Variation in the Glucocorticoid Receptor Gene at rs41423247 Moderates the Effect of Prenatal Maternal Psychological Symptoms on Child Cortisol Reactivity and Behavior

Prenatal maternal psychopathology affects child development, but some children seem more vulnerable than others. Genetic variance in hypothalamic-pituitary-adrenal axis genes may influence the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems. This hypothesis was tested in the Generation R Study, a population-based cohort from fetal life onward. In total, 1727 children of Northern European descent and their mothers participated in this study and were genotyped for variants in the glucocorticoid receptor (GR) gene (rs6189/rs6190, rs10052957, rs41423247, rs6195, and rs6198) and the FK506-binding protein 5 (FKBP5) gene (rs1360780). Prenatal maternal psychological symptoms were assessed at 20 weeks pregnancy and child behavior was assessed by both parents at 3 years. In a subsample of 331 children, data about cortisol reactivity were available. Based on power calculations, only those genetic variants with sufficient minor allele frequencies (rs41423247, rs10052957, and rs1360780) were included in the interaction analyses. We found that variation in GR at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child emotional and behavioral problems (beta 0.41, SE 0.16, p=0.009). This prenatal interaction effect was independent of mother's genotype and maternal postnatal psychopathology, and not found for prenatal psychological symptoms of the father. Moreover, the interaction between rs41423247 and prenatal psychological symptoms was also associated with decreased child cortisol reactivity (beta -2.30, p-value 0.05). These findings emphasize the potential effect of prenatal gene-environment interaction, and give insight in possible mechanisms accounting for children's individual vulnerability to develop emotional and behavioral problems.     

Prenatal exposure to maternal depression and cortisol influences infant temperament

BACKGROUND: Accumulating evidence indicates that prenatal maternal and fetal processes can have a lasting influence on infant and child development. Results from animal models indicate that prenatal exposure to maternal stress and stress hormones has lasting consequences for development of the offspring. Few prospective studies of human pregnancy have examined the consequences of prenatal exposure to stress and stress hormones. METHOD: In this study the effects of prenatal maternal psychosocial (anxiety, depression, and perceived stress) and endocrine (cortisol) indicators of stress on infant temperament were examined in a sample of 247 full-term infants. Maternal salivary cortisol and psychological state were evaluated at 18-20, 24-26, and 30-32 weeks of gestation and at 2 months postpartum. Infant temperament was assessed with a measure of negative reactivity (the fear subscale of the Infant Temperament Questionnaire) at 2 months of age. RESULTS: Elevated maternal cortisol at 30-32 weeks of gestation, but not earlier in pregnancy, was significantly associated with greater maternal report of infant negative reactivity. Prenatal maternal anxiety and depression additionally predicted infant temperament. The associations between maternal cortisol and maternal depression remained after controlling for postnatal maternal psychological state. CONCLUSIONS: These data suggest that prenatal exposure to maternal stress has consequences for the development of infant temperament.     

Long-term effects of prenatal stress and postnatal handling on age-related glucocorticoid secretion and cognitive performance: a longitudinal study in the rat.

There is growing evidence that stress during prenatal and postnatal periods of life can modify adaptive capacities in adulthood. The hypothalamo-pituitary-adrenal axis may mediate an animal's responses to perinatal stressful events and thus serve as a neurobiological substrate of the behavioural consequences of these early events. However, little is known about the long-term effects of prenatal stressors throughout the entire life of the animals. The focus of the present study was to examine the long-term influences of a prenatal and postnatal stress on glucocorticoid secretion and cognitive performance. Prenatal stress of rat dams during the last week of pregnancy and postnatal daily handling of rat pups during the first 3 weeks of life were used as stressors. The long-term effects of these manipulations were analysed using a longitudinal approach throughout the entire life of the animals, and were repeatedly tested in adulthood (4-7 months), middle age (13-16 months) and in later life (20-24 months). The study demonstrated that prenatal stress and postnatal handling induced opposite effects on both glucocorticoid secretion and cognitive performance. Prenatal stress accelerated the age-related hypothalamo-pituitary-adrenal axis dysfunctions; indeed, circulating glucocorticoids levels of prenatally stressed middle-aged animals are similar to old control ones, and also induced cognitive impairments. In contrast, postnatal handling protected from the age-related neuroendocrine and behavioural alterations. These results show that the altered glucocorticoid secretion induced by early environmental manipulations is primary to the cognitive alterations observed only later in life and could be one cause of age-related memory deficits.     

