Prenatal alcohol exposure alters biobehavioral reactivity to pain in newborns

To examine biobehavioral responses to an acute pain event in a Cape Town, South Africa, cohort consisting of 28 Cape Colored (mixed ancestry) newborns (n = 14) heavily exposed to alcohol during pregnancy (exposed), and born to abstainers (n = 14) or light (<or = 0.5 oz absolute alcohol/d) drinkers (controls).

Prenatal alcohol exposure and childhood balance ability:findings from a UK birth cohort study

OBJECTIVE: To investigate the association of prenatal alcohol exposure with balance in10-year-old children. DESIGN: Population-based prospective longitudinal study. SETTING: Former Avon region of UK (Southwest England). PARTICIPANTS: 6915 children from the Avon Longitudinal Study of Parents and Children who had a balance assessment at age 10 and had data on maternal alcohol consumption. OUTCOME MEASURES: 3 composite balance scores: dynamic balance (beam-walking), static balance eyes open, static balance eyes closed (heel-to-toe balance on a beam and standing on one leg, eyes open or closed). RESULTS: Most mothers (95.5%) consumed no-to-moderate amounts (3-7 glasses/week) of alcohol during pregnancy. Higher total-alcohol consumption was associated with maternal-social advantage, whereas binge drinking (≥4 units/day) and abstinence were associated with maternal social disadvantage. No evidence was found of an adverse effect of maternal-alcohol consumption on childhood balance. Higher maternal-alcohol use during pregnancy was generally associated with better offspring outcomes, with some specific effects appearing strong (static balance eyes open and moderate total alcohol exposure at 18 weeks, adjusted OR 1.23 (95% CI 1.01 to 1.49); static balance eyes closed and moderate total alcohol exposure at 18 weeks, adjusted OR 1.25 (95% CI 1.06 to 1.48). Similar results were found for both paternal and postnatal maternal alcohol exposure. A Mendelian-randomization approach was used to estimate the association between maternal genotype and offspring balance using the non-synonymous variant rs1229984*A (ADH1B) to proxy for lower maternal alcohol consumption; no strong associations were found between this genotype/proxy and offspring balance. CONCLUSIONS: No evidence was found to indicate that moderate maternal alcohol consumption in this population sample had an adverse effect on offspring balance at age 10. An apparent beneficial effect of higher total maternal alcohol consumption on offspring balance appeared likely to reflect residual confounding.

A variant in LIN28B is associated with 2D:4D finger-length ratio, a putative retrospective biomarker of prenatal testosterone exposure

The ratio of the lengths of an individual's second to fourth digit (2D:4D) is commonly used as a noninvasive retrospective biomarker for prenatal androgen exposure. In order to identify the genetic determinants of 2D:4D, we applied a genome-wide association approach to 1507 11-year-old children from the Avon Longitudinal Study of Parents and Children (ALSPAC) in whom 2D:4D ratio had been measured, as well as a sample of 1382 12- to 16-year-olds from the Brisbane Adolescent Twin Study. A meta-analysis of the two scans identified a single variant in the LIN28B gene that was strongly associated with 2D:4D (rs314277: p = 4.1 x 10(-8)) and was subsequently independently replicated in an additional 3659 children from the ALSPAC cohort (p = 1.53 x 10(-6)). The minor allele of the rs314277 variant has previously been linked to increased height and delayed age at menarche, but in our study it was associated with increased 2D:4D in the direction opposite to that of previous reports on the correlation between 2D:4D and age at menarche. Our findings call into question the validity of 2D:4D as a simplistic retrospective biomarker for prenatal testosterone exposure.

Detour behavior changes associated with prenatal morphine exposure in 11-day-old chicks

The central nervous system exhibits remarkable plasticity in early life. Prenatal morphine exposure may induce adverse behavioral effects on the neonate and the developing offspring. In the present study, we investigated the effect of prenatal morphine exposure (daily from embryonic days 12-16, 20 mg/kg) on 11-day-old chicks using two forms of spatial paradigms: one trial detour behavior task in which animals must bypass an obstacle to reach the desired goal without any training and detour learning task which required several trials of training to reach the detour criterion. The results showed that, on the condition that chicks could successfully detour in the first trial, morphine exposed chicks exhibited longer detour latency to finish the task, coupled by a preference for turning right versus turning left. In contrast, no significant difference in learning and memory was found in detour learning task between morphine exposed chicks and saline chicks. These findings suggest specific behavioral changes associated with prenatal exposure to opioids during mid to late gestation, also raise attention to the possible health hazard from pregnancy drug use in everyday life. (C) 2010 ISDN. Published by Elsevier Ltd. All rights reserved.

