Prenatal exposure to alcohol and drugs is associated with physical, cognitive, and behavioral problems across the offspring's lifespan and an increased risk of alcohol and drug use in adolescent and ...young adult offspring. These prenatal effects continue to be evident after control for demographic background and parental alcohol and drug use. Behavior problems in childhood and adolescence associated with prenatal exposures may serve as a mediator of the prenatal exposure effects on offspring substance use.
This study aimed to assess associations between prenatal and postnatal exposure to lead (Pb), mercury (Hg) and polychlorinated biphenyls (PCBs) and gray matter volume of key regions of the brain ...reward circuit, namely the caudate nucleus, putamen, nucleus accumbens (nAcc), the amygdala, the orbitofrontal cortex (OFC) and the anterior cingulate cortex (ACC). Structural magnetic resonance imaging (MRI) was conducted in 77 Inuit adolescents (mean age = 18.39) from Nunavik, Canada, who also completed the Brief Sensation Seeking Scale (BSSS-4) and Sensation Seeking – 2 (SS-2), two self-report questionnaires evaluating the tendency toward sensation seeking, which is a proxy of reward-related behaviors. Exposures to Pb, Hg and PCBs were measured in cord blood at birth, in blood samples at 11 years old and at time of testing (18 years old). Multivariate linear regressions were corrected for multiple comparisons and adjusted for potential confounders, such as participants’ sociodemographic characteristics and nutrient fish intake. Results showed that higher cord blood Pb levels predicted smaller gray matter volume in the bilateral nAcc, caudate nucleus, amygdala and OFC as well as in left ACC. A moderating effect of sex was identified, indicating that the Pb-related reduction in volume in the nAcc and caudate nucleus was more pronounced in female. Higher blood Hg levels at age 11 predicted smaller right amygdala independently of sex. No significant associations were found between blood PCBs levels at all three times of exposure. This study provides scientific support for the detrimental effects of prenatal Pb and childhood Hg blood concentrations on gray matter volume in key reward-related brain structures.
•Prenatal Pb exposure was negatively linked to subcortical and frontal gray matter volume at age 18 in a sex-specific manner.•Higher childhood Hg exposure, but not prenatal, was associated with reduced gray matter volume in bilateral amygdala.•Developmental PCBs exposure was not related to brain volume of reward-related regions.
Despite several decades of research and prevention efforts, fetal alcohol spectrum disorders (FASD) remain the most common preventable cause of neurodevelopmental disabilities worldwide. Animal and ...human studies have implicated fetal alcohol-induced alterations in epigenetic programming as a chief mechanism in FASD. Several studies have demonstrated fetal alcohol-related alterations in methylation and expression of imprinted genes in placental, brain, and embryonic tissue. Imprinted genes are epigenetically regulated in a parent-of-origin-specific manner, in which only the maternal or paternal allele is expressed, and the other allele is silenced. The chief functions of imprinted genes are in placental development, somatic growth, and neurobehavior—three domains characteristically affected in FASD. In this review, we summarize the growing body of literature characterizing prenatal alcohol-related alterations in imprinted gene methylation and/or expression and discuss potential mechanistic roles for these alterations in the teratogenic effects of prenatal alcohol exposure. Future research is needed to examine potential physiologic mechanisms by which alterations in imprinted genes disrupt development in FASD, which may, in turn, elucidate novel targets for intervention. Furthermore, mechanistic alterations in imprinted gene expression and/or methylation in FASD may inform screening assays that identify individuals with FASD neurobehavioral deficits who may benefit from early interventions.
Background
Cognitive and behavioral sequelae of prenatal alcohol exposure (PAE) continue to be prevalent in the United States and worldwide. Because these sequelae are also common in other ...neurodevelopmental disorders, researchers have attempted to identify a distinct neurobehavioral profile to facilitate the differential diagnosis of fetal alcohol spectrum disorders (FASD). We used an innovative, individual participant meta‐analytic technique to combine data from six large U.S. longitudinal cohorts to provide a more comprehensive and reliable characterization of the neurobehavioral deficits seen in FASD than can be obtained from smaller samples.
Methods
Meta‐analyses were performed on data from 2236 participants to examine effects of PAE (measured as oz absolute alcohol/day (AA/day)) on IQ, four domains of cognition function (learning and memory, executive function, reading achievement, and math achievement), sustained attention, and behavior problems, after adjusting for potential confounders using propensity scores.
Results
The effect sizes for IQ and the four domains of cognitive function were strikingly similar to one another and did not differ at school age, adolescence, or young adulthood. Effect sizes were smaller in the more middle‐class Seattle cohort and larger in the three cohorts that obtained more detailed and comprehensive assessments of AA/day. PAE effect sizes were somewhat weaker for parent‐ and teacher‐reported behavior problems and not significant for sustained attention. In a meta‐analysis of five aspects of executive function, the strongest effect was on set‐shifting.