Postnatal stimulation of the pups counteracts prenatal stress-induced deficits in hippocampal neurogenesis.

BACKGROUND: Prenatal stress constitutes a developmental risk factor for later psychopathology. The behavioral disorders are sustained by neurobiological alterations including long-term reduction of hippocampal neurogenesis; its deregulation has been involved in cognitive impairments, mood disorders and addiction. A major goal is to define periods in development and strategies for intervening to prevent the effects of early stressful events. We investigated the ability of a postnatal infantile stimulation to prevent prenatal stress-induced alteration in hippocampal neurogenesis. METHODS: The influence of postnatal handling on prenatal stress-induced changes in hippocampal neurogenesis was examined in 4 and 26 month-old male rats. Three distinct phases of the neurogenesis were studied: proliferation, survival and neuronal differentiation. RESULTS: Prenatal stress reduced hippocampal cell proliferation all throughout life. Furthermore, the survival rate of newborn cells, the number of immature neurons and the number of differentiated new neurons were reduced in young and old prenatally-stressed rats. All those deleterious effects were counteracted by neonatal handling. CONCLUSIONS: These data show that finer aspects of brain shaping can be rewired by environmental influences occurring at sensitive phase of development. They also suggest that infantile stimulation may reverse the appearance of behavioral disorders induced by early life stress.     

Effect of environmental enrichment on fearful behavior and gastrin-releasing peptide receptor expression in the amygdala of prenatal stressed rats

Prenatal stressed offspring exhibit more fearful behavior in behavioral tests, which can be reversed by environmental enrichment (EE). However, the physiological basis of these phenomena remains unclear. Previous studies revealed that abnormal fearful behavior of prenatally stressed offspring may be a consequence of increased activities of CRFergic systems (corticotropin-releasing factor and its receptors) in the amygdala. Gastrin-releasing peptide receptors (GRPR) also have an important role in regulating amygdala-dependent, fear-related learning. The aim of this study was to examine weather prenatal stress and EE can affect the expression of GRPR in the amygdala. We reported here that prenatal chronic stress (subjected to immobilization and bright light stress for 45 min three times per day) caused increased fearfulness in defensive withdrawal test but had no effect on the expression of GRPR in the amygdala. However, enriched environment housing treatment on postnatal days 21-60 can dramatically increase the expression of GRPR in amygdala and reduce fearfulness in the defensive withdrawal test. Our results demonstrate for the first time that EE can modify the expression of GRPR in the amygdala, which might contribute to our understanding of the physiological effects of environmental enrichment.     

Associations between maternal prenatal cortisol concentrations and child outcomes: A systematic review

A frequently proposed mechanism underlying the link between maternal prenatal stress/anxiety and child outcomes is heightened concentrations of maternal cortisol. In this systematic review, empirical findings on associations between maternal prenatal cortisol concentrations and child outcomes (physical/health, cognitive/motor, psychological/behavioral, and cortisol) are summarized. The number of empirical studies that find significant associations between maternal prenatal cortisol and child outcomes is small, but the majority of the studies that do find associations show that maternal cortisol is related to altered child outcomes (e.g. more physical/health problems, lower cognitive/motor development, more psychological/behavioral problems, and higher child cortisol concentrations). Inspection of the studies reveals possible critical gestational periods for maternal cortisol to affect different child outcomes.The heterogeneity in study designs and cortisol assessment methods makes drawing strong conclusions premature. However, the fact that most studies did not find significant associations suggests that maternal cortisol may not to be the sole or even main underlying mechanism in the relation between maternal prenatal stress/anxiety and child outcomes. Limitations of the reviewed studies are discussed, and directions for future research and reporting strategies are provided.     

