RESUMO
The investigation of the effects of prenatal cocaine exposure (PCE) on offspring has been inconsistent, with few studies investigating biological outcomes in humans. We profiled genome-wide DNA methylation (DNAm) of umbilical cord blood (UCB) from newborns with (n = 35) and without (n = 47) PCE. We used DNAm data to (1) assess pediatric epigenetic clocks at birth and (2) to estimate epigenetic scores (ES) for lifetime disorders. We generated gestational epigenetic age estimates (DNAmGA) based on Knight and Bohlin epigenetic clocks. We also investigated the association between DNAmGA and UCB serum brain-derived neurotrophic factor (BDNF) levels. Considering the large-scale DNAm data availability and existing evidence regarding PCE as a risk for health problems later in life, we generated ES for tobacco smoking, psychosis, autism, diabetes, and obesity. A gene ontology (GO) analysis on the CpGs included in the ES with group differences was performed. PCE was associated with lower DNAmGA in newborns, and this effect remained significant when controlling for potential confounders, such as blood cell type composition predicted by DNAm and obstetric data. DNAmGA was negatively correlated with BDNF levels in the serum of UCB. Higher tobacco smoking, psychosis, and diabetes ES were found in the PCE group. The GO analysis revealed GABAergic synapses as a potential pathway altered by PCE. Our findings of decelerated DNAmGA and ES for adverse phenotypes associated with PCE, suggest that the effects of gestational cocaine exposure on the epigenetic landscape of human newborns are detectable at birth.
Assuntos
Transtorno Autístico , Cocaína , Diabetes Mellitus , Recém-Nascido , Feminino , Gravidez , Humanos , Criança , Fator Neurotrófico Derivado do Encéfalo/genética , Cocaína/toxicidade , Epigênese GenéticaAssuntos
Estimulação Encefálica Profunda , Transtornos Relacionados ao Uso de Substâncias , Estimulação Transcraniana por Corrente Contínua , Encéfalo , Humanos , Transtornos Relacionados ao Uso de Substâncias/terapia , Estimulação Transcraniana por Corrente Contínua/métodos , Estimulação Magnética Transcraniana/métodosRESUMO
White matter (WM) abnormalities in patients with cocaine use disorder (CUD) have been studied; however, the reported effects on the human brain are heterogenous and most results have been obtained from male participants. In addition, biological data supporting the imaging findings and revealing possible mechanisms underlying the neurotoxic effects of chronic cocaine use (CU) on WM are largely restricted to animal studies. To evaluate the neurotoxic effects of CU in the WM, we performed an in vivo diffusion tensor imaging assessment of male and female cocaine users (n = 75) and healthy controls (HC) (n = 58). Moreover, we performed an ex vivo large-scale proteomic analysis using liquid chromatography-tandem mass spectrometry in postmortem brains of patients with CUD (n = 8) and HC (n = 12). Compared with the HC, the CUD group showed significant reductions in global fractional anisotropy (FA) (p < 0.001), and an increase in global mean (MD) and radial diffusion (RD) (both p < 0.001). The results revealed that FA, RD, and MD alterations in the CUD group were widespread along the major WM tracts, after analysis using the tract-based special statistics approach. Global FA was negatively associated with years of CU (p = 0.0421) and female sex (p < 0.001), but not with years of alcohol or nicotine use. Concerning the fibers connecting the left to the right prefrontal cortex, Brodmann area 9 (BA9), the CUD group presented lower FA (p = 0.006) and higher RD (p < 0.001) values compared with the HC group. A negative association between the duration of CU in life and FA values in this tract was also observed (p = 0.019). Proteomics analyses in BA9 found 11 proteins differentially expressed between cocaine users and controls. Among these, were proteins related to myelination and neuroinflammation. In summary, we demonstrate convergent evidence from in vivo diffusion tensor imaging and ex vivo proteomics analysis of WM disruption in CUD.
Assuntos
Cocaína , Substância Branca , Anisotropia , Encéfalo/diagnóstico por imagem , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Proteômica , Substância Branca/diagnóstico por imagemRESUMO
OBJECTIVE: To evaluate a hospital-initiated intervention to reduce tobacco smoke exposure in infants in the neonatal intensive care unit. STUDY DESIGN: A randomized, controlled trial compared motivational interviewing plus financial incentives with conventional care on infant urine cotinine at 1 and 4 months' follow-up. Mothers of infants in the neonatal intensive care unit (N = 360) who reported a smoker living in the home were enrolled. Motivational interviewing sessions were delivered in both the hospital and the home. Financial incentives followed session attendance and negative infant cotinine tests postdischarge. RESULTS: The intervention effect on infant cotinine was not significant, except among mothers who reported high baseline readiness/ability to protect their infant (P ≤ .01) and mothers who completed the study within 6 months postdischarge (per protocol; P ≤ .05). Fewer mothers in the motivational interviewing plus financial incentives condition were smoking postdischarge (P ≤ .01). More mothers in the motivational interviewing plus financial incentives group reported a total home and car smoking ban at follow-up (P ≤ .05). CONCLUSIONS: Motivational interviewing combined with financial incentives reduced infant tobacco smoke exposure in a subset of women who were ready/able to protect their infant. The intervention also resulted in less maternal smoking postpartum. More robust interventions that include maternal and partner/household smoking cessation are likely needed to reduce the costly effects of tobacco smoke exposure on children and their families. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01726062.