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.
Prenatal cocaine exposure (PCE) is associated with behavioral, cognitive, and social consequences in children that might persist into later development. However, there are still few data concerning ...epigenetic mechanisms associated with the effects of gestational cocaine exposure, particularly in human newborns.
We investigated the effects of PCE on DNA methylation patterns of the Oxytocin Receptor (
) gene in the umbilical cord blood (UCB). The relationship between UCB DNA methylation levels and the severity of the mother's cocaine use during pregnancy was also evaluated.
In this cross-sectional study, 28 UCB samples of newborns with a history of crack cocaine exposure
and 30 UCB samples of non-exposed newborns (NEC) were compared for DNA methylation levels at two genomic loci located in exon III of the
gene (OXTR1 and OXTR2) through pyrosequencing. Maternal psychopathology was investigated using the Mini International Neuropsychiatric Interview, and substance use characteristics and addiction severity were assessed using the Smoking and Substance Involvement Screening Test (ASSIST).
No differences between newborns with a history of PCE and NEC were observed in OXTR1 or OXTR2 DNA methylation levels. However, regression analyses showed that maternal addiction severity for crack cocaine use predicted OXTR1 DNA methylation in newborns.
These data suggest that
methylation levels in the UCB of children are affected by the severity of maternal crack cocaine usage. Larger studies are likely to detect specific changes in DNA methylation relevant to the consequences of PCE.
To compare levels of a marker of lipid peroxidation (thiobarbituric acid reactive substances, TBARS) and brain-derived neurotrophic factor (BDNF) in umbilical cord blood (UCB) between newborns ...exposed to crack/cocaine in utero (exposed newborns EN, n=57) and non-exposed newborns (NEN, n=99), as well as in maternal peripheral blood at delivery.
This was a cross-sectional study. Potential confounders, including perinatal parameters, psychopathology, and use of other substances, were assessed.
After adjusting for potential confounders, adjusted mean BDNF was significantly higher in EN (3.86 ng/mL, 95% confidence interval 95%CI 2.29-5.43) than in NEN (0.85 ng/mL, 95%CI 0.47-1.23; p < 0.001; Cohen effect size: 1.12), and significantly lower in crack/cocaine mothers than in control mothers (4.03 ng/mL, 95%CI 2.87-5.18 vs. 6.67 ng/mL, 95%CI 5.60-7.74; p = 0.006). The adjusted mean TBARS level was significantly lower in EN (63.97 µM MDA, 95%CI 39.43-88.50) than NEN (177.04 µM MDA, 95%CI 140.93-213.14; p < 0.001; effect size = 0.84), with no difference between mother groups (p = 0.86).
The changes in TBARS levels observed in EN suggest that fetuses exposed to cocaine mobilize endogenous antioxidant routes since very early stages of development. The increase in BDNF levels in EN might indicate changes in fetal development, whereas the changes in BDNF levels in mothers provide evidence of the complex metabolic processes involved in drug use during pregnancy.
Prenatal cocaine exposure (PCE) is associated with neurobehavioral problems during childhood and adolescence. Early activation of the inflammatory response may contribute to such changes. Our aim was ...to compare inflammatory markers (IL-6 and IL-10) both in umbilical cord blood and in maternal peripheral blood at delivery between newborns with history of crack/cocaine exposure in utero and non-exposed newborns.
In this cross-sectional study, 57 newborns with a history of crack/cocaine exposure in utero (EN) and 99 non-exposed newborns (NEN) were compared for IL-6 and IL-10 levels. Sociodemographic and perinatal data, maternal psychopathology, consumption of nicotine and other substances were systematically collected in cases and controls.