Cognitive ability predicts degree of genetic abnormality in participants with 18q deletions.

One of the most common chromosomal deletions is a loss of genetic material from the long arm of chromosome 18. Most individuals with this condition exhibit mental retardation (68%), yet previous attempts to link cognitive status to deletion size have not shown an association, possibly because cases with additional genetic abnormalities were included. We studied 46 participants ranging from 3 to 35 years of age who had a pure genetic abnormality by excluding those with mosaicism or complex genetic rearrangements. Our patients had terminal deletions ranging from a proximal breakpoint at 18q21.1 (greater genetic abnormality, larger deletion size) to a more distal breakpoint at 18q23 characterized with molecular genetic techniques. Cognitive ability, assessed with the age-appropriate measure (Bayley, 1993 , Differential Ability Scale, Wechsler Scales), ranged from IQ = 49 to 113, with a predominance of mild and moderate mental retardation. Using multivariate regression, deletion size breakpoint rank order was predicted by cognitive ability, age, and adaptive behavior (Vineland Adaptive Behavior Scales), accounting for 36% of the variance in deletion size. However, lower cognitive ability (beta = .34, p = .032) and younger age (beta = .296, p = .024) predicted a larger deletion size, but adaptive behavior (beta = .225, p = .15) did not. An additional multivariate regression showed that cognitive ability and age together accounted for 33% of the variance in deletion size, whereas univariate regression showed that cognitive ability accounted for 26% of the variance and age accounted for 11% of the variance. These findings suggest that degree of cognitive impairment is associated with genetic abnormality when a large sample of individuals with "pure" deletions of genetic material from chromosome 18 is examined.     

Prenatal corticosteroid exposure alters early developmental seizures and behavior

In humans, corticosteroids are often administered prenatally to improve lung development in preterm neonates. Studies in exposed children as well as in children, whose mothers experienced significant stress during pregnancy indicate behavioral problems and possible increased occurrence of epileptic spasms. This study investigated whether prenatal corticosteroid exposure alters early postnatal seizure susceptibility and behaviors. On gestational day 15, pregnant rats were injected i.p. with hydrocortisone (2×10mg/kg), betamethasone (2×0.4mg/kg) or vehicle. On postnatal day (P)15, seizures were induced by flurothyl or kainic acid (3.5 or 5.0mg/kg). Horizontal bar holding was determined prior to seizures and again on P17. Performance in the elevated plus maze was assessed on P20-22. Prenatal exposure to betamethasone decreased postnatal susceptibility to flurothyl-induced clonic seizures but not to kainic acid-induced seizures. Prenatal hydrocortisone decreased postnatal weight but did not affect seizure susceptibility. Hydrocortisone alone did not affect performance in behavioral tests except for improving horizontal bar holding on P17. A combination of prenatal hydrocortisone and postnatal seizures resulted in increased anxiety. Prenatal exposure to mineralocorticoid receptor blocker canrenoic acid did not attenuate, but surprisingly amplified the effects of hydrocortisone on body weight and significantly worsened horizontal bar performance. Thus, prenatal exposure to excess corticosteroids alters postnatal seizure susceptibility and behaviors. Specific effects may depend on corticosteroid species.     

