Impacto dos maus-tratos infantis sofridos por mulheres sobre o perfil de expressão de microRNA no seu sangue e de seus filhos
Data
2024-06-10
Tipo
Dissertação de mestrado
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ISSN da Revista
Título de Volume
Resumo
Introdução: Os maus-tratos na infância e/ou adolescência (do inglês child maltreatment), abrangendo abuso físico, sexual e emocional, bem como negligência física e emocional, exercem efeitos adversos na saúde não apenas dos indivíduos diretamente expostos, mas também das gerações subsequentes. Alterações epigenéticas, como mudanças no perfil de expressão dos microRNAs (miRNAs), podem estar associadas a esses eventos traumáticos. Mudanças nos níveis de miRNAs possuem o potencial de ser um dos mecanismos biológicos subjacentes que conectam a exposição aos maus-tratos infantis a desfechos patológicos ao longo da vida. Objetivo: Neste estudo, investigamos a associação entre maus-tratos infantis maternos e os níveis de expressão de miRNAs em sangue materno e perinatal. Material e Métodos: Recrutamos 43 mulheres gestantes e avaliamos a exposição aos maus-tratos infantis usando o Questionário de Trauma Infantil (QUESI). Coletamos sangue materno e sangue do cordão umbilical durante o parto, utilizando tubos PAXGene. Obtivemos os perfis de expressão de miRNA de cada tecido por meio de sequenciamento de nova geração. As leituras foram alinhadas ao miRBase (v.22) e ao genoma de referência (GRCh38) para identificar sequências candidatas a miRNAs. Normalizamos as leituras usando o software DESeq2. Testamos a associação entre maus-tratos infantis maternos e expressão de miRNAs utilizando modelos de regressão linear múltipla, controlando para possíveis confundidores. Previmos os genes-alvo para os miRNAs associados e sequências candidatas a miRNAs com o software miRwalk e targetscan, respectivamente, e analisamos o enriquecimento para vias biológicas utilizando a função “gene2func” do mapeamento funcional e anotação de estudos de associação genômica em larga escala (FUMA GWAS). Resultados: A idade média das mães foi de 28,6 anos (desvio padrão [DP] 6,7 anos), 67,4% delas foram classificadas no nível socioeconômico mais baixo (D-E) e apenas 12% iniciaram o ensino superior. Houve 21 partos por via vaginal, 20 cesáreas e 2 por fórceps. A idade gestacional média ao nascimento foi de 39,7 semanas (DP = 1,4 semanas) e 53,5% dos recém-nascidos são do sexo feminino. Encontramos a expressão de hsa-miR-582-3p em sangue de cordão umbilical negativamente associada à pontuação do QUESI (beta = -0,04, valor p = 0,00008, FDR = 0,045, R2 = 0,33). SSX5, RTL8C, AMD1 e INO80D foram os principais genes-alvo desse miRNA. As vias enriquecidas pelos genes-alvo de hsa-miR-582-3p incluíram diferenciação e desenvolvimento celular, desenvolvimento embrionário, e enriquecimento para genes associados com nascimento prematuro espontâneo precoce em estudos de associação em larga escala. Também, identificamos 84 sequências candidatas a miRNAs, mas nenhuma associada a maus-tratos. Fornecemos resultados de enriquecimento de vias biológicas para auxiliar a identificar as prováveis funções dos candidatos a miRNAs. Discussão: Embora os miRNAs sejam reguladores finos e transitórios da expressão gênica, estudos anteriores demonstraram efeitos fisiológicos duradouros do maus-tratos infantis nos níveis de expressão de miRNAs. Neste estudo, identificamos alterações em hsa-miR-582-3p no sangue do cordão umbilical e investigamos suas possíveis implicações biológicas. Conclusão: Ao identificar a associação da expressão de hsa-miR-582-3p com maus-tratos infantis maternos no sangue do cordão umbilical, fornecemos suporte para a influência de mecanismos moleculares no impacto intergeracional da exposição materna a maus-tratos infantis, na próxima geração.
