Early Environmental Insults Research Articles

Asthma Inception: Epidemiologic Risk Factors and Natural History Across the Life Course.

Asthma is a descriptive label for an obstructive inflammatory disease in the lower airways manifesting with symptoms including breathlessness, cough, difficulty in breathing, and wheezing. From a clinician's point of view, asthma symptoms can commence at any age, although most patients with asthma-regardless of their age of onset-seem to have had some form of airway problems during childhood. Asthma inception and related pathophysiologic processes are therefore very likely to occur early in life, further evidenced by recent lung physiologic and mechanistic research. Herein, we present state-of-the-art updates on the role of genetics and epigenetics, early viral and bacterial infections, immune response, and pathophysiology, as well as lifestyle and environmental exposures, in asthma across the life course. We conclude that early environmental insults in genetically vulnerable individuals inducing abnormal, pre-asthmatic airway responses are key events in asthma inception, and we highlight disease heterogeneity across ages and the potential shortsightedness of treating all patients with asthma using the same treatments. Although there are no interventions that, at present, can modify long-term outcomes, a precision-medicine approach should be implemented to optimize treatment and tailor follow-up for all patients with asthma.

Preventive Aspects of Early Resveratrol Supplementation in Cardiovascular and Kidney Disease of Developmental Origins.

The increase in the incidence of cardiovascular diseases (CVDs) and kidney disease has stimulated research for strategies that could prevent, rather than just treat, both interconnected disorders. Resveratrol, a polyphenolic compound with pleiotropic biofunctions, has shown health benefits. Emerging epidemiological data supports that early life environmental insults are regarded as increased risks of developing CVDs and kidney disease in adulthood. Conversely, both disorders could be reversed or postponed by shifting interventions from adulthood to earlier stage by so-called reprogramming. The purpose of this review is first to highlight current epidemiological studies linking cardiovascular and renal programming to resulting CVD and kidney disease of developmental origins. This will be followed by a summary of how resveratrol could exert a positive influence on CVDs and kidney disease. This review also presents an overview of the evidence documenting resveratrol as a reprogramming agent to protect against CVD and kidney disease of developmental origins from animal studies and to outline the advances in understanding the underlying molecular mechanisms. Overall, this review reveals the need for future research to further clarify the reprogramming effects of resveratrol before clinical translation.

Alterations of mitochondrial bioenergetics, dynamics, and morphology support the theory of oxidative damage involvement in autism spectrum disorder.

Autism spectrum disorder (ASD) has been hypothesized to be a result of the interplay between genetic predisposition and increased vulnerability to early environmental insults. Mitochondrial dysfunctions appear also involved in ASD pathophysiology, but the mechanisms by which such alterations develop are not completely understood. Here, we analyzed ASD primary fibroblasts by measuring mitochondrial bioenergetics, ultrastructural and dynamic parameters to investigate the hypothesis that defects in these pathways could be interconnected phenomena responsible or consequence for the redox imbalance observed in ASD. High levels of 4-hydroxynonenal protein adducts together with increased NADPH (nicotinamide adenine dinucleotide phosphateoxidase) activity and mitochondrial superoxide production coupled with a compromised antioxidant response guided by a defective Nuclear Factor Erythroid 2-Related Factor 2 pathway confirmed an unbalanced redox homeostasis in ASD. Moreover, ASD fibroblasts showed overactive mitochondrial bioenergetics associated with atypical morphology and altered expression of mitochondrial electron transport chain complexes and dynamics-regulating factors. We suggest that many of the changes observed in mitochondria could represent compensatory mechanisms by which ASD cells try to adapt to altered energy demand, possibly resulting from a chronic oxinflammatory status.