Periadolescent maturation of the prefrontal cortex is sex‐specific and is disrupted by prenatal stress

The prefrontal cortex (PFC) undergoes dramatic, sex‐specific maturation during adolescence. Adolescence is a vulnerable window for developing mental illnesses that show significant sexual dimorphisms. Gestational stress is associated with increased risk for both schizophrenia, which is more common among men, and cognitive deficits. We have shown that male, but not female, rats exposed to prenatal stress develop postpubertal deficits in cognitive behaviors supported by the prefrontal cortex. Here we tested the hypothesis that repeated variable prenatal stress during the third week of rat gestation disrupts periadolescent development of prefrontal neurons in a sex‐specific fashion. Using Golgi‐Cox stained tissue, we compared dendritic arborization and spine density of prelimbic layer III neurons in prenatally stressed and control animals at juvenile (day 20), prepubertal (day 30), postpubertal (day 56), and adult (day 90) ages (N = 115). Dendritic ramification followed a sex‐specific pattern that was disrupted during adolescence in prenatally stressed males, but not in females. In contrast, the impact of prenatal stress on the female PFC was not evident until adulthood. Prenatal stress also caused reductions in brain and body weights, and the latter effect was more pronounced among males. Additionally, there was a trend toward reduced testosterone levels for adult prenatally stressed males. Our findings indicate that, similarly to humans, the rat PFC undergoes sex‐specific development during adolescence and furthermore that this process is disrupted by prenatal stress. These findings may be relevant to both the development of normal sex differences in cognition as well as differential male–female vulnerability to psychiatric conditions. J. Comp. J. Comp. Neurol. 521:1828–1843, 2013. © 2012 Wiley Periodicals, Inc.     

Prenatal and Postpartum Maternal Psychological Distress and Infant Development: A Systematic Review

Infant development plays a foundational role in optimal child development and health. Some studies have demonstrated an association between maternal psychological distress and infant outcomes, although the main emphasis has been on postpartum depression and infant-maternal attachment. Prevention and early intervention strategies would benefit from an understanding of the influence of both prenatal and postpartum maternal distress on a broader spectrum of infant developmental outcomes. We conducted a systematic review of studies assessing the effect of prenatal and postpartum maternal psychological distress on five aspects of infant development: global; cognitive; behavioral; socio-emotional; and psychomotor. These findings suggest that prenatal distress can have an adverse effect on cognitive, behavioral, and psychomotor development, and that postpartum distress contributes to cognitive and socio-emotional development.     

Predictors of self-reported resilience in parents of autistic children

BackgroundThough an emerging evidence base has documented the elevated stress and unique challenges among parents of autistic children, less is known about resilience. Based on the resilience-stress model (Fletcher & Sarkar, 2013; Masten, 2011), resilience may be a promising area of investigation given its inverse relationship with stress.MethodFifty parents of autistic children (4:0–10:11 years) self-reported resilience on the Connor-Davidson Resilience Scale (CD-RISC) and completed additional questionnaires, which were categorized into three classes of predictors: psychological functioning, child factors and parenting stress, and positive mental health practices. Regression analyses were conducted to identify the amount of variance in CD-RISC scores explained by the overall model and each class of predictors. The relative strength of individual predictors was investigated.ResultsThe overall model accounted for 66% of the variance in self-reported resilience scores. Two classes of predictors were significant – psychological functioning and positive mental health practices – while child factors and parenting stress were not. Specifically, the class of psychological functioning variables accounted for 45% of the variance in resilience scores and positive mental health practices accounted for an additional 19%. The individual predictors of anxiety, stress, optimism, and self-compassion were the most robust.ConclusionsFindings indicate that certain factors – anxiety, stress, optimism, and self-compassion – are important in understanding self-reported resilience among some parents of autistic children. This may suggest treatment targets for resilience interventions. Continued investigations with larger, more representative samples are needed to expand the present findings.     

Prenatal stress reduces S100B in the neonatal rat hippocampus

Prenatal stress has been shown to disturb neonatal rat brain development. The astroglial-specific neurotrophic factor S100B is known to play an important role in normal brain development. In the present study, we investigated the effects of prenatal stress on S100B concentrations in the hippocampus of 1-day-old Fischer 344 rats. Overall, prenatal stress resulted in a 25% reduction in hippocampal S100B content. Further, male hippocampal S100B content was negatively correlated with plasma corticosterone levels. Positive correlations were found between female S100B levels and fetal growth, and hippocampal brain-derived neurotrophic factor content. In conclusion, the observed reduction in neonatal hippocampal S100B levels, as a consequence of prenatal stress, may be involved in affecting postnatal brain development.     

