Fetal programming of neuropsychiatric disorders

Vomhof-DeKrey E., Darland D., Ghribi O., Bundy A., Roemmich J., Claycombe K.

A maternal low-protein (LP) diet in Sprague-Dawley rats results in low birth weight, rapid adipose tissue catch-up growth, adult obesity, and insulin resistance. The placenta functions to fulfill the fetus' nutrient demands. Adequate angiogenic factor concentrations help to ensure normal growth and vasculature development of the placenta and, in turn, optimum maternal-to-fetal nutrient delivery. Maternal malnutrition creates a proinflammatory environment that leads to inhibition of placental tissue growth. Therefore, we hypothesized that a maternal LP diet will lead to abnormal angiogenesis via dysregulation of immune cells resulting in increased secretion of proinflammatory cytokines and reduced angiogenic factor expression. Sprague-Dawley dams were fed 8% LP or 20% normal protein diets for 3 weeks prior to breeding and throughout pregnancy. Placenta from dams fed a LP diet weighed less; had increased M2 macrophages producing TNFα, decreased M1 macrophages and iNKT cells; greater angiogenic factor (FGF2, VEGFR-1, IGF2) expression and protein content, and greater CD31/PECAM (platelet endothelial cell adhesion molecule) expression. Prenatal protein restriction may induce the placenta to upregulate compensatory mechanisms of angiogenesis in order to meet the nutrient demands of the fetus.

Hunter D.S., Hazel S.J., Kind K.L., Owens J.A., Pitcher J.B., Gatford K.L.

IUGR in humans is associated with impaired pre- and postnatal neurodevelopment, and subsequent postnatal cognition, resulting in lower IQ, poorer memory, visuomotor and executive function skills, as well as behavioural and attentional problems. Experimental models of IUGR are needed to allow direct testing of causality and interventions, and have benefits in reducing both confounding by comorbidities such as prematurity, and variation due to environment and genetics. This review describes and discusses experimental models of IUGR in which neurodevelopmental and cognitive outcomes of IUGR have been reported. We consider the timing of neurodevelopment relative to birth and to the period of restriction, as well as the effects of each experimental perturbation on the fetal environment and development, before discussing neurodevelopmental and cognitive outcomes for progeny as fetuses, neonates and into adolescent and adult life. Experimental IUGR induces broadly similar outcomes to human IUGR, with altered brain morphology, in particular grey matter loss and discordant trajectory of white matter development, and poorer cognition and memory reported in various studies. Nevertheless, there remain gaps in knowledge of neurodevelopment in experimental models. We end the review with recommendations for the design of future studies to further investigate the mechanisms underlying adverse neurodevelopmental consequences of IUGR, and to evaluate interventions that may subsequently improve outcomes of IUGR in humans.

Hossain S., Bhowmick S., Jahan S., Rozario L., Sarkar M., Islam S., Basunia M.A., Rahman A., Choudhury B.K., Shahjalal H.

The presence of lead (Pb) in fetal brain may affect brain development-related proteins. We studied whether gestational/lactational Pb-exposure affects oxidative stress, proinflammatory response, apoptosis and levels of brain development/cognition-related proteins, including presynaptic synaptosome-associated protein-25 (SNAP-25), postsynaptic density protein-95 (PSD-95), brain-derived neurotropic factor (BDNF), tyrosine receptor-kinase protein B (TrkB) and vesicular acetylcholine transporter (VAChT) in the offspring. Female Wistar rats were randomly divided into control and Pb-exposed mother groups. The Pb-exposed rats received 0.1% (w/v) Pb acetate via drinking water during pregnancy and lactation. Milk and mammary glands were collected from lactating mothers to measure milk/mammary gland levels of lipid peroxide (LPO), as indicator of oxidative stress and proinflammatory TNF-α. Afterwards, the pups were sacrificed to determine brain levels of Pb, LPO, TNF-α, cytochrome C, SNAP-25, PSD-95, BDNF, TrkB and VAChT. The levels of LPO and TNF-α increased in the milk/mammary glands of the Pb-exposed mothers, concurrently with increases in the levels of Pb, LPO, TNF-α and cytochrome C and decreases in the levels of SNAP-25, PSD-95, BDNF, TrkB and VAChT in the brains of their offspring. Our results demonstrate that Pb-exposure during development reduces the brain levels of PSD-95 and SNAP-25 (synaptogenesis-markers), with concomitant upsurges of oxidative stress, TNF-α and apoptosis in the offspring. Furthermore, BDNF-TrkB proteins that comprehend memory-related brain cognitions and/or VAChT that comprises cholinergic-neuromotor activities might be impaired by Pb-exposure. These findings provide evidence of toxic effects of Pb on brain development, at least, partially by decreasing the levels of PSD-95, SNAP-25 and other cognition-related proteins.