Altered Hippocampal Epigenetic Regulation Underlying Reduced Cognitive Development in Response to Early Life Environmental Insults

The hippocampus is involved in learning and memory and undergoes significant growth and maturation during the neonatal period. Environmental insults during this developmental timeframe can have lasting effects on brain structure and function. This study assessed hippocampal DNA methylation and gene transcription from two independent studies reporting reduced cognitive development stemming from early life environmental insults (iron deficiency and porcine reproductive and respiratory syndrome virus (PRRSv) infection) using porcine biomedical models. In total, 420 differentially expressed genes (DEGs) were identified between the reduced cognition and control groups, including genes involved in neurodevelopment and function. Gene ontology (GO) terms enriched for DEGs were associated with immune responses, angiogenesis, and cellular development. In addition, 116 differentially methylated regions (DMRs) were identified, which overlapped 125 genes. While no GO terms were enriched for genes overlapping DMRs, many of these genes are known to be involved in neurodevelopment and function, angiogenesis, and immunity. The observed altered methylation and expression of genes involved in neurological function suggest reduced cognition in response to early life environmental insults is due to altered cholinergic signaling and calcium regulation. Finally, two DMRs overlapped with two DEGs, VWF and LRRC32, which are associated with blood brain barrier permeability and regulatory T-cell activation, respectively. These results support the role of altered hippocampal DNA methylation and gene expression in early life environmentally-induced reductions in cognitive development across independent studies.

Relationship between executive function, attachment style, and psychotic like experiences in typically developing youth

Psychotic like experiences (PLE's) are common in the general population, particularly during adolescence, which has generated interest in how PLE's emerge, and the extent to which they reflect either risk for, or resilience to, psychosis. The “attachment-developmental-cognitive” (ADC) model is one effort to model the effect of risk factors on PLEs. The ADC model proposes attachment insecurity as an early environmental insult that can contribute to altered neurodevelopment, increasing the likelihood of PLE's and psychosis. In particular, early-life attachment disruptions may negatively impact numerous aspects of executive function (EF), including behavioral inhibition and emotion regulation. Yet despite the relationship of disrupted attachment to EF impairments, no studies have examined how these factors may combine to contribute to PLE's in adolescents. Here, we examined the relative contributions of daily-life EF and attachment difficulties (avoidance and anxiety) to PLEs in typically developing youth (N=52; ages 10–21). We found that EF deficits and high attachment insecurity both accounted for a significant proportion of the variance in PLE's, and interacted to predict PLE manifestation. Specifically, positive PLEs were predicted by greater trouble monitoring behavioral impact, less difficulty completing tasks, greater difficulty regulating emotional reactions, greater difficulty controlling impulses and higher attachment anxiety. Negative PLEs were predicted by greater difficulty in alternating attention, transitioning across situations, and regulating emotional reactions as well as higher attachment anxiety. These results are consistent with the ADC model, providing evidence that early-life attachment disruptions may impact behavioral regulation and emotional control, which together may contribute to PLEs.

Early Development of Parvalbumin-, Somatostatin-, and Cholecystokinin-Expressing Neurons in Rat Brain following Prenatal Immune Activation and Maternal Iron Deficiency

Prenatal maternal infection and maternal iron deficiency during pregnancy are 2 early environmental insults associated with increased risk for schizophrenia in offspring. Substantial evidence suggests that abnormalities in inhibitory γ-aminobutyric acid (GABA) interneuron function, especially in the parvalbumin subtype of GABA interneuron, both developmentally and in adulthood, may contribute mechanistically to cognitive deficits and psychotic symptoms in schizophrenia. This study used a rat model to test whether prenatal immune activation with lipopolysaccharide (LPS; at gestation days, GD, 15 and 16) or maternal iron deficiency (from GD2 to postnatal day P7) or the combination of both insults alters major subtypes of GABAergic interneurons (parvalbumin, somatostatin, cholecystokinin) in brain regions relevant to schizophrenia (medial and dorsolateral prefrontal cortex [PFC], hippocampal CA1 and dentate gyrus, ventral subiculum) in offspring at P14 or P28. Prenatal LPS treatment significantly increased the density of parvalbumin-immunoreactive neurons at P14 in the medial PFC, dorsolateral PFC, and ventral subiculum of offspring born from iron-sufficient but not iron-deficient dams. Prenatal LPS also increased cholecystokinin neuron density in the medial PFC at P28, under both iron-sufficient and iron-deficient conditions. We observed a large increase in parvalbumin neuron density from P14 to P28 in the medial PFC and subiculum across all birth groups, that was not observed in other brain regions, and significant decreases in somatostatin neuron density from P14 to P28 in all brain regions examined across all birth groups, indicating differential developmental trajectories for parvalbumin and somatostatin neurons in various brain regions during this early postnatal period. Thus, it appears that the medial PFC and ventral subiculum, brain regions involved in circuitry modulating ventral tegmental dopamine and nucleus accumbens activities, may be regions vulnerable to effects of prenatal LPS on specific subpopulations of interneurons. It is known that the timing of maturation and expansion of parvalbumin neurons in early development provides threshold levels of inhibition that trigger critical periods for cortical plasticity, leading to long-term circuit consolidation. Thus, our finding of increased parvalbumin neuron density at early developmental times might suggest a mechanism by which an acute prenatal insult like LPS exposure could produce long-term changes in prefrontal cortical or subicular function.