Different brain profiles in children with prenatal alcohol exposure with or without early adverse exposures

Prenatal alcohol exposure (PAE) can alter brain development and impact mental health outcomes, and often occurs in conjunction with postnatal adversity (e.g., maltreatment). However, it is unclear how postnatal adverse exposures may moderate mental health and brain outcomes in children with PAE. T1‐weighted and diffusion magnetic resonance imaging were obtained from 66 participants aged 7–16 years. Twenty‐one participants had PAE and adverse postnatal exposures (PAE+), 12 had PAE without adverse postnatal exposures (PAE?), and 33 were age‐ and gender‐matched controls unexposed to either prenatal alcohol or postnatal adversity. Internalizing and externalizing mental health symptoms were assessed using the Behavioral Assessment System for Children II, Parent‐Rating Scale. ANCOVAs were used to compare mental health symptoms, limbic and prefrontal cortical volumes, and diffusion parameters of cortico‐limbic white matter tracts between groups, and to assess brain‐mental health relationships. Both PAE groups had worse externalizing behavior (higher scores) than controls. The PAE? group had lower fractional anisotropy (FA) in the bilateral cingulum and left uncinate fasciculus, and smaller volumes in the left anterior cingulate cortex than controls and the PAE+ group. The PAE? group also had higher mean diffusivity (MD) in the left uncinate than the PAE+ group, and smaller right anterior cingulate and superior frontal gyrus volumes than controls. These findings show different brain structure and mental health symptom profiles in children with PAE with and without postnatal adversity, highlighting the need to consider adverse postnatal exposures in individuals with PAE.     

Biosocial factors, sexual orientation and neurocognitive functioning

It has been proposed that sexual orientation related differences in cognitive performance are either due to the actions of prenatal factors early in development or the influence of gender role learning. This study examined the performance of 240 healthy, right-handed heterosexual and homosexual males and females (N = 60 per group) on a battery of cognitive tasks comprising mental rotation, judgement of line orientation (JLO), verbal fluency, perceptual speed and object location memory. Measures were also taken of the psychological gender, birth order, sibling sex composition and the 2nd to 4th finger length ratios of the right and left hands. A series of stepwise regression analyses revealed that sex and sexual orientation were the strongest predictors of cognitive performance, with IQ also contributing considerable variance. Psychological gender (M/F scores) added a small, but significant, amount of variance to mental rotation and perceptual speed scores in addition to these main factors, but prenatal hormone related indices, such as 2nd to 4th finger ratios, birth order and sibling sex composition added no independent predictive power. These findings are discussed in relation to biosocial influences on cognitive differences between heterosexuals and homosexuals.     

Prenatal anxiety predicts individual differences in cortisol in pre-adolescent children.

BACKGROUND: Animal studies suggest that prenatal stress is associated with long-term disturbance in hypothalamic-pituitary-adrenal (HPA) axis function, but evidence in humans is lacking. This study examined the long-term association between prenatal anxiety and measures of diurnal cortisol at age 10 years. METHODS: Measures of cortisol were collected at awakening, 30 min after awakening, and at 4 pm and 9 pm on 3 consecutive days in a sample of 10-year-olds (n = 74) from the Avon Longitudinal Study of Parents and Children, a prospective longitudinal cohort study of mothers and children on whom measures of anxiety and depression were collected in pregnancy and the postpartum period. Analyses examined the links between symptoms of prenatal anxiety and multiple indicators of cortisol, an index of HPA axis functioning. RESULTS: Prenatal anxiety was significantly associated with individual differences in awakening and afternoon cortisol after accounting for obstetric and sociodemographic risk (partial correlations were .32 and .25, p < .05). The effect for awakening cortisol remained significant after controlling for multiple postnatal assessments of maternal anxiety and depression. CONCLUSIONS: This study provides the first human evidence that prenatal anxiety might have lasting effects on HPA axis functioning in the child and that prenatal anxiety might constitute a mechanism for an increased vulnerability to psychopathology in children and adolescents.     