McQuire C., Paranjothy S., Hurt L., Mann M., Farewell D., Kemp A.

CONTEXT:Objective measurement of prenatal alcohol exposure (PAE) is essential for identifying children at risk for adverse outcomes, including fetal alcohol spectrum disorders. Biomarkers have been advocated for use in universal screening programs, but their validity has not been comprehensively evaluated.OBJECTIVE:To systematically review the validity of objective measures of PAE.DATA SOURCES:Thirteen electronic databases and supplementary sources were searched for studies published between January 1990 and October 2015.STUDY SELECTION:Eligible studies were those that evaluated the diagnostic accuracy of objective measures of PAE.DATA EXTRACTION:Three reviewers independently verified study inclusion, quality assessments, and extracted data.RESULTS:Twelve studies met inclusion criteria. Test performance varied widely across studies of maternal blood (4 studies; sensitivity 0%–100%, specificity 79%–100%), maternal hair (2 studies; sensitivity 19%–87%, specificity 56%–86%) maternal urine (2 studies; sensitivity 5%–15%, specificity 97%–100%), and biomarker test batteries (3 studies; sensitivity 22%–50%, specificity 56%–97%). Tests of the total concentration of 4 fatty acid ethyl esters (in meconium: 2 studies; in placenta: 1 study) demonstrated high sensitivity (82%–100%); however, specificity was variable (13%–98%).LIMITATIONS:Risk of bias was high due to self-report reference standards and selective outcome reporting.CONCLUSIONS:Current evidence is insufficient to support the use of objective measures of prenatal alcohol exposure in practice. Biomarkers in meconium and placenta tissue may be the most promising candidates for further large-scale population-based research.

Tang W.W., Kobayashi T., Irie N., Dietmann S., Surani M.A.

In early germline development, extra-embryonic signals trigger a regulatory network that induces the specification and subsequent epigenetic reprogramming of primordial germ cells, the precursors of sperm and eggs. Here, the authors review germline specification and reprogramming in humans, and discuss the crucial mechanistic differences between these processes in humans and mice. Primordial germ cells (PGCs), the precursors of sperm and eggs, are established in perigastrulation-stage embryos in mammals. Signals from extra-embryonic tissues induce a unique gene regulatory network in germline-competent cells for PGC specification. This network also initiates comprehensive epigenome resetting, including global DNA demethylation and chromatin reorganization. Mouse germline development has been studied extensively, but the extent to which such knowledge applies to humans was unclear. Here, we review the latest advances in human PGC specification and epigenetic reprogramming. The overall developmental dynamics of human and mouse germline cells appear to be similar, but there are crucial mechanistic differences in PGC specification, reflecting divergence in the regulation of pluripotency and early development.

Muller C.L., Anacker A.M., Rogers T.D., Goeden N., Keller E.H., Forsberg C.G., Kerr T.M., Wender C.L., Anderson G.M., Stanwood G.D., Blakely R.D., Bonnin A., Veenstra-VanderWeele J.

Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo. We therefore used different combinations of maternal and embryo SERT Ala56 genotypes to examine effects on blood, placenta and embryo serotonin levels and neurodevelopment at embryonic day E14.5, when peripheral sources of 5-HT predominate, and E18.5, when midbrain 5-HT projections have reached the forebrain. Maternal SERT Ala56 genotype was associated with decreased placenta and embryonic forebrain 5-HT levels at E14.5. Low 5-HT in the placenta persisted, but forebrain levels normalized by E18.5. Maternal SERT Ala56 genotype effects on forebrain 5-HT levels were accompanied by a broadening of 5-HT-sensitive thalamocortical axon projections. In contrast, no effect of embryo genotype was seen in concepti from heterozygous dams. Blood 5-HT levels were dynamic across pregnancy and were increased in SERT Ala56 dams at E14.5. Placenta RNA sequencing data at E14.5 indicated substantial impact of maternal SERT Ala56 genotype, with alterations in immune and metabolic-related pathways. Collectively, these findings indicate that maternal SERT function impacts offspring placental 5-HT levels, forebrain 5-HT levels, and neurodevelopment.