Alcohol Availability, Prenatal Conditions, and Long-Term Economic Outcomes

This study examines how a policy that sharply increased alcohol availability during 8.5 months affected the labor productivity of those exposed to it in utero. Compared to the surrounding cohorts, the prenatally exposed children have substantially worse labor market and educational outcomes and lower cognitive and noncognitive ability. Effects on earnings are found throughout the distribution but are largest below the median. Males are more affected than females, consistent with growing evidence that boys are less resilient to early environmental insults. The long-term effects seem primarily driven by changes in prenatal health rather than changes in the childhood environment.

Small RNA regulation of neural gene expression in response to environmental exposure associated with neuropsychiatric syndromes

Postmortem molecular analysis of the human brain during development and aging suggests there are epigenetic changes reflecting early life experiences. This includes changes in the expression of non-coding RNAs such as microRNA. These molecules alter the regulation of gene expression and can interact with underlying genetic risk factors, contributing to neurological and neuropsychiatric syndromes such as schizophrenia. Recent evidence suggests that these dynamic and influential molecules play an important role in both brain development and the cellular response to stress. In our recent studies, we investigate the role of microRNA in the brains’ response to maternal immune activation and adolescent cannabinoid exposure, alone and in combination, as both have been identified as environmental risk factors for this disorder. We found that combined exposure to significantly altered microRNA expression in the left hemisphere of the entorhinal cortex as compared to the right. These changes were dominated by a large subgroup of microRNA transcribed from a single imprinted locus on chromosome 6q32 that is associated with schizophrenia. These changes correlated with altered gene expression in the combined treatment group, with microRNA-gene interactions predicted to regulate neuronal growth and differentiation; development of specific cortical layers; synaptic plasticity and transmission; axonogenesis; gamma-aminobutyric acid neurotransmitter system; and learning and memory formation. These findings suggested that the interaction of both an early and late environmental insult enhances changes in offspring microRNA expression in the brain with possible outcomes relevant to neurological disorders in adulthood.

P2003 Altered hippocampal DNA methylation, gene transcription, and RNA editing in response to early life environmental insults in 2 independent studies of cognitive development

P2003 Altered hippocampal DNA methylation, gene transcription, and RNA editing in response to early life environmental insults in 2 independent studies of cognitive development

Early Life Nutrition and Energy Balance Disorders in Offspring in Later Life.

The global pandemic of obesity and type 2 diabetes is often causally linked to changes in diet and lifestyle; namely increased intake of calorically dense foods and concomitant reductions in physical activity. Epidemiological studies in humans and controlled animal intervention studies have now shown that nutritional programming in early periods of life is a phenomenon that affects metabolic and physiological functions throughout life. This link is conceptualised as the developmental programming hypothesis whereby environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the health and well-being of the offspring. The mechanisms by which early environmental insults can have long-term effects on offspring remain poorly defined. However there is evidence from intervention studies which indicate altered wiring of the hypothalamic circuits that regulate energy balance and epigenetic effects including altered DNA methylation of key adipokines including leptin. Studies that elucidate the mechanisms behind these associations will have a positive impact on the health of future populations and adopting a life course perspective will allow identification of phenotype and markers of risk earlier, with the possibility of nutritional and other lifestyle interventions that have obvious implications for prevention of non-communicable diseases.

Alteration of imprinted Dlk1-Dio3 miRNA cluster expression in the entorhinal cortex induced by maternal immune activation and adolescent cannabinoid exposure.