Prenatal psychobiological predictors of anxiety risk in preadolescent children

Experimental animal models have demonstrated that one of the primary consequences of prenatal stress is increased fear and anxiety in the offspring. Few prospective human studies have evaluated the consequences of prenatal stress on anxiety during preadolescence. The purpose of this investigation is to determine the consequences of prenatal exposure to both maternal biological stress signals and psychological distress on anxiety in preadolescent children. Participants included 178 mother-child pairs. Maternal psychological distress (general anxiety, perceived stress, depression and pregnancy-specific anxiety) and biological stress signals were evaluated at 19, 25, and 31 gestational weeks. Anxiety was evaluated in the children at 6-9 years of age using the Child Behavior Checklist. Analyses revealed that prenatal exposure to elevated maternal cortisol, depression, perceived stress and pregnancy-specific anxiety was associated with increased anxiety in children. These associations remained after considering obstetric, sociodemographic and postnatal maternal psychological distress; factors that could influence child development. When all of the prenatal measures were considered together, cortisol and pregnancy-specific anxiety independently predicted child anxiety. Children exposed to elevated prenatal maternal cortisol and pregnancy-specific anxiety were at an increased risk for developing anxiety problems during the preadolescent period. This project identifies prenatal risk factors associated with lasting consequences for child mental health and raises the possibility that reducing maternal distress during the prenatal period will have long term benefits for child well-being.     

Prenatal stress alters microglial development and distribution in postnatal rat brain

Stress affects microglial function and viability during adulthood and early postnatal life; however, it is unknown whether stress to the pregnant dam might alter offspring microglia. The effects of prenatal stress on microglial development and distribution in the postnatal brain were studied using Wistar rats. Prenatal stress consisting of 20 min of forced swimming occurred on embryonic days 10–20. On postnatal days 1 and 10, stressed and control pups were killed. Microglia were identified using Griffonia simplicifolia lectin and quantified in the whole encephalon. In addition, plasma corticosterone was measured in dams at embryonic day 20, and in pups on postnatal days 1 and 10. At postnatal day 1, there was an increase in number of ramified microglia in the parietal, entorhinal and frontal cortices, septum, basal ganglia, thalamus, medulla oblongata and internal capsule in the stressed pups as compared to controls, but also there was a reduction of amoeboid microglia and the total number of microglia in the corpus callosum. By postnatal day 10, there were no differences in the morphologic type or the distribution of microglia between the prenatal stress and control groups, except in the corpus callosum; where prenatal stress decreased the number of ramified microglia. The stress procedure was effective in producing plasma rise in corticosterone levels of pregnant rats at embryonic day 20 when compared to same age controls. Prenatal stress reduced the number of immature microglia and promoted an accelerated microglial differentiation into a ramified form. These findings may be related to an increase in plasma corticosterone in the pregnant dam.     

Prenatal phthalate exposure,oxidative stress-related genetic vulnerability and early life neurodevelopment: A birth cohort study