The Impact of Prenatal Nicotine Exposure on Impulsivity and Neural Firing in the Medial Prefrontal Cortex

Prenatal nicotine exposure (PNE) is linked to a large number of psychiatric disorders, including attention deficit hyperactivity disorder (ADHD). Current literature suggests that core deficits observed in ADHD reflect abnormal inhibitory control governed by the prefrontal cortex (PFC) of the brain. The PFC is structurally altered by PNE, but it is still unclear how neural firing is affected during tasks that test behavioral inhibition, such as the stop-signal task, or if neural correlates related to inhibitory control are affected after PNE in awake behaving animals. To address these questions, we recorded from single medial PFC (mPFC) neurons in control rats and PNE rats as they performed our stopsignal task. We found that PNE rats were faster for all trial types and were less likely to inhibit the behavioral response on STOP trials. Neurons in mPFC fired more strongly on STOP trials and were correlated with accuracy and reaction time. Although the number of neurons exhibiting significant modulation during task performance did not differ between groups, overall activity in PNE was reduced. We conclude that PNE makes rats impulsive and reduces firing in mPFC neurons that carry signals related to response inhibition.

The effect of acute alcohol exposure on hepatic oxidative stress and function: prevention by micronutrients

Alcohol binge drinking, especially in teenagers and young adults is a major public health issue in the UK, with the number of alcohol related liver disorders steadily increasing. Understanding the mechanisms behind liver disease arising from binge-drinking and finding ways to prevent such damage are currently important areas of research. In the present investigation the effect of acute ethanol administration on hepatic oxidative damage and apoptosis was examined using both an in vivo and in vitro approach; the effect of micronutrient supplementation prior and during ethanol exposure was also studied. The following studies were performed: (1) ethanol administration (75 mmol/kg body weight) and cyanamide pre-treatment followed by ethanol to study elevated acetaldehyde levels with liver tissue analysed 2.5, 6 and 24 hours post-alcohol; (2). Using juvenile animals, 2% betaine supplementation followed by acute ethanol with tissue analysed 24 hrs post ethanol; and (3). Micronutrient supplementation during concomitant ethanol exposure to hepG2 cells. It was found that a single dose of alcohol caused oxidative damage to the liver of rats at 2.5 hr post-alcohol as evidenced by decreased glutathione levels and increased malondialdehyde levels in both the cytosol and mitochondria. Liver function was also depressed but there were no findings of apoptosis as cytochrome c levels and caspase 3 activity was unchanged. At 6 hours, the effect of ethanol was reduced suggesting some degree of recovery, however, by 24 hours, increased mitochondrial oxidative stress was apparent. The effect of elevated acetaldehyde on hepatic damage was particularly evident at 24 hours, with some oxidative changes at earlier time points. At 24 hours, acetaldehyde caused a profound drop in glutathione levels in the cytosol and hepatic function was still deteriorating. Studies examining ethanol exposure to juvenile livers showed that glutathione levels were increased, suggesting an overtly protective response not seen in with older animals. It also showed that despite cytochrome c release into the cytosol, caspase-3 levels were not increased. This suggests that ATP depletion is preventing apoptosis initiation. Betaine supplementation prevented almost all of the alcohol-mediated changes, suggesting that the main mechanism behind alcohol-mediated liver damage is oxidative stress. Results using the hepG2 cell line model showed that micronutrients involved in glutathione synthesis can protect against hepatocyte damage caused by alcohol metabolism, with reduced reactive oxygen species and increased/maintained glutathione levels. In summary, these results demonstrate that both acute alcohol and acetaldehyde can have damaging effects to the liver, but that dietary intervention may be able to protect against ethanol induced oxidative stress.

Prenatal testosterone exposure as a model for the study of endocrine-disrupting chemicals on the gerbil prostate

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Single early prenatal lipopolysaccharide exposure impairs striatal monoamines and maternal care in female rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Gross Motor Deficits in Children Prenatally Exposed to Alcohol: A Meta-analysis