Newman L., Judd F., Olsson C.A., Castle D., Bousman C., Sheehan P., Pantelis C., Craig J.M., Komiti A., Everall I.

There is increasing understanding of the significance of early neurodevelopment in establishing risk for the range of mental disorders. Models of the early aetiology of mental disorders are complex with a range of potential factors from genetic and epigenetic to environmental influencing neurological and psychological development. Whilst the mechanisms are not fully understood, this paper provides an overview of potential biological and neurobiological factors that might be involved. An aetiological model is presented and discussed. The discussion includes a range of risk factors for mental disorder. Maternal anxiety disorder is presented and reviewed as an example of the interaction of placental, epigenetic and early parenting factors elevating risk of poor neonatal outcome. Available evidence points to the importance of in-utero influences as well as the role of early attachment and emotional care. Transgenerational mechanisms such as the impact of maternal mental disorder on foetal development are important models for examination of early risk. Maternal anxiety, as an example, is a significant risk factor for compromised mental health. Development of models for understanding the early origins of mental disorder is an important step in elaborating risk reduction strategies. Comprehensive early identification of risk raises the possibility of preventive interventions.

Dang F., Croy B., Stroman P., Figueiró-Filho E.

Preeclampsia (PE) is a significant gestational disorder that causes complications in 3-5% of all human pregnancies. Apart from the immediate risks and complications for mother and fetus, both additionally carry elevated lifelong risks for specific complications. Offspring of PE pregnancies (PE-F1) have higher risks for hypertension, stroke and cognitive impairment compared with well-matched offspring (F1) from uncomplicated pregnancies. Prior to the clinical onset of PE, placental angiokines secreted into the maternal plasma are deviated. In many PE patients this includes deficits in placental growth factor (PGF). Our laboratory found that mice genetically-deleted for PGF (PGF - / - ) have altered cerebrovascular and brain neurological development detectable from midgestation to adulthood. We hypothesized that the PGF deficits seen in human PE, deviate fetal cerebrovascular and neurological development in a manner that impairs cognitive functions and elevates stroke risk. Here we summarize the initial analytical outcomes from a pilot study of 8-10 year old male and female PE-F1s and matched controls. Our studies were the first to report magnetic resonance imaging (MRI), magnetic resonance angiography (MRA) and functional brain region assessment by eye movement control and clinical psychometric testing in PE-F1s. Further studies in larger cohorts are essential to define whether there are image-based biomarkers that describe unique anatomical features in PE-F1 brains.

Owen M.J., Sawa A., Mortensen P.B.

Schizophrenia is a complex, heterogeneous behavioural and cognitive syndrome that seems to originate from disruption of brain development caused by genetic or environmental factors, or both. Dysfunction of dopaminergic neurotransmission contributes to the genesis of psychotic symptoms, but evidence also points to a widespread and variable involvement of other brain areas and circuits. Disturbances of synaptic function might underlie abnormalities of neuronal connectivity that possibly involves interneurons, but the precise nature, location, and timing of these events are uncertain. At present, treatment mainly consists of antipsychotic drugs combined with psychological therapies, social support, and rehabilitation, but a pressing need for more effective treatments and delivery of services exists. Advances in genomics, epidemiology, and neuroscience have led to great progress in understanding the disorder, and the opportunities for further scientific breakthrough are numerous--but so are the challenges.

Post R.M.

