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Volume 13
Issue 11
10.3390/biomedicines13112753
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Prematurity and Epigenetic Regulation of SLC6A4: Longitudinal Insights from Birth to the First Month of Life

by
Aline de Araújo Brasil
1,
Leo Travassos Vieira Milone
1,
Paulo Victor Barbosa Eleutério dos Santos
1,
Stephanie Cristina Alves de Oliveira Saide
1,
Vitor Barreto Paravidino
2,3,4,
Georgia Chalfun
1,5,
Letícia Santiago da Silva Ferreira
1,
Mariana Berquó Carneiro Ferreira
1,
Anna Beatriz Muniz Ferreira
1,
Geovanna Barroso de Farias
1,
Jaqueline Rodrigues Robaina
1,
Mariana Barros Genuíno de Oliveira
1,
Maria Clara de Magalhães-Barbosa
1,
Arnaldo Prata-Barbosa
1,* and
Antonio José Ledo Alves da Cunha
1,6
1
Department of Pediatrics, D’Or Institute for Research and Education (IDOR), Rio de Janeiro 22281-100, RJ, Brazil
2
Department of Epidemiology, Institute of Social Medicine, State University of Rio (UERJ), Rio de Janeiro 20550-900, RJ, Brazil
3
National School of Public Health, Oswaldo Cruz Foundation, Rio de Janeiro 21040-900, RJ, Brazil
4
Department of Physical Education and Sports, Naval Academy, Brazilian Navy, Rio de Janeiro 20021-010, RJ, Brazil
5
Department of Neonatology, Maternity School, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 22240-003, RJ, Brazil
6
Department of Pediatrics, School of Medicine, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, RJ, Brazil
*
Author to whom correspondence should be addressed.
Biomedicines 2025, 13(11), 2753; https://doi.org/10.3390/biomedicines13112753
Submission received: 3 October 2025 / Revised: 6 November 2025 / Accepted: 8 November 2025 / Published: 11 November 2025
(This article belongs to the Special Issue Epigenetic Regulation and Its Impact for Medicine (2nd Edition))
Review Reports Versions Notes

Abstract

Background/Objectives: Prematurity is a significant global health concern, often associated with neurodevelopmental challenges. Solute Carrier Family 6 Member 4 (SLC6A4), the gene encoding the serotonin transporter, a key component in serotonin reuptake in the synaptic cleft, plays a key role in stress response and neurodevelopment. Epigenetic regulation of stress-related genes, such as SLC6A4, influences neonatal stress adaptation and developmental outcomes. This study aimed to quantify and compare DNA methylation levels at 13 CpG sites in the promoter region of the SLC6A4 gene between preterm and term neonates at three time points. Methods: A cohort of 46 preterm infants and a cohort of 49 full-term infants were analyzed. Blood samples collected at birth (D0), the fifth day (D5), and the thirtieth day (D30) were used to analyze DNA methylation, using bisulfite conversion and pyrosequencing. Results: Significant differences in SLC6A4 methylation were observed. At D0, CpGs 12 and 13 showed higher methylation in preterm infants. CpG 9 showed lower methylation in preterm infants at D5. Extremely preterm infants had the highest values of methylation at the three time points. Longitudinal mixed-effects analysis revealed distinct temporal patterns between groups. Total and site-specific methylation at CpGs 2, 8, and 9 increased over time in full-term infants, while methylation remained stable over time in very preterm and extremely preterm infants. Conclusions: This study reveals significant differences in SLC6A4 methylation between very preterm, extremely preterm, and full-term infants, highlighting the impact of prematurity and early-life stress on the epigenome. These findings contribute to improving our understanding of the epigenetic mechanisms shaping neurodevelopment and stress adaptation in neonates.
Keywords: prematurity; epigenetics; serotonin transporter; SLC6A4; DNA methylation; neonatal stress; neurodevelopment prematurity; epigenetics; serotonin transporter; SLC6A4; DNA methylation; neonatal stress; neurodevelopment

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MDPI and ACS Style

Brasil, A.d.A.; Milone, L.T.V.; dos Santos, P.V.B.E.; Saide, S.C.A.d.O.; Paravidino, V.B.; Chalfun, G.; Ferreira, L.S.d.S.; Ferreira, M.B.C.; Ferreira, A.B.M.; de Farias, G.B.; et al. Prematurity and Epigenetic Regulation of SLC6A4: Longitudinal Insights from Birth to the First Month of Life. Biomedicines 2025, 13, 2753. https://doi.org/10.3390/biomedicines13112753

AMA Style

Brasil AdA, Milone LTV, dos Santos PVBE, Saide SCAdO, Paravidino VB, Chalfun G, Ferreira LSdS, Ferreira MBC, Ferreira ABM, de Farias GB, et al. Prematurity and Epigenetic Regulation of SLC6A4: Longitudinal Insights from Birth to the First Month of Life. Biomedicines. 2025; 13(11):2753. https://doi.org/10.3390/biomedicines13112753

Chicago/Turabian Style

Brasil, Aline de Araújo, Leo Travassos Vieira Milone, Paulo Victor Barbosa Eleutério dos Santos, Stephanie Cristina Alves de Oliveira Saide, Vitor Barreto Paravidino, Georgia Chalfun, Letícia Santiago da Silva Ferreira, Mariana Berquó Carneiro Ferreira, Anna Beatriz Muniz Ferreira, Geovanna Barroso de Farias, and et al. 2025. "Prematurity and Epigenetic Regulation of SLC6A4: Longitudinal Insights from Birth to the First Month of Life" Biomedicines 13, no. 11: 2753. https://doi.org/10.3390/biomedicines13112753

APA Style

Brasil, A. d. A., Milone, L. T. V., dos Santos, P. V. B. E., Saide, S. C. A. d. O., Paravidino, V. B., Chalfun, G., Ferreira, L. S. d. S., Ferreira, M. B. C., Ferreira, A. B. M., de Farias, G. B., Robaina, J. R., de Oliveira, M. B. G., de Magalhães-Barbosa, M. C., Prata-Barbosa, A., & da Cunha, A. J. L. A. (2025). Prematurity and Epigenetic Regulation of SLC6A4: Longitudinal Insights from Birth to the First Month of Life. Biomedicines, 13(11), 2753. https://doi.org/10.3390/biomedicines13112753

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