Conclusions
The similarity in the effect sizes for the four domains of cognitive function suggests that PAE affects an underlying component or components of cognition involving learning and memory and executive function that are reflected in IQ and academic achievement scores. The weaker effects in the more middle‐class cohort may reflect a more cognitively stimulating environment, a different maternal drinking pattern (lower alcohol dose/occasion), and/or better maternal prenatal nutrition. These findings identify two domains of cognition—learning/memory and set‐shifting—that are particularly affected by PAE, and one, sustained attention, which is apparently spared.
We used an innovative, individual participant meta‐analytic technique to combine data from six large U.S. longitudinal cohorts to provide a more comprehensive and reliable characterization of the neurobehavioral deficits seen in FASD than can be obtained from smaller samples. Prenatal alcohol exposure (PAE) effects on cognitive function were stronger than for behaviour problems or sustained attention. This analysis identified two domains of cognition—learning/memory and set‐shifting—that are particularly affected by PAE, and one domain, sustained attention, which is spared.
Background
Prenatal alcohol exposure (PAE) is associated with smaller regional and global brain volumes. In rats, gestational choline supplementation mitigates adverse developmental effects of ...ethanol exposure. Our recent randomized, double‐blind, placebo‐controlled maternal choline supplementation trial showed improved somatic and functional outcomes in infants at 6.5 and 12 months postpartum. Here, we examined whether maternal choline supplementation protected the newborn brain from PAE‐related volume reductions and, if so, whether these volume changes were associated with improved infant recognition memory.
Methods
Fifty‐two infants born to heavy‐drinking women who had participated in a choline supplementation trial during pregnancy underwent structural magnetic resonance imaging with a multi‐echo FLASH protocol on a 3T Siemens Allegra MRI (median age = 2.8 weeks postpartum). Subcortical regions were manually segmented. Recognition memory was assessed at 12 months on the Fagan Test of Infant Intelligence (FTII). We examined the effects of choline on regional brain volumes, whether choline‐related volume increases were associated with higher FTII scores, and the degree to which the regional volume increases mediated the effects of choline on the FTII.
Results
Usable MRI data were acquired in 50 infants (choline: n = 27; placebo: n = 23). Normalized volumes were larger in six of 12 regions in the choline than placebo arm (t ≥ 2.05, p ≤ 0.05) and were correlated with the degree of maternal choline adherence (β ≥ 0.28, p ≤ 0.04). Larger right putamen and corpus callosum were related to higher FTII scores (r = 0.36, p = 0.02) with a trend toward partial mediation of the choline effect on recognition memory.
Conclusions
High‐dose choline supplementation during pregnancy mitigated PAE‐related regional volume reductions, with larger volumes associated with improved 12‐month recognition memory. These results provide the first evidence that choline may be neuroprotective against PAE‐related brain structural deficits in humans.
Prenatal alcohol exposure (PAE) and prenatal stress (PS) are highly prevalent conditions known to affect fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis. The objectives of this ...study were to assess the effect of light PAE, PS, and PAE-PS interaction on fetal HPA axis activity assessed via placental and umbilical cord blood biomarkers. Participants of the ENRICH-2 cohort were recruited during the second trimester and classified into the PAE and unexposed control groups. PS was assessed by the Perceived Stress Scale. Placental tissue was collected promptly after delivery; gene and protein analysis for 11
-HSD1, 11
-HSD2, and pCRH were conducted by qPCR and ELISA, respectively. Umbilical cord blood was analyzed for cortisone and cortisol. Pearson correlation and multivariable linear regression examined the association of PAE and PS with HPA axis biomarkers. Mean alcohol consumption in the PAE group was ~2 drinks/week. Higher PS was observed in the PAE group (
< 0.01). In multivariable modeling, PS was associated with pCRH gene expression (
= 0.006,
< 0.01), while PAE was associated with 11
-HSD2 protein expression (
= 0.56,
< 0.01). A significant alcohol-by-stress interaction was observed with respect to 11
-HSD2 protein expression (
< 0.01). Results indicate that PAE and PS may independently and in combination affect fetal programming of the HPA axis.
