L, et al. Stress susceptibility-specific phenotype associated with different hippocampal transcriptomic responses to chronic tricyclic antidepressant treatment in mice [Internet]. 2013. Available from: http://www.biomedcentral.com/1471-2202/14/144 https://doi.org/10.1186/1471-2202-14-144 PMid:24225037 PMCid:PMC3831054
42. Matsubara H, Saito D, Abe G, Yokoyama H, Suzuki T, Tamura K. Upstream regulation for initiation of restricted Shh expression in the chick limb bud. Developmental Dynamics. 2017 May 1;246(5):417-30. https://doi.org/10.1002/dvdy.24493 PMid:28205287
43. Tayyab M, Shahi MH, Farheen S, Mariyath MPM, Khanam N, Castresana JS, et al. Sonic hedgehog, Wnt, and brain-derived neurotrophic factor cell signaling pathway crosstalk: potential therapy for depression. Vol. 96, Journal of Neuroscience Research. John Wiley and Sons Inc.; 2018. p. 53-62. https://doi.org/10.1002/jnr.24104 PMid:28631844
44. Håvardstun A. Neurodevelopmental toxicity of escitalopram and venlafaxine in PC12 and chicken cerebellum granule neurons, and kinetic studies of escitalopram in chicken embryo [Internet]. 2023. Available from: http://www.uio.duo.no/
45. Zosen D, Kondratskaya E, Kaplan-Arabaci O, Haugen F, Paulsen RE. Antidepressants escitalopram and venlafaxine up-regulate BDNF promoter IV but down-regulate neurite outgrowth in differentiating SH-SY5Y neurons. Neurochem Int. 2023 Oct 1;169. https://doi.org/10.1016/j.neuint.2023.105571 PMid:37451345
Published



How to Cite
Issue
Section
Copyright (c) 2025 Pinakin Shrikant Wagh , Riddhi Bhaskar Walimbe , Aarushi Jeetendra Poyrekar , Sayali Avinash Phatak , Anish Anil Divekar

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).