A significant feature of the cortical neuropathology of schizophrenia is a disturbance in the biogenesis of short non-coding microRNA (miRNA) that regulate translation and stability of mRNA. While the biological origin of this phenomenon has not been defined, it is plausible that it relates to major environmental risk factors associated with the disorder such as exposure to maternal immune activation (MIA) and adolescent cannabis use. To explore this hypothesis, we administered the viral mimic poly I:C to pregnant rats and further exposed some of their maturing offsprings to daily injections of the synthetic cannabinoid HU210 for 14 days starting on postnatal day 35. Whole-genome miRNA expression analysis was then performed on the left and right hemispheres of the entorhinal cortex (EC), a region strongly associated with schizophrenia. Animals exposed to either treatment alone or in combination exhibited significant differences in the expression of miRNA in the left hemisphere, whereas the right hemisphere was less responsive. Hemisphere-associated differences in miRNA expression were greatest in the combined treatment and highly over-represented in a single imprinted locus on chromosome 6q32. This observation was significant as the syntenic 14q32 locus in humans encodes a large proportion of miRNAs differentially expressed in peripheral blood lymphocytes from patients with schizophrenia, suggesting that interaction of early and late environmental insults may affect miRNA expression, in a manner that is relevant to schizophrenia.

Early life nutrition, epigenetics and programming of later life disease.

The global pandemic of obesity and type 2 diabetes is often causally linked to marked changes in diet and lifestyle; namely marked increases in dietary intakes of high energy diets and concomitant reductions in physical activity levels. However, less attention has been paid to the role of developmental plasticity and alterations in phenotypic outcomes resulting from altered environmental conditions during the early life period. Human and experimental animal studies have highlighted the link between alterations in the early life environment and increased risk of obesity and metabolic disorders in later life. This link is conceptualised as the developmental programming hypothesis whereby environmental influences during critical periods of developmental plasticity can elicit lifelong effects on the health and well-being of the offspring. In particular, the nutritional environment in which the fetus or infant develops influences the risk of metabolic disorders in offspring. The late onset of such diseases in response to earlier transient experiences has led to the suggestion that developmental programming may have an epigenetic component, as epigenetic marks such as DNA methylation or histone tail modifications could provide a persistent memory of earlier nutritional states. Moreover, evidence exists, at least from animal models, that such epigenetic programming should be viewed as a transgenerational phenomenon. However, the mechanisms by which early environmental insults can have long-term effects on offspring are relatively unclear. Thus far, these mechanisms include permanent structural changes to the organ caused by suboptimal levels of an important factor during a critical developmental period, changes in gene expression caused by epigenetic modifications (including DNA methylation, histone modification, and microRNA) and permanent changes in cellular ageing. A better understanding of the epigenetic basis of developmental programming and how these effects may be transmitted across generations is essential for the implementation of initiatives aimed at curbing the current obesity and diabetes crisis.

The impact of early nutrition on the ageing trajectory

Epidemiological studies, including those in identical twins, and in individuals in utero during periods of famine have provided robust evidence of strong correlations between low birth-weight and subsequent risk of disease in later life, including type 2 diabetes (T2D), CVD, and metabolic syndrome. These and studies in animal models have suggested that the early environment, especially early nutrition, plays an important role in mediating these associations. The concept of early life programming is therefore widely accepted; however the molecular mechanisms by which early environmental insults can have long-term effects on a cell and consequently the metabolism of an organism in later life, are relatively unclear. So far, these mechanisms include permanent structural changes to the organ caused by suboptimal levels of an important factor during a critical developmental period, changes in gene expression caused by epigenetic modifications (including DNA methylation, histone modification and microRNA) and permanent changes in cellular ageing. Many of the conditions associated with early-life nutrition are also those which have an age-associated aetiology. Recently, a common molecular mechanism in animal models of developmental programming and epidemiological studies has been development of oxidative stress and macromolecule damage, specifically DNA damage and telomere shortening. These are phenotypes common to accelerated cellular ageing. Thus, this review will encompass epidemiological and animal models of developmental programming with specific emphasis on cellular ageing and how these could lead to potential therapeutic interventions and strategies which could combat the burden of common age-associated disease, such as T2D and CVD.

A longitudinal analysis of regional brain volumes in macaques exposed to X-irradiation in early gestation.

