Fetal Neurodevelopment Research Articles

House Dust Avoidance during Pregnancy and Subsequent Infant Development: The Japan Environment and Children's Study.

House dust, well known for causing allergy, contains chemicals that are harmful to fetal neurodevelopment. However, whether countermeasures for house dust allergy, such as frequent use of vacuum cleaners, frequent airing of futons, and the usage of anti-mite covers during pregnancy, are related to subsequent reduced risk of infant developmental delay remains unknown. Therefore, we examined this association by analyzing 81,106 mother-infant pairs who participated in a nationwide birth cohort in Japan. Infant developmental delays at 6 and 12 months postpartum were assessed using the Ages and Stages Questionnaire, Third Edition. A generalized linear model analysis was used to derive adjusted odds ratios (AORs) with the lowest care frequency as reference, while controlling 22 covariates. Our analysis showed that the above-mentioned cleaning measures were overall associated with a reduced risk of developmental delays, both at 6 and 12 months postpartum (AOR varied from 0.73 to 0.95, median: 0.84). Additionally, risks tended to decrease with an increase in the cleaning frequency. In conclusion, a negative dose-response association existed between these measures during pregnancy and infant developmental delay. Our results identify a potential role of frequent vacuum cleaning, airing bedding, and usage of anti-mite bedding covers in promoting intact infant development.

Maternal multiple sclerosis is not a risk factor for neurodevelopmental disorders in offspring.

BackgroundChildhood neurodevelopmental disorders (NDDs), including specific learning disorders (SLD), attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), are pathogenically linked to familial autoimmunity and maternal immune-mediated diseases during pregnancy.ObjectiveWe studied maternal MS as a potential risk factor for NDDs occurrence in offspring.MethodsMS and control mothers were subjected to questionnaires to ascertain NDD diagnosis in their progeny and the occurrence of both autoimmune and neurodevelopment disorders in their families. Suspected NDD cases were evaluated to confirm or rule out the diagnosis.ResultsOf the 322 MS women, 206 (64%) have 361 children; of these, 27 (7.5%) were diagnosed with NDD (11% ADHD; 22% ASD; 67% SLD). NDD-risk in offspring was associated to family history of autoimmunity and to NDDs both in MS and non-MS mother families (r = 0.75; p = 0.005) whereas it was not associated to maternal MS.ConclusionsFor the first time, we demonstrate that maternal MS does not predispose children to higher risk for NDD. On a mechanistic view, we suggest that the intrinsic organ-specific nature of MS does not impair the mother–child cross-talk in decidua nor does it influence fetal neurodevelopment.

Maternal Opioid Exposure Culminates in Perturbed Murine Neurodevelopment and Hyperactive Phenotype in Adolescence

Opioid use by women during pregnancy has risen dramatically since 2004, accompanied by a striking increase in the prevalence of neonatal opioid withdrawal syndrome (NOWS) and other long-term neurological deficits. However, the mechanisms underlying the impact of prenatal opioid exposure on fetal neurodevelopment are largely unknown. To translate from the clinical presentation, we developed a novel mouse model to study the neurodevelopmental consequences of maternal opioid use and management. Female mice were treated with oxycodone (OXY) before mating to mimic opioid use disorder (OUD) in humans. Following pregnancy confirmation, dams were switched to buprenorphine (BUP) via oral administration, simulating medication management of OUD (MOUD) in pregnant women. Here, we document critical changes in fetal brain development including reduced cortical thickness, altered corticogenesis, and ventriculomegaly in embryos from dams that were treated with opioids before and throughout pregnancy. Maternal care giving behavior was slightly altered without affecting gross growth of offspring. However, adolescent offspring exposed to maternal opioid use during pregnancy exhibited hyperactivity in late adolescence. Remarkably, we also show increased generation of dopaminergic neurons within the ventral tegmental area (VTA) of mice exposed to prenatal opioids. These data provide critical evidence of teratogenic effects of opioid use during pregnancy and suggest a causal relationship between maternal opioid use and neurodevelopmental/behavioral anomalies in adolescence.

A Translational Perspective of Maternal Immune Activation by SARS-CoV-2 on the Potential Prenatal Origin of Neurodevelopmental Disorders: The Role of the Cholinergic Anti-inflammatory Pathway.

The emergent Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) could produce a maternal immune activation (MIA) via the inflammatory response during gestation that may impair fetal neurodevelopment and lead to postnatal and adulthood mental illness and behavioral dysfunctions. However, so far, limited evidence exists regarding long-term physiological, immunological, and neurodevelopmental modifications produced by the SARS-CoV-2 in the human maternal-fetal binomial and, particularly, in the offspring. Relevant findings derived from epidemiological and preclinical models show that a MIA is indeed linked to an increased risk of neurodevelopmental disorders in the offspring. We hypothesize that a gestational infection triggered by SARS-CoV-2 increases the risks leading to neurodevelopmental disorders of the newborn, which can affect childhood and the long-term quality of life. In particular, disruption of either the maternal or the fetal cholinergic anti-inflammatory pathway (CAP) could cause or exacerbate the severity of COVID-19 in the maternal-fetal binomial. From a translational perspective, in this paper, we discuss the possible manifestation of a MIA by SARS-CoV-2 and the subsequent neurodevelopmental disorders considering the role of the fetal-maternal cytokine cross-talk and the CAP. Specifically, we highlight the urgent need of preclinical studies as well as multicenter and international databanks of maternal-fetal psychophysiological data obtained pre-, during, and post-infection by SARS-CoV-2 from pregnant women and their offspring.