After adjusting for potential confounders, mean IL-6 was significantly higher in EN than in NEN (10,208.54, 95% confidence interval 95%CI 1,328.54-19,088.55 vs. 2,323.03, 95%CI 1,484.64-3,161.21; p = 0.007; generalized linear model GLM). Mean IL-10 was also significantly higher in EN than in NEN (432.22, 95%CI 51.44-812.88 vs. 75.52, 95%CI 5.64-145.39, p = 0.014; GLM). Adjusted postpartum measures of IL-6 were significantly higher in mothers with a history of crack/cocaine use (25,160.05, 95%CI 10,958.15-39,361.99 vs. 8,902.14, 95%CI 5,774.97-12,029.32; p = 0.007; GLM), with no significant differences for IL-10. There was no correlation between maternal and neonatal cytokine levels (Spearman test, p ≥ 0.28 for all measures).
IL-6 and IL-10 might be early biomarkers of PCE in newborns. These findings could help to elucidate neurobiological pathways underlying neurodevelopmental changes and broaden the range of possibilities for early intervention.
Adult mood disorders and childhood psychological trauma Zavaschi, Maria Lucrécia Scherer; Graeff, Maria Elisa; Menegassi, Marcos Tatit ...
Brazilian Journal of Psychiatry,
09/2006, Letnik:
28, Številka:
3
Journal Article
Recenzirano
Odprti dostop
To evaluate the association between adult mood disorders and childhood psychological trauma in a developing country.
Adults with and without mood disorders were assessed in a case-control study using ...the Mini International Neuropsychiatric Interview. Assessment of childhood trauma included physical and sexual abuse, frequent exposure to violence, and parental loss.
In two independent multivariate analyses, after adjusting for potential confounding factors, we found a higher odds ratio for frequent exposure to violence in the community (p = .037) and for physical abuse by parents or caregivers during childhood/adolescence (p = .012) in the group with mood disorders than in the control group. In secondary analyses splitting the mood disorder group in two subgroups (manic episode, and major depressive episodes/ dysthymia), only manic patients showed significantly higher rates of frequent exposure to violence in the community (p = 0.01) and physical abuse during childhood (p = 0.02) than did patients in the control group. In addition, maniac patients had significantly higher rates of sexual abuse than did controls (p = .03).
Our findings document an association between violence during childhood and adult mood disorders, especially for manic patients, in a developing country.
Background
Cocaine and amphetamine-regulated transcript (CART) is an endogenous antioxidant present since the embryonic period. CART is activated by high levels of dopamine and might be of interested ...in understanding the changes in the REDOX system associated with crack/cocaine intake. The goal of this study was to determine whether exposure to crack in utero is associated with increased CART levels.
Methods
In this cross-sectional study with consecutive sampling, we compared the umbilical cord blood (UCB) CART levels (μg/mL) of newborns exposed to crack/cocaine in utero (EN,
n
= 57) to levels in non-exposed newborns (NEN,
n
= 99). In addition, we compared serum CART levels between EN and NEN mothers, in the immediate postpartum period. Potential confounders, such as perinatal data (e.g., weight, Apgar, etc.), psychopathology (DSM-IV), and use of drugs other than crack (ASSIST) were assessed.
Results
According to general linear model analysis, the adjusted mean CART was significantly higher in EN (0.180, 95% CI 0.088–0.272) than in NEN (0.048, 95% CI 0.020–0.076;
p
< 0.002;
d
= 0.68). The difference in CART levels between EN and NEN mothers was not significant (
p
≥ 0.05).
Conclusion
The increase in CART levels in EN UBC suggests a response to crack/cocaine-induced oxidative stress during gestational period, as a potential attempt of neuroprotection. In adult women in puerperium, however, this endogenous antioxidant recruitment does not seem to operate.
The study aims to compare the mental states and countertransference responses of 92 psychodynamically oriented psychotherapists, male and female, experienced and inexperienced, facing written reports ...of real patients who experienced traumatic events. Two vignettes were presented: one of a sexual violence, the other the sudden death of a significant person. The Mental States Rating System (MSRS; Bouchard, Picard, Audet, Brisson, & Carrier, 1998), the MSRS Self-Report (Goldfeld & Bouchard, 2004), and the Inventory of Countertransference Behavior (ICB; Friedman & Gelso, 2000) were used. Results showed that the mourning vignette led to more reflective responses (MSRS) and the rape case was associated with more negative countertransference reactions (ICB). Female participants were more reflective (MSRS); male therapists used less mentalized states (MSRS Self-Report) and expressed more negative reactions (ICB) for both scenarios. Experienced therapists showed more positive reactions on the ICB. The construct validity of the instruments is discussed in relation to the findings.