The process of sensitization (increased responsivity) to the recurrence of stressors, affective episodes, and bouts of substance abuse that can drive illness progression in the recurrent affective disorders requires a memory of and increased reactivity to the prior exposures. A wealth of studies now supports the postulate that epigenetic mechanisms underlie both normal and pathological memory processes.We selectively reviewed the literature pertinent to the role of epigenetics in behavioral sensitization phenomena and discuss its clinical implications.Epigenetics means above genetics and refers to environmental effects on the chemistry of DNA, histones (around which DNA is wound), and microRNA that change how easily genes are turned on and off. The evidence supports that sensitization to repeated stressor, affective episodes, and substance is likely based on epigenetic mechanisms and that these environmentally based processes can then become targets for prevention, early intervention, and ongoing treatment. Sensitization processes are remediable or preventable risk factors for a poor illness outcome and deserve increased clinical, public health, and research attention in the hopes of making the recurrent unipolar and bipolar affective disorders less impairing, disabling, and lethal by suicide and increased medical mortality.The findings that epigenetic chemical marks, which change in the most fundamental way how genes are regulated, mediate the long-term increased responsivity to recurrent stressors, mood episodes, and bouts of substance abuse should help change how the affective disorders are conceptualized and move treatment toward earlier, more comprehensive, and sustained pharmacoprophylaxis.

Videman M., Tokariev A., Saikkonen H., Stjerna S., Heiskala H., Mantere O., Vanhatalo S.

Recent experimental animal studies have shown that fetal exposure to serotonin reuptake inhibitors (SRIs) affects brain development. Modern recording methods and advanced computational analyses of scalp electroencephalography (EEG) have opened a possibility to study if comparable changes are also observed in the human neonatal brain. We recruited mothers using SRI during pregnancy (n = 22) and controls (n = 62). Mood and anxiety of mothers, newborn neurology, and newborn cortical function (EEG) were assessed. The EEG parameters were compared between newborns exposed to drugs versus controls, followed by comparisons of newborn EEG features with maternal psychiatric assessments. Neurological assessment showed subtle abnormalities in the SRI-exposed newborns. The computational EEG analyses disclosed a reduced interhemispheric connectivity, lower cross-frequency integration, as well as reduced frontal activity at low-frequency oscillations. These effects were not related to maternal depression or anxiety. Our results suggest that antenatal serotonergic treatment might change newborn brain function in a manner compatible with the recent experimental studies. The present EEG findings suggest links at the level of neuronal activity between human studies and animal experiments. These links will also enable bidirectional translation in future studies on the neuronal mechanisms and long-term neurodevelopmental effects of early SRI exposure.

Goeden N., Velasquez J., Arnold K.A., Chan Y., Lund B.T., Anderson G.M., Bonnin A.

Maternal inflammation during pregnancy affects placental function and is associated with increased risk of neurodevelopmental disorders in the offspring. The molecular mechanisms linking placental dysfunction to abnormal fetal neurodevelopment remain unclear. During typical development, serotonin (5-HT) synthesized in the placenta from maternall-tryptophan (TRP) reaches the fetal brain. There, 5-HT modulates critical neurodevelopmental processes. We investigated the effects of maternal inflammation triggered in midpregnancy in mice by the immunostimulant polyriboinosinic-polyribocytidylic acid [poly(I:C)] on TRP metabolism in the placenta and its impact on fetal neurodevelopment. We show that a moderate maternal immune challenge upregulates placental TRP conversion rapidly to 5-HT through successively transient increases in substrate availability and TRP hydroxylase (TPH) enzymatic activity, leading to accumulation of exogenous 5-HT and blunting of endogenous 5-HT axonal outgrowth specifically within the fetal forebrain. The pharmacological inhibition of TPH activity blocked these effects. These results establish altered placental TRP conversion to 5-HT as a new mechanism by which maternal inflammation disrupts 5-HT-dependent neurogenic processes during fetal neurodevelopment.SIGNIFICANCE STATEMENTThe mechanisms linking maternal inflammation during pregnancy with increased risk of neurodevelopmental disorders in the offspring are poorly understood. In this study, we show that maternal inflammation in midpregnancy results in an upregulation of tryptophan conversion to serotonin (5-HT) within the placenta. Remarkably, this leads to exposure of the fetal forebrain to increased concentrations of this biogenic amine and to specific alterations of crucially important 5-HT-dependent neurogenic processes. More specifically, we found altered serotonergic axon growth resulting from increased 5-HT in the fetal forebrain. The data provide a new understanding of placental function playing a key role in fetal brain development and how this process is altered by adverse prenatal events such as maternal inflammation. The results uncover important future directions for understanding the early developmental origins of mental disorders.

Forray A.