BACKGROUND AND OBJECTIVES: Gross motor (GM) deficits are often reported in children with prenatal alcohol exposure (PAE), but their prevalence and the domains affected are not clear. The objective of this review was to characterize GM impairment in children with a diagnosis of fetal alcohol spectrum disorder (FASD) or moderate to heavy maternal alcohol intake.METHODS: A systematic review with meta-analysis was conducted. Medline, Embase, Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, PEDro, and Google Scholar databases were searched. Published observational studies including children aged 0 to <= 18 years with (1) an FASD diagnosis or moderate to heavy PAE, or a mother with confirmed alcohol dependency or binge drinking during pregnancy, and (2) GM outcomes obtained by using a standardized assessment tool. Data were extracted regarding participants, exposure, diagnosis, and outcomes by using a standardized protocol. Methodological quality was evaluated by using Strengthening the Reporting of Observational Studies in Epidemiology guidelines.RESULTS: The search recovered 2881 articles of which 14 met the systematic review inclusion criteria. The subjects' mean age ranged from 3 days to 13 years. Study limitations included failure to report cutoffs for impairment, nonstandardized reporting of PAE, and small sample sizes. The meta-analysis pooled results (n = 10) revealed a significant association between a diagnosis of FASD or moderate to heavy PAE and GM impairment (odds ratio: 2.9; 95% confidence interval: 2.1-4.0). GM deficits were found in balance, coordination, and ball skills. There was insufficient data to determine prevalence.CONCLUSIONS: The significant results suggest evaluation of GM proficiency should be a standard component of multidisciplinary FASD diagnostic services.

Prenatal zinc prevents communication impairments and BDNF disturbance in a rat model of autism induced by prenatal lipopolysaccharide exposure

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Fish Consumption and Prenatal Mercury Exposure

Methyl mercury levels in fish tissues have recently become a health issue. Does this toxin adversely affect humans to the point that fish consumption should be severely limited? Health effects of high levels of mercury exposure to human adults are fairly well known, however the effects of lower levels of exposure on human fetal development are less understood. Recent guidelines issued by the United States Food and Drug Agency and the Environmental Protection Agency recommended that pregnant women should refrain from consuming some types of fish, and limit consumption to certain levels, but results of health studies used to develop recommendations were inconclusive when low levels of in-utero methyl mercury exposure were compared. Other studies demonstrated health benefits of fish consumption to developing fetuses. These health benefits may be an over-riding factor, and my interpretation of various studies concludes that restricted consumption of some fish species may be premature at this time due to a need to balance potential health benefits against mercury toxicity hazard.

Prenatal environmental exposure and neurodevelopmentally important gene expression in malformed brain tissue from pediatric intractable epilepsy patients

The primary objective of this proposal was to determine whether mitochondrial oxidative stress and variation in a particular mtDNA lineage contribute to the risk of developing cortical dysplasia and are potential contributing factors in epileptogenesis in children. The occurrence of epilepsy in children is highly associated with malformations of cortical development (MCD). It appears that MCD might arise from developmental errors due to environmental exposures in combination with inherited variation in response to environmental exposures and mitochondrial function. Therefore, it is postulated that variation in a particular mtDNA lineage of children contributes to the effects of mitochondrial DNA damage on MCD phenotype. Quantitative PCR and dot blot were used to examine mitochondrial oxidative damage and single nucleotide polymorphism (SNP) in the mitochondrial genome in brain tissue from 48 pediatric intractable epilepsy patients from Miami Children’s Hospital and 11 control samples from NICHD Brain and Tissue Bank for Developmental Disorders. Epilepsy patients showed higher mtDNA copy number compared to normal health subjects (controls). Oxidative mtDNA damage was lower in non-neoplastic but higher in neoplastic epilepsy patients compared to controls. There was a trend of lower mtDNA oxidative damage in the non-neoplastic (MCD) patients compared to controls, yet, the reverse was observed in neoplastic (MCD and Non-MCD) epilepsy patients. The presence of mtDNA SNP and haplogroups did not show any statistically significant relationships with epilepsy phenotypes. However, SNPs G9804A and G9952A were found in higher frequencies in epilepsy samples. Logistic regression analysis showed no relationship between mtDNA oxidative stress, mtDNA copy number, mitochondrial haplogroups and SNP variations with epilepsy in pediatric patients. The levels of mtDNA copy number and oxidative mtDNA damage and the SNPs G9952A and T10010C predicted neoplastic epilepsy, however, this was not significant due to a small sample size of pediatric subjects. Findings of this study indicate that an increase in mtDNA content may be compensatory mechanisms for defective mitochondria in intractable epilepsy and brain tumor. Further validation of these findings related to mitochondrial genotypes and mitochondrial dysfunction in pediatric epilepsy and MCD may lay the ground for the development of new therapies and prevention strategies during embryogenesis.

Preschoolers’ Executive Control and Diurnal Cortisol as Mediators of the Relations of Prenatal Stress to Child Adjustment

Thesis (Ph.D.)--University of Washington, 2016-08

Fetal Alcohol Spectrum Disorder Primary Prevention through FASD Diagnosis: Identification of High-Risk Birth Mothers through the Diagnosis of their Children. Follow-up Study

Thesis (Master's)--University of Washington, 2016-08