Background: Child maltreatment, encompassing physical, sexual, and emotional abuse, as well as physical and emotional neglect, adversely affects the health of not only directly exposed individuals but also subsequent generations. Epigenetic alterations, such as changes in microRNA (miRNA) expression profiles, may be associated with these traumatic events. Changes in miRNA levels have the potential to be one of the biological mechanisms linking child maltreatment exposure to pathological outcomes throughout life. Objective: This study investigates the association between maternal child maltreatment and miRNA expression levels in maternal and perinatal blood. Materials and Methods: We recruited 43 pregnant women and assessed child maltreatment exposure using the Childhood Trauma Questionnaire (CTQ). Maternal blood and umbilical cord blood were collected during childbirth using PAXGene tubes. miRNA expression profiles for each tissue were obtained through next-generation sequencing. The reads were aligned to miRBase (v.22) and the reference genome (GRCh38) to identify candidate miRNA sequences. We normalized the reads using DESeq2 software. Associations between maternal child maltreatment and miRNA expression were tested using multiple linear regression models, controlling for potential confounders. Target genes for the associated miRNAs and candidate miRNAs were predicted using miRwalk and TargetScan, respectively, and enrichment for biological pathways was analyzed using the "gene2func" function of FUMA GWAS. Results: The average maternal age was 28.6 years (standard deviation [SD] 6.7 years); 67.4% were classified in the lowest socioeconomic level (D-E), and only 12% had some college education. There were 21 vaginal deliveries, 20 cesarean sections, and 2 forceps deliveries. The average gestational age at birth was 39.7 weeks (SD = 1.4 weeks), and 53.5% of the newborns were female. We found that hsa-miR-582-3p expression in umbilical cord blood was negatively associated with CTQ scores (beta = -0.04, p-value = 0.00008, FDR = 0.045, R2 = 0.33). SSX5, RTL8C, AMD1, and INO80D were the main target genes of this miRNA. Enriched pathways for the predicted target genes of hsa-miR-582-3p included cell differentiation and development, embryonic development, and enrichment for genes associated with early spontaneous preterm birth in large-scale association studies. Additionally, we identified 84 candidate miRNA sequences, none of which were associated with child maltreatment. We provided pathway enrichment results to help identify the likely functions of the candidate miRNAs. Discussion: Although miRNAs are fine and transient regulators of gene expression, previous studies have shown lasting physiological effects of child maltreatment on miRNA expression levels. In this study, we identified alterations in hsa-miR-582-3p in umbilical cord blood and investigated their potential biological implications. Conclusion: By identifying the association of hsa-miR-582-3p expression with maternal child maltreatment in umbilical cord blood, we provide support for the influence of molecular mechanisms on the intergenerational impact of maternal exposure to child maltreatment on the next generation.
Background: Child maltreatment, encompassing physical, sexual, and emotional abuse, as well as physical and emotional neglect, adversely affects the health of not only directly exposed individuals but also subsequent generations. Epigenetic alterations, such as changes in microRNA (miRNA) expression profiles, may be associated with these traumatic events. Changes in miRNA levels have the potential to be one of the biological mechanisms linking child maltreatment exposure to pathological outcomes throughout life. Objective: This study investigates the association between maternal child maltreatment and miRNA expression levels in maternal and perinatal blood. Materials and Methods: We recruited 43 pregnant women and assessed child maltreatment exposure using the Childhood Trauma Questionnaire (CTQ). Maternal blood and umbilical cord blood were collected during childbirth using PAXGene tubes. miRNA expression profiles for each tissue were obtained through next-generation sequencing. The reads were aligned to miRBase (v.22) and the reference genome (GRCh38) to identify candidate miRNA sequences. We normalized the reads using DESeq2 software. Associations between maternal child maltreatment and miRNA expression were tested using multiple linear regression models, controlling for potential confounders. Target genes for the associated miRNAs and candidate miRNAs were predicted using miRwalk and TargetScan, respectively, and enrichment for biological pathways was analyzed using the "gene2func" function of FUMA GWAS. Results: The average maternal age was 28.6 years (standard deviation [SD] 6.7 years); 67.4% were classified in the lowest socioeconomic level (D-E), and only 12% had some college education. There were 21 vaginal deliveries, 20 cesarean sections, and 2 forceps deliveries. The average gestational age at birth was 39.7 weeks (SD = 1.4 weeks), and 53.5% of the newborns were female. We found that hsa-miR-582-3p expression in umbilical cord blood was negatively associated with CTQ scores (beta = -0.04, p-value = 0.00008, FDR = 0.045, R2 = 0.33). SSX5, RTL8C, AMD1, and INO80D were the main target genes of this miRNA. Enriched pathways for the predicted target genes of hsa-miR-582-3p included cell differentiation and development, embryonic development, and enrichment for genes associated with early spontaneous preterm birth in large-scale association studies. Additionally, we identified 84 candidate miRNA sequences, none of which were associated with child maltreatment. We provided pathway enrichment results to help identify the likely functions of the candidate miRNAs. Discussion: Although miRNAs are fine and transient regulators of gene expression, previous studies have shown lasting physiological effects of child maltreatment on miRNA expression levels. In this study, we identified alterations in hsa-miR-582-3p in umbilical cord blood and investigated their potential biological implications. Conclusion: By identifying the association of hsa-miR-582-3p expression with maternal child maltreatment in umbilical cord blood, we provide support for the influence of molecular mechanisms on the intergenerational impact of maternal exposure to child maltreatment on the next generation.
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Citação
ROSA, Joice Santos. Impacto dos maus-tratos infantis sofridos por mulheres sobre o perfil de expressão de microRNA no seu sangue e de seus filhos. 2024. 202 f. Dissertação (Mestrado em Psiquiatria e Psicologia Médica) – Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2024.