Prenatal substance use is a critical public health concern that is linked with several harmful maternal and fetal consequences. The most frequently used substance in pregnancy is tobacco, followed by alcohol, cannabis and other illicit substances. Unfortunately, polysubstance use in pregnancy is common, as well as psychiatric comorbidity, environmental stressors, and limited and disrupted parental care, all of which can compound deleterious maternal and fetal outcomes. There are few existing treatments for prenatal substance use and these mainly comprise behavioral and psychosocial interventions. Contingency management has been shown to be the most efficacious of these. The purpose of this review is to examine the recent literature on the prenatal use of tobacco, alcohol, cannabis, stimulants, and opioids, including the effects of these on maternal and fetal health and the current therapeutic options.

Judge M.P., Casavant S.G., Dias J.A., McGrath J.M.

Infants born to diabetic mothers have a higher frequency of impaired neurodevelopment. The omega-3 or n-3 fatty acid docosahexaenoic acid (DHA) is an important structural component of neural tissue and is critical for fetal brain development. Maternal DHA supplementation during pregnancy is linked to better infant neurodevelopment; however, maternal-fetal transfer of DHA is reduced in women with diabetes. Evidence of mechanisms explaining altered maternal-fetal DHA transfer in this population is limited. This review explores existing evidence underpinning reduced maternal-fetal DHA transfer in maternal fuel metabolism in this population. Further research is necessary to evaluate the role of peroxisome proliferator-activated receptors in modulating placental fatty acid binding and maternal-fetal DHA transfer. Considerations for clinical practice include a diet high in DHA and/or provision of supplemental DHA to obstetric diabetic patients within minimum guidelines.

Malm H., Brown A.S., Gissler M., Gyllenberg D., Hinkka-Yli-Salomäki S., McKeague I.W., Weissman M., Wickramaratne P., Artama M., Gingrich J.A., Sourander A.

To investigate the impact of gestational exposure to selective serotonin reuptake inhibitors (SSRIs) on offspring neurodevelopment.This is a cohort study using national register data in Finland between the years 1996 and 2010. Pregnant women and their offspring were categorized into 4 groups: SSRI exposed (n = 15,729); exposed to psychiatric disorder, no antidepressants (n = 9,651); exposed to SSRIs only before pregnancy (n = 7,980); and unexposed to antidepressants and psychiatric disorders (n = 31,394). We investigated the cumulative incidence of offspring diagnoses of depression, anxiety, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) for the 4 groups from birth to 14 years, adjusting for confounders.The cumulative incidence of depression among offspring exposed prenatally to SSRIs was 8.2% (95% CI = 3.1-13.3%) by age 14.9 years, compared with 1.9% (95% CI = 0.9-2.9%) in the psychiatric disorder, no medication group (adjusted hazard ratio [HR] = 1.78; 95% CI = 1.12-2.82; p = .02) and to 2.8% (95% CI = 1.4-4.3%) in the SSRI discontinued group (HR = 1.84; 95% CI = 1.14-2.97; p = .01). Rates of anxiety, ASD, and ADHD diagnoses were comparable to rates in offspring of mothers with a psychiatric disorder but no medication during pregnancy. Comparing SSRI exposed to unexposed individuals, the HRs were significantly elevated for each outcome.Prenatal SSRI exposure was associated with increased rates of depression diagnoses in early adolescence but not with ASD or ADHD. Until confirmed, these findings must be balanced against the substantial adverse consequences of untreated maternal depression.

Kirthana Kunikullaya U.

Cainelli E., Stramucci G., Bisiacchi P.

Corcoran A.W., Feuerriegel D., Robinson J.E., Perrykkad K.

Dinleyici E.C.

Background:: Current scientific research on breastfeeding provides substantial evidence of its numerous positive impacts, not only for children in both the short and long term but also for mothers who engage in breastfeeding. Summary:: In addition to the gold standard effect of human milk on infant nutrition, breastfeeding is associated with a lower incidence of infections, reduced infant/childhood mortality, necrotizing enterocolitis, and obesity during childhood and later in life, better cognitive performance, and a higher IQ score. For mothers, breastfeeding prolongs lactational amenorrhea, may facilitate postpartum weight loss, and may reduce breast and ovarian cancers and cardiovascular diseases. Breastfeeding can also play a beneficial role in preventing antibiotic resistance, which is a global concern across all age groups. Implementing exclusive breastfeeding for all infants has the potential to enhance child development and decrease healthcare expenses, leading to economic savings for both individual families and society. Human milk is a biologically active food that functions as both prebiotic and probiotic because of its oligosaccharides and the composition of its microbiota, which act as synergistic synbiotics.

de Sena Barbosa M.G., Vilela de Souza R.L., Gonçalves Cherain L.G., Santos Ferreira L.H., Santos Affi Peixoto M.E., Lemos Passos M., Matias Piza L., Almeida Carneiro R., Nunes Rabelo N., Chaurasia B.