A presente tese abordou o tema de potenciais biomarcadores em uma população altamente vulnerável – díades mães/bebês com história de exposição ao crack na gestação. Foram avaliados 57 bebês expostos ...e 99 não expostos, e as suas mães. No primeiro artigo, a ênfase foi à ativação inflamatória, onde se detectou um aumento da IL-6 (perfil pró-inflamatório) nos expostos, mesmo mediante ajuste para confundidores (10.208,54 IC95% 1.328,54–19.088,55 vs. 2.323,03 IC95% 1.484,64–3.161,21; p= 0.007). A IL-10 (perfil antiinflamatório) também se mostrou elevada nos bebês expostos (432,22 IC95% 51,44–812,88 vs. 75,52 IC95% 5,64– 145,39, p = 0.014). A IL-6 esteve aumentada nas mães expostas ao crack (25.160,05, IC95% 10.958,15–39.361,99 vs. 8.902,14 IC95% 5.774,97–12.029,32; p = 0.007), sem alterações de IL-10 entre as puérperas. Não houve correlação entre os níveis de citocina materna e do bebê (Spearman test; p ≥ 0.28). Neste estudo, concluiu-se que IL-6 e IL-10 podem ser marcadores da ativação inflamatória precoce em bebês com exposição intrauterina ao crack. Nossos resultados corroboram com os achados da literatura indicando que as citocinas possam ser mediadores potenciais para explicar os efeitos comportamentais e cognitivos do estresse prénatal sobre o feto, integrando imunologia e a hipótese da neuroinflamação a saúde mental da criança. No segundo artigo, avaliou-se uma medida de estresse oxidativo (EO), o TBARS, e de Fator Neurotrófico Derivado do Cérebro (BDNF), nas referidas díades. Os resultados encontrados na análise multivariada do TBARS no sangue de cordão umbilical (SCU) apontam para um menor EO nos bebês expostos (63,97 IC95% 39,43 – 88,50 em expostos vs 177,04 IC95% 140,93 – 213,14 em não expostos, p < 0.001). Trata-se de um achado inovador, apontando na direção de uma ativação do sistema antioxidante endógeno nos recém-nascidos expostos, em função da ruptura da homeostase causada pela toxicidade do crack durante a gestação. O feto mobilizaria rotas de antioxidantes endógenos desde muito precocemente no seu desenvolvimento, como a promovida pela Cocaine and Amphetamine Regulated Transcript (CART). Ainda neste estudo, pode-se ver um aumento de BDNF nos bebês expostos (3,86 IC95% 2,29 – 5,43 vs 0,85 IC95% 0,47- 1,23; p < 0.001), mas uma diminuição nas gestantes expostas em relação às não expostas (4,03 IC95% 2.87 – 5.18 vs 6,67 IC95% 5,60 – 7,74; p = 0.006). Os dados de BDNF em bebês expostos ao crack são bastante inovadores, mas coerentes com a literatura, no sentido de uma reação de neuroplasticidade. Em gestantes, o dado surpreende, tendo em vista que a literatura de adultos indica aumento de BDNF em usuários de crack em relação a controles. Uma possibilidade para explicar este achado é uma possível variação na cronicidade e intensidade no consumo de crack do grupo teste. Alternativamente, a maior prevalência de estresse pós-traumático (TEPT) nas gestantes usuárias de crack poderia justificar este achado. Pacientes com TEPT tendem a apresenta níveis de BDNF menores que os controles normais. Em suma, apontam-se quatro possíveis biomarcadores, em uma população de difícil acesso e de alta relevância em saúde pública. Percebe-se que pode haver diferentes respostas de acordo com a etapa do desenvolvimento e que gestantes podem ter um perfil de recrutamento de neurotrofinas, e talvez outros biomarcadores, diferentes do que não gestantes. Portanto, observa-se que as mudanças estruturais, fisiológicas e moleculares promovidas pela cocaína resultam do envolvimento de uma vasta rede de neurotransmissores, interligados, e atuantes em diferentes áreas do cérebro e em diferentes momentos de maturação.