BackgroundEarly gestation represents a period of vulnerability to environmental insult that has been associated with adult psychiatric disease. However, little is known about how prenatal perturbation translates into adult brain dysfunction. Here, we use a longitudinal study design to examine the effects of disruption of early gestational neurogenesis on brain volume in the non-human primate.Methods and Principal FindingsFive Rhesus macaques were exposed to x-irradiation in early gestation (E30–E41), and four control monkeys were sham-irradiated at comparable ages. Whole brain magnetic resonance imaging was performed at 6 months, 12 months, and 3 and 5 years of age. Volumes of whole cerebrum, cortical gray matter, caudate, putamen, and thalamus were estimated using semi-automated segmentation methods and high dimensional brain mapping. Volume reductions spanning all ages were observed in irradiated monkeys in the putamen (15–24%, p = 0.01) and in cortical gray matter (6–15%, p = 0.01). Upon covarying for whole cerebral volume, group differences were reduced to trend levels (putamen: p = 0.07; cortical gray matter: p = 0.08). No group-by-age effects were significant.ConclusionsDue to the small number of observations, the conclusions drawn from this study must be viewed as tentative. Early gestational irradiation may result in non-uniform reduction of gray matter, mainly affecting the putamen and cerebral cortex. This may be relevant to understanding how early prenatal environmental insult could lead to brain morphological differences in neurodevelopmental diseases.

Commentary: Marking the epigenome—in search of the fingerprints of intrauterine nutritional deficiencies

Commentary: Marking the epigenome—in search of the fingerprints of intrauterine nutritional deficiencies

Overview of Intellectual/Developmental Disabilities

Patients with intellectual/developmental disabilities (IDD) present many challenges to mental health professionals. The capacity to work with such patients requires a working knowledge of IDD as well as an awareness and understanding of the factors that affect the clinical presentation of mental health disorders across the spectrum of IDD.

Effect by acupuncture on hypothalamic expression of maternally separated rats: proteomic approach

Objectives: Early stressors can influence the development of biological and neurological systems. Maternal separation (social isolation) in early life may increase vulnerability to neurodegenerative diseases and neuropsychiatric disorders over the lifespan. To identify new proteins on acupuncture effects in maternally separated rats, an animal model for study of early environmental insults, proteomic approach on the expression of the hypothalamic proteins was performed.Methods: On post-natal day 14, rat pups were randomly divided into four groups: pups kept with their mothers for 7 days; pups kept with their mothers with acupuncture daily to HT8 (Sobu); maternally separated pups; maternally separated pups with acupuncture. The hypothalamic proteins were analysed by two-dimensional electrophoresis coupled with matrix assisted laser desorption/ionization time-of-flight mass spectrometer.Results: The results showed that 27 spots were differentially and commonly expressed. Of 27 spots, 21 spots were identified while six spots were not, and 15 proteins were known proteins. In maternally separated group, the expressions of 14 proteins were down-regulated, compared to control group. In group of maternally separation with acupuncture, five proteins were down-regulated and nine were up-regulated, compared to the maternally separated group. Among nine proteins up-regulated by acupuncture treatment, we found four proteins (dihydropyrimidinase-like 2, dystrophin-related protein 2, tubulin, alpha 1a and syntaxin 1b) related to neurodevelopment.Discussion: The result suggests that acupuncture to HT8 may affect neurodevelopment, and acupuncture may be a possible therapy for neurodevelopmental disorders.

Neonatal lipopolysaccharide and adult stress exposure predisposes rats to anxiety-like behaviour and blunted corticosterone responses: Implications for the double-hit hypothesis