Background: Autism spectrum disorder (ASD) is characterized by social disabilities and stereotyped behaviors. There is a relevant social impact on autistic people’s lives and, therefore, biomarkers have become relevant for understanding neurobiological mechanisms. Objective: This study aims to review current knowledge about the role of biomarkers and their main scientific evidence in autism. Methods: The authors performed a non-systematic literature review through the PubMed database, using the keywords “biomarkers”, “autism” and “autism spectrum disorder”. The search was restricted to articles written in English, in the last 10 years. Results: Analyzing the articles found, it is possible to delimit the biomarkers according to the development of ASD, from the prenatal period with exposure to diseases or association of autism with other genetic diseases, through the immune and nutritional factors exposed during pregnancy, and for end those associated with diagnoses phase in which there is the presence of symptoms in which these markers can be used to aid in the diagnosis. Conclusion: Although preliminary, biomarkers may hold promise for prenatal and presymptomatic screening. It may also be used as predictors of treatment for autism spectrum disorder.

Eberhardt N., Roedig T., Schmidt L., Bartmann P., Holterhus P., Kulle A.E., Schulte S., Gohlke B.

Low birthweight may have adverse sequelae in later life. Therefore, we analyzed behavioral difficulties and salivary glucocorticoid profiles in monozygotic twins with intra-twin birthweight differences due to twin-to-twin transfusion syndrome (TTTS). 46 monozygotic TTTS twin pairs with birthweight differences of

Vancamp P., Frapin M., Parnet P., Amarger V.

Fetal brain development requires an increased maternal protein intake to ensure that offspring reach their optimal cognitive potential in infancy and adulthood. While protein deficiency remains a prevalent issue in developing countries, it is also re-emerging in western societies due to the growing adoption of plant-based diets, some of which are monotonous and may fail to provide sufficient amino acids crucial for the brain's critical developmental phase. Confounding variables in human nutritional research impede to grasp the precise impact of protein deficiency on fetal neurodevelopment, as well as its implications for childhood neurocognitive performance. Moreover, it remains uncertain whether such deficiency could predispose to mental health problems in adulthood, mirroring observations in individuals exposed to prenatal famine. This review seeks to evaluate mechanistic data derived from rodent models, placing special emphasis on the involvement of neuroendocrine axes, the influence of sex and timing, epigenetic modifications, and cellular metabolism. Despite notable progress, critical knowledge gaps remain, including understanding the long-term reversibility of effects due to fetal protein restriction, and the interplay between genetic predisposition and environmental factors. Enhancing our understanding of the precise mechanisms connecting prenatal nutrition to brain development in future research endeavors can be significantly advanced by integrating multi-omics approaches and utilizing additional alternative models such as non-human primates. Furthermore, it is crucial to investigate potential interventions aimed at alleviating adverse outcomes. Ultimately, this research carries profound implications for guiding public health strategies aimed at raising awareness about the crucial role of optimal maternal nutrition in supporting fetal neurodevelopment.

Ha S.

Climate change continues to cause extreme weather events such as wildfires, heatwaves, floods, droughts, and hurricanes with increased frequency, intensity, duration, and spatial distribution. In addition to their immediate physical health impacts, these extreme weather events directly and indirectly contribute to short- and long-term mental health complications, especially in underserved populations who are already burdened by other stressors. Evidence shows that exposures during periods with developmental plasticity have the strongest implications and that the effects may accumulate over the life course and potentially across generations. This chapter describes the current evidence linking climate change and mental health outcomes through a developmental and life course perspective. It will also discuss the existing challenges and opportunities for efforts aimed at addressing the health impacts of climate change.

Herbein M., Barbosa S., Collet O., Khalfallah O., Navarro M., Bailhache M., IV N., Aouizerate B., Sutter-Dallay A., Koehl M., Capuron L., Ellul P., Peyre H., Van der Waerden J., Melchior M., et. al.