Prenatal alcohol exposure (PAE) is associated with alterations in maternal and infant iron homeostasis that are consistent with changes seen in the setting of inflammation. We hypothesized that PAE ...leads to alterations in the placental expression of genes related to iron metabolism and inflammation that play functional roles in the teratogenic effects of alcohol on iron homeostasis. A total of 126 heavy-drinking women (≥1 oz (30 mL) absolute alcohol/day (~1.67 standard drinks/day) or women reporting binge drinking (≥2 drinks/occasion)) and 80 control women (<0.5 oz AA per day, no binging) in Cape Town, South Africa were interviewed prenatally regarding demographics, and alcohol, smoking, and drug use around conception and during pregnancy. Prenatal/maternal and infant hemoglobin and ferritin were measured. Whole-transcriptome RNA sequencing analysis was performed on flash-frozen transplacental tissue samples. Gene sets related to iron metabolism (
= 398) and inflammation (
= 467) were constructed by searching the Molecular Signatures Database for related ontology terms. Principal component analysis (PCA) yielded 59 factors for each theme. In multivariable regression models, PAE was related to 2 iron metabolism PCA factors (PCs) and 5 inflammation PCs, among which 2 iron metabolism and 4 inflammation factors were related to at least 1 key maternal or infant iron outcome. In causal inference analyses based on marginal structural models and the product method, the alterations in the expression profile of genes with functions in immune cell regulation, cytokine activity, angiogenesis, hematopoiesis, and ubiquitous cell processes appeared to partially mediate the relation of prenatal drinking frequency (days/week) around conception to a lower maternal hemoglobin-to-log(ferritin) ratio (proportion mediation = 51.35%). These findings suggest that placental inflammation may be partly responsible for the differences in alcohol-related iron homeostasis patterns between pregnant and non-pregnant adults.
► Mercury was associated with decreased heart rate variability during childhood. ► No association was observed between mercury during childhood and blood pressure. ► Mercury in cord blood was not ...associated with blood pressure. ► Mercury in cord blood was not associated with heart rate variability.
Studies conducted in the Faeroe Islands and Japan suggest a negative impact of mercury on heart rate variability (HRV) among children while the results regarding blood pressure (BP) are less consistent.
To assess the impact of mercury on HRV and BP among Nunavik Inuit children.
A cohort of 226 children was followed from birth to 11 years old. Mercury concentration in cord blood and in blood and hair at 11 years old were used as markers of prenatal and childhood exposure, respectively. HRV was measured using ambulatory 2h-Holter monitoring while BP was measured through a standardized protocol. Simple regression was used to assess the relationship of mercury to BP and HRV parameters. Multiple linear regressions were performed adjusting for covariates such as age, sex, birth weight, body mass index (BMI), height, total n-3 fatty acids, polychlorinated biphenyls (PCB 153), lead, selenium and maternal smoking during pregnancy.
Median cord blood mercury and blood mercury levels at 11 years old were 81.5nmoL/L (IQR: 45.0–140.0) and 14.5nmol/L (IQR: 7.5–28.0), respectively. After adjusting for the covariates, child blood mercury was associated with low frequency (LF) (β=−0.21, p=0.05), the standard deviation of R–R intervals (SDNN) (β=−0.26, p=0.02), the standard deviation of R–R intervals measured over 5min periods (SDANN) (β=−0.31, p=0.01) and the coefficient of variation of R–R intervals (CVRR) (β=−0.06, p=0.02). No significant association was observed with BP.
Mercury exposure during childhood seems to affect HRV among Nunavik Inuit children at school age.
Animal models have demonstrated that maternal nutrition can alter fetal vulnerability to prenatal alcohol exposure (PAE). Few human studies have examined the role of nutrition in fetal alcohol ...spectrum disorders (FASD).
Our objectives were to examine whether fetal vulnerability to PAE-related growth restriction is modified by: 1) rate of gestational weight gain; or prenatal dietary intakes of 2) energy, 3) iron, or 4) choline.
In a prospective longitudinal birth cohort in Cape Town, South Africa, 118 heavy-drinking and 71 abstaining/light-drinking pregnant women were weighed and interviewed regarding demographics, alcohol, cigarette/other drug use, and diet at prenatal visits. Infant length, weight, and head circumference were measured at 2 wk and 12 mo postpartum.
Heavy-drinking mothers reported a binge pattern of drinking Mean = 129 mL (∼7.2 drinks)/occasion on 1.3 d/wk). Rate of gestational weight gain and average daily dietary energy, iron, and choline intakes were similar between heavy-drinking women and controls. In regression models adjusting for maternal age, socioeconomic status, cigarette use, and weeks gestation at delivery, PAE ounces (30 mL) absolute alcohol per day was related to smaller 2-wk length and head circumference and 12-mo length, weight, and head circumference z-scores (β = –0.43 to –0.67; all P values <0.05). In stratified analyses for each maternal nutritional measure (inadequate compared with adequate weight gain; tertiles for dietary energy, iron, and choline intakes), PAE-related growth restriction was more severe in women with poorer nutrition, with effect modification seen by weight gain, energy, iron, and/or choline for several anthropometric outcomes.
Gestational weight gain and dietary intakes of energy, choline, and iron appeared to modify fetal vulnerability to PAE-related growth restriction. These findings suggest a need for screening programs for pregnant women at higher risk of having a child with FASD to identify alcohol-using women who could benefit from nutritional interventions.
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