Prenatal phthalate chemicals may have adverse effects on brain development by various mechanisms including oxidant damage. However, birth cohort findings have been conflicting. This study aimed to (i) investigate the interplay between maternal prenatal phthalate levels, infant genetic vulnerability to oxidative stress, and child neurodevelopment and (ii) examine combined putative oxidant exposures. In a population-based birth cohort of 1064 women with prenatal recruitment in Victoria, Australia, maternal urine was collected at 36 weeks of pregnancy and phthalate metabolite concentrations measured. An unweighted genetic score for oxidative stress was made using a candidate gene approach. Cognition was assessed using the BAYLEY-III at two years (n = 678). Parents completed questionnaires for doctor diagnosed autism spectrum disorder (ASD) (1.4 %), ASD traits (4.9 %) and child inattention/hyperactivity (n = 791). Analyses included multiple linear and logistic regression. Higher prenatal phthalate levels and a higher oxidative stress genetic score were each associated with subsequent ASD. Several oxidative stress-related SNPs modified the association between prenatal phthalates and ASD and other outcomes. Consistent patterns were evident across gene score-phthalate combinations for cognition, ASD, ASD traits and inattention/hyperactivity. Other putative oxidant factors such as prenatal smoking further increased risk. Prenatal phthalate levels and infant oxidative stress-related genetic vulnerability are associated with adverse neurodevelopment. Combined exposures are important. Current recommendations and regulation on maternal phthalate exposure during pregnancy require re-evaluation.     

Prenatal bystander stress alters brain, behavior, and the epigenome of developing rat offspring

The prenatal environment, including prenatal stress, has been extensively studied in laboratory animals and humans. However, studies of the prenatal environment usually directly stress pregnant females, but stress may come 'indirectly', through stress to a cage-mate. The current study used indirect prenatal bystander stress and investigated the effects on the gross morphology, pre-weaning behavior, and epigenome of rat offspring. Pregnant Long-Evans rats were housed with another female rat that underwent elevated platform stress from gestational days 12 to 16. We found that ultrasonic vocalizations of female cage-mates were disrupted following the stress procedure. After birth, offspring were tested on two behavioral tasks and sacrificed at postnatal day 21 (p21). Frontal cortex and hippocampal tissue was used to measure global DNA methylation and gene expression changes. At p21, bystander-stressed female offspring exhibited increased body weight. Offspring behavior on the negative geotaxis task was altered by prenatal bystander stress, and locomotor behavior was reduced in female offspring. Global DNA methylation increased in the frontal cortex and hippocampus of bystander-stressed offspring. Microarray analysis revealed significant gene expression level changes in 558 different genes, of which only 10 exhibited overlap between males and females or brain areas. These alterations in gene expression were associated with overrepresentation of 36 biological processes and 34 canonical pathways. Prenatal stress thus does not have to be experienced by the mother herself to influence offspring brain development. Furthermore, this type of 'indirect' prenatal stress alters offspring DNA methylation patterns, gene expression profiles, and behavior.     

Exposure to prenatal carbon monoxide and postnatal hyperthermia: short and long-term effects on neurochemicals and neuroglia in the developing brain

The effects of prenatal exposure to carbon monoxide (CO), a major component of cigarette smoke, was studied alone or in combination with postnatal hyperthermia, on the structural and neurochemical development of the postnatal brain at 1 and 8 weeks. Pregnant guinea pigs (n = 11) were exposed to 200 p.p.m CO for 10 h/day from midgestation until term (68 days), whereas control mothers (n = 10) breathed room air. On postnatal day 4, neonates from the control and CO-exposed pregnancies were exposed to hyperthermia (35 degrees C) for 75 min or remained at ambient (23 degrees C) temperature. Using semiquantitative immunohistochemical techniques the following neurotransmitter alterations were found in the medulla at 1 week: a decrease in met-enkephalin-immunoreactivity (IR) following postnatal hyperthermia and an increase in 5-hydroxytryptamine-IR following a combination of CO and hyperthermia. No alterations were observed in substance P- or tyrosine-hydroxylase-IR in any paradigm. At 8 weeks of age the combination of prenatal CO exposure followed by a brief hyperthermic stress postnatally resulted in lesions throughout the brain and an increase in glial fibrillary acidic protein-IR in the medulla. Such effects on brain development could be of relevance in cardiorespiratory control in the neonate and could have implications for the etiology of Sudden Infant Death Syndrome, where smoking and hyperthermia are major risk factors.