There is growing evidence that in utero imbalance immune activity plays a role in the development of neurodevelopmental and psychiatric disorders in children. Mood dysregulation (MD) is a debilitating transnosographic syndrome whose underlying pathophysiological mechanisms could be revealed by studying its biomarkers using the Research Domain Criteria (RDoC) model. Our aim was to study the association between the network of cord serum cytokines, and mood dysregulation trajectories in offsprings between 3 and 8 years of age. We used the data of a study nested in the French birth cohort EDEN that took place from 2003 to 2014 and followed mother-child dyads from the second trimester of pregnancy until the children were 8 years of age. The 2002 mother-child dyads were recruited from the general population through their pregnancy follow-up in two French university hospitals. 871 of them were included in the nested cohort and cord serum cytokine levels were measured at birth. Children's mood dysregulation symptoms were assessed with the Strengths and Difficulties Questionnaire Dysregulation Profile at the ages 3, 5 and 8 years in order to model their mood dysregulation trajectories. Out of the 871 participating dyads, 53% of the children were male. 2.1% of the children presented a high mood dysregulation trajectory whereas the others were considered as physiological variations. We found a significant negative association between TNF-α cord serum levels and a high mood dysregulation trajectory when considering confounding factors such as maternal depression during pregnancy (adjusted Odds Ratio (aOR) = 0.35, 95% Confidence Interval (CI) [0.18-0.67]). Immune imbalance at birth could play a role in the onset of mood dysregulation symptoms. Our findings throw new light on putative immune mechanisms implicated in the development of mood dysregulation and should lead to future animal and epidemiological studies.

Faa G., Messana I., Coni P., Piras M., Pichiri G., Piludu M., Iavarone F., Desiderio C., Vento G., Tirone C., Manconi B., Olianas A., Contini C., Cabras T., Castagnola M.

This review summarizes the results of a series of studies performed by our group with the aim to define the expression levels of thymosin β4 and thymosin β10 over time, starting from fetal development to different ages after birth, in different human organs and tissues. The first section describes the proteomics investigations performed on whole saliva from preterm newborns and gingival crevicular fluid, which revealed to us the importance of these acidic peptides and their multiple functions. These findings inspired us to start an in-depth investigation mainly based on immunochemistry to establish the distribution of thymosin β4 and thymosin β10 in different organs from adults and fetuses at different ages (after autopsy), and therefore to obtain suggestions on the functions of β-thymosins in health and disease. The functions of β-thymosins emerging from these studies, for instance, those performed during carcinogenesis, add significant details that could help to resolve the nowadays so-called “β-thymosin enigma”, i.e., the potential molecular role played by these two pleiotropic peptides during human development.

Catalano R., Bonham J., Gemmill A., Bruckner T.

Background: “Scarring in utero” posits that populations exposed to injurious stressors yield birth cohorts that live shorter lives than expected from history. This argument implies a positive historical association between period life expectancy (i.e., average age at death in year t) and cohort life expectancy (i.e., average lifespan of persons born in year t). Tests of the argument have not produced consistent results and appear confounded by autocorrelation, migration, and access to medical care. Here we test whether, as predicted by scarring in utero, sex-specific period and cohort life expectancy appear positively related among Swedes born from 1751 through 1800. If scarring has ever influenced longevity, we should detect signals of its effects in these cohorts because, unlike other populations with known life span, they aged in place and unlikely benefitted from increased access to efficacious medical care. Methods: We use Box–Jenkins methods to control autocorrelation and measure associations. Results: Contrary to the scarring hypothesis, we find an inverse association between period and cohort life expectancy. Our findings imply that, among males, variation in injurious stress on the population predicted changes in cohort life span ranging from a gain of approximately 67 weeks to a loss of about 45 weeks of life and among females from a gain of approximately 68 weeks to a loss of about 38 weeks of life. Conclusion: Epidemiologists trying to understand and explain temporal variation in cohort life expectancy should view the scarring argument with greater skepticism than currently found in the literature.

Kim J., Wortinger L., Sheehan B., Mukherjee S., Ha J., Punzi G., Ursini G.