The double-hit hypothesis posits that an early life genetic or environmental insult sets up a neural predisposition to psychopathology, which may emerge in the presence of a subsequent insult, or 'second hit' in later life. The current study assessed the effect of neonatal lipopolysaccharide (LPS) exposure on anxiety-like behaviours in the adult Wistar rat. Rats were administered either LPS (Salmonella enterica, serotype enteritidis, 0.05 mg/kg, i.p.) or saline (equivolume) on days 3 and 5 of life (birth=day 1). In adulthood (85 days), subjects were allocated to either "stress" or "no stress" treatment groups. For the "stress" group, subjects were exposed to a three-day stress protocol consisting of a 30 min period of restraint and isolation. The "no stress" group was left unperturbed but were handled during this period to control for handling effects between adult "stress" and "no stress" conditions. All animals then underwent behavioural testing using standardised tests of anxiety-like behaviour, including either the Hide Box/Open Field, Elevated Plus Maze (EPM) or Acoustic Startle Response (ASR). Time and event measures for restraint and isolation, the Hide Box/Open Field and EPM were recorded using automated tracking software. Startle amplitude and habituation across time was measured in the ASR test. Prior to and following behavioural test sessions, peripheral blood was collected to assess serum corticosterone and ACTH levels. Data analysis indicated that LPS-treated animals exposed to stress in adulthood exhibited increased anxiety-like behaviour across all behavioural tests compared to controls. Sexually dimorphic effects were observed with males exhibiting increased anxiety-related behaviours compared to females (p<.05). Neonatal LPS exposure induced a significant increase in corticosterone compared to controls (p<.05), whereas corticosterone responses to stress in adulthood were associated with a significantly blunted HPA axis response (p<.05). No differences in ACTH were observed. These results lend support to the double-hit hypothesis of anxiety-related behaviour, demonstrating that neonatal immune activation produces an enhanced propensity toward anxiety-related behaviour following stress in adulthood, and that this susceptibility is associated with alterations to HPA axis ontogeny.

Early maternal deprivation in rats induces gender-dependent effects on developing hippocampal and cerebellar cells

Adult animals submitted to a single prolonged episode of maternal deprivation [24h, postnatal day 9–10] show behavioral alterations that resemble specific symptoms of schizophrenia. According to the neurodevelopmental theory, these behavioral deficits might be mediated by detrimental neurodevelopmental processes that might be associated, at least partially, with stress-induced corticosterone responses. In order to address this hypothesis, we have focused on the hippocampus and cerebellar cortex, two brain regions that show high density of glucocorticoid receptors, and analyzed possible neuronal and glial alterations by immunohistochemical techniques. To evaluate the presence of degenerated neurons we used Fluoro-Jade-C (FJ-C) staining and for the study of astrocytes we employed glial fibrillary acidic protein (GFAP). Within control animals, females showed significantly more GFAP positive cells than males and a trend towards more FJ-C positive cells. Maternal deprivation induced neuronal degeneration and astroglial changes in the hippocampus and cerebellar cortex of neonatal rats that, in general, were more marked in males. This differential effect may be attributable to a greater vulnerability of males to this kind of early environmental insult and/or to sex-dependent differences in the onset and/or progression of the effects. The present experimental procedure may be instrumental in elucidating sex-dependent mechanisms of neurodevelopmental psychiatric disorders with a basis in early environmental insults.

Bridging from Cells to Cognition in Autism Pathophysiology: Biological Pathways to Defective Brain Function and Plasticity

We review evidence to support a model where the disease process underlying autism may begin when an in utero or early postnatal environmental, infectious, seizure, or autoimmune insult triggers an immune response that increases reactive oxygen species (ROS) production in the brain that leads to DNA damage (nuclear and mitochondrial) and metabolic enzyme blockade and that these inflammatory and oxidative stressors persist beyond early development (with potential further exacerbations), producing ongoing functional consequences. In organs with a high metabolic demand such as the central nervous system, the continued use of mitochondria with damaged DNA and impaired metabolic enzyme function may generate additional ROS which will cause persistent activation of the innate immune system leading to more ROS production. Such a mechanism would self-sustain and possibly progressively worsen. The mitochondrial dysfunction and altered redox signal transduction pathways found in autism would conspire to activate both astroglia and microglia. These activated cells can then initiate a broad-spectrum proinflammatory gene response. Beyond the direct effects of ROS on neuronal function, receptors on neurons that bind the inflammatory mediators may serve to inhibit neuronal signaling to protect them from excitotoxic damage during various pathologic insults (e.g., infection). In autism, over-zealous neuroinflammatory responses could not only influence neural developmental processes, but may more significantly impair neural signaling involved in cognition in an ongoing fashion. This model makes specific predictions in patients and experimental animal models and suggests a number of targets sites of intervention. Our model of potentially reversible pathophysiological mechanisms in autism motivates our hope that effective therapies may soon appear on the horizon.