The present thesis addressed the theme on potential biomarkers in a highly vulnerable population – dyads mothers/babies with a history of exposure to crack/cocaine during the pregnancy 57 exposed babies and 99 not exposed babies and their mothers were assessed. In the first article, the emphasis was the inflammatory activation, were detected an increase of IL-6 (pro-inflammatory profile) in exposed, even within adjustments for confounders (10,208.54, 95%CI 1,328.54–19,088.55 vs. 2,323.03, 95%CI 1,484.64–3,161.21; p= 0.007). The IL-10 (anti-inflammatory profile) was also shown elevated on exposed babies (432.22, 95%CI 51.44–812.88 vs. 75.52, 95%CI 5.64–145.39, p = 0.014). The IL-6 was increased in the mothers exposed to crack (25,160.05, 95%CI 10,958.15–39,361.99 vs. 8,902.14, 95%CI 5,774.97–12,029.32; p = 0.007), without alterations of IL-10 amongst the mothers. There were no correlation amongst the levels of maternal cytosine and the babies (Spearman test; p>0.28). In this study, it was concluded that IL-6 and IL-10 could be markers of early inflammatory activation on babies exposed to crack/cocaine. Our results support the findings of the literature indicating that the cytosine could be potential mediators to explain the behavior and cognitive effects of prenatal stress on the fetus, integrating immunology and the hypothesis of the neuroinflammation to the child’s mental health. In the second article, we assessed a measurement of oxidative stress, the TBARS and the BDNF in the referred dyads. The results found in the multivariate analysis of the TBARS in the umbilical chord’s blood (UCB) point to a less oxidative stress in the babies exposed to (63.97, 95%CI 39.43 – 88.50 in exposed vs. 177.04, 95%CI 140.93 – 213.14 non exposed, p < 0.001). This is an innovative finding, pointing in the direction of an endogenous antioxidant activation system on the newly born exposed, on the basis of the homeostasis rupture caused by the crack toxicity during the pregnancy. The fetus would mobilize endogenous antioxidant routes since very early in its development, as promoted by Cocaine and Amphetamine Regulated Transcript (CART). Still in this study, we can see the increase of the BDNF in the exposed babies (3.86, 95%CI 2.29 – 5.43 vs 0.85, 95%CI 0.47- 1.23; p < 0.001), but a decrease in the exposed pregnant women in relation to the non-exposed (4.03, 95%CI 2.87 – 5.18 vs. 6.67, 95%CI 5.60 – 7.74; p = 0.006). The data of BDNF in babies exposed to crack are highly innovative, but consistent to the literature in the sense of a reaction of neuroplasticity. In pregnant women the data is surprising, having in mind that the adult literature indicates an increase of BDNF in crack/cocaine users in relation to controllers. A possibility to explain this finding is a possible variation in the practicality and intensity of usage of crack/cocaine from the test group. Alternatively the most prevalence post-traumatic stress (PTSD) in the crack pregnant users could justify this finding. Patients with PTSD tend to present levels of BDNF less than the normal controllers. This leads us to four possible biomarkers, in a population difficult to access and in a highly relevance to public health. We can tell that there are different answers according to the development stage and that the pregnant women could have a neurotrophins recruitment profile and perhaps other biomarkers, different to non pregnant. Therefore, we can observe that structural, physiological, molecular changes promoted by cocaine result from an involvement from a vast network of neurotransmitters integrated and active in different areas of the brain and in different moments of maturation.
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