Most individuals with genomic risk for schizophrenia do not develop the disorder, suggesting that the path that goes from genetic susceptibility to disease is not linear. Research suggests that schizophrenia etiopathogenesis may rest in the altered functioning of the epigenetic machinery that regulates interactions with the environment since early life. Some of the genetic variants associated with schizophrenia play a role very early in placenta, interacting with severe complications during prenatal and early postnatal life, and with sex-biased gene expression. Risk genes appear to contribute to biological processes crucial for the physiology of the placenta, and its ability to adapt to environmental conditions in order to provide support to the embryo/fetus. In this scenario, the developing brain may be canalized toward altered paths that, if maintained, may lead to the onset of the disorder; however, such paths do not imply certainty of developing the disorder and are likely reversible, hence they can be rescued. Identifying the placental mediators of schizophrenia trajectories of risk may help defining strategies of prenatal prevention, aimed at improving placental health; further, it may enable us to identify high-risk individuals, who could benefit from specific postnatal prevention.

Faa G., Pichiri G., Piras M., Coni P., Fanos V.

Recent findings of stem/progenitor cells in maternal milk and their ability to cross the intestinal barrier of lactating newborns and integrate into neonatal organs to promote optimal child development present a new challenge in perinatal medicine. These findings emphasize the need for all mothers to breastfeed their babies for a long time. According to recent research, breastfeeding protects the lactating newborn from multiple infectious agents that can cause severe and fatal early infancy diseases. The second benefit is that maternal stem cells accelerate the development of several organs, including the brain, protecting lactating infants from severe childhood and adult diseases. The success and diffusion of exclusive breastfeeding, especially in low-resource settings, depends on mothers' knowledge of the many benefits for their child, including recent discoveries on breastfeeding's powerful benefits. Every mother may need simple booklets to learn about the unique benefits of maternal breastfeeding, including the nutrients and multiple cell types that protect the newborn from infections and accelerate neonatal organ development. Social media should also be encouraged to spread news about breastfeeding and maternal stem cells' impact on lactating infants' health. Health belief model interventions may boost breastfeeding. In conclusion, the discovery of massive amounts of cells in maternal milk and the identification of stem/progenitors with previously unknown potential in newborn development after birth should be considered a new valuable tool for exclusive breastfeeding advocates. Data here suggests that every action to spread this message and educate mothers and families about breastfeeding's irreplaceable role is mandatory.

Faa G., Manchia M., Fanos V.

Assisted reproductive technology (ART) is an emerging field in medicine that incorporates complex procedures and has profound ethical, moral, social, religious, and economic implications not just for the individuals who have access to this method but also for society. In this narrative review, we summarise multiple aspects of ART procedures and the possible consequences on the mother and newborn. Moreover, we provide an overview of the possible long-term consequences of ART procedures on the health of newborns, although longitudinal evidence is particularly scant. Users should be informed that ART procedures are not risk-free to prepare them for the possible negative outcomes that may occur in the perinatal period or even in childhood and adulthood. Indeed, risk estimates point to increased liability for major nonchromosomal birth defects; cardiovascular, musculoskeletal, and urogenital (in male newborns) defects; and any other birth defects. Less certainty is present for the risk of neuropsychiatric sequelae in children conceived through ART. Thus, its application should be accompanied by adequate counselling and psychological support, possibly integrated into specific multidisciplinary clinical programmes.

Stepien B.K., Wielockx B.

Embryonic neurogenesis can be defined as a period of prenatal development during which divisions of neural stem and progenitor cells give rise to neurons. In the central nervous system of most mammals, including humans, the majority of neocortical neurogenesis occurs before birth. It is a highly spatiotemporally organized process whose perturbations lead to cortical malformations and dysfunctions underlying neurological and psychiatric pathologies, and in which oxygen availability plays a critical role. In case of deprived oxygen conditions, known as hypoxia, the hypoxia-inducible factor (HIF) signaling pathway is activated, resulting in the selective expression of a group of genes that regulate homeostatic adaptations, including cell differentiation and survival, metabolism and angiogenesis. While a physiological degree of hypoxia is essential for proper brain development, imbalanced oxygen levels can adversely affect this process, as observed in common obstetrical pathologies such as prematurity. This review comprehensively explores and discusses the current body of knowledge regarding the role of hypoxia and the HIF pathway in embryonic neurogenesis of the mammalian cortex. Additionally, it highlights existing gaps in our understanding, presents unanswered questions, and provides avenues for future research.