Association Between Socioeconomic Status and In Utero Fetal Brain Development

Children raised in settings with lower parental socioeconomic status are at increased risk for neuropsychological disorders. However, to date, the association between socioeconomic status and fetal brain development remains poorly understood. To determine the association between parental socioeconomic status and in vivo fetal brain growth and cerebral cortical development using advanced, 3-dimensional fetal magnetic resonance imaging. This cohort study of fetal brain development enrolled 144 healthy pregnant women from 2 low-risk community obstetrical hospitals from 2012 through 2019 in the District of Columbia. Included women had a prenatal history without complications that included recommended screening laboratory and ultrasound studies. Exclusion criteria were multiple gestation pregnancy, known or suspected congenital infection, dysmorphic features of the fetus, and documented chromosomal abnormalities. T2-weighted fetal brain magnetic resonance images were acquired. Each pregnant woman was scanned at up to 2 points in the fetal period. Data were analyzed from June through November 2020. Parental education level and occupation status were documented. Regional fetal brain tissue volume (for cortical gray matter, white matter, cerebellum, deep gray matter, and brainstem) and cerebral cortical features (ie, lobe volume, local gyrification index, and sulcal depth) in the frontal, parietal, temporal, and occipital lobes were calculated. Fetal brain magnetic resonance imaging studies were performed among 144 pregnant women (median [interquartile range] age, 32.5 [27.0-36.1] years) with gestational age from 24.0 to 39.4 weeks; 75 fetuses (52.1%) were male, and 69 fetuses (47.9%) were female. Higher parental education level was associated with significantly increased volume in the fetal white matter (mothers: β, 2.86; 95% CI, 1.26 to 4.45; P = .001; fathers: β, 2.39; 95% CI, 0.97 to 3.81; P = .001), deep gray matter (mothers: β, 0.16; 95% CI, 0.002 to 0.32; P = .048; fathers: β, 0.16; 95% CI, 0.02 to 0.31; P = .02), and brainstem (mothers: β, 0.06; 95% CI, 0.02 to 0.10; P = .01; fathers: β, 0.04; 95% CI, 0.004 to 0.08; P = .03). Higher maternal occupation status was associated with significantly increased volume in the fetal white matter (β, 2.07; 95% CI, 0.88 to 3.26; P = .001), cerebellum (β, 0.17; 95% CI, 0.04 to 0.29; P = .01), and brainstem (β, 0.03; 95% CI, 0.001 to 0.07; P = .04), and higher paternal occupation status was associated with significantly increased white matter volume (β, 1.98; 95% CI, 0.71 to 3.25; P < .01). However, higher socioeconomic status was associated with significantly decreased fetal cortical gray matter volume (mothers: β, -0.11; 95% CI, -0.18 to -0.03; P = .01; fathers: β, -0.10; 95% CI, -0.18 to -0.03; P = .01). Higher parental socioeconomic status was associated with increased volumes of 3 brain lobes of white matter: frontal lobe (mothers: β, 0.07; 95% CI, 0.02 to 0.13; P = .01; fathers: β, 0.06; 95% CI, 0.01 to 0.11; P = .03), parietal lobe (mothers: β, 0.07; 95% CI, 0.03 to 0.11; P < .001; fathers: β, 0.06; 95% CI, 0.03 to 0.10; P = .001), and temporal lobe (mothers: β, 0.04; 95% CI, 0.02 to 0.07; P < .001; fathers: β, 0.04; 95% CI, 0.02 to 0.07; P < .001), and maternal SES score was associated with significantly decreased volume in the occipital lobe (β, 0.02; 95% CI, 0.002 to 0.04; P = .03). Higher parental socioeconomic status was associated with decreased cortical local gyrification index (for example, for the frontal lobe, mothers: β, -1.1; 95% CI, -1.9 to -0.3; P = .01; fathers: β, -0.8; 95% CI, -1.6 to -0.1; P = .03) and sulcal depth, except for the frontal lobe (for example, for the parietal lobe, mothers: β, -9.5; 95% CI, -13.8 to -5.3; P < .001; fathers: β, -8.7; 95% CI, -13.0 to -4.4; P < .001). This cohort study found an association between parental socioeconomic status and altered in vivo fetal neurodevelopment. While being born and raised in a lower socioeconomic status setting is associated with poorer neuropsychological, educational, and socioeconomic outcomes in children, these findings suggest that altered prenatal programming may be associated with these outcomes and that future targeted prenatal interventions may be needed.

Mild to moderate iodine deficiency in pregnancy: A matter of debate

During the last few decades painstaking efforts have been made to eliminate iodine deficiency through the world. Nowadays in regions where dietary iodine intake is adequate or borderline, the main focus is increasing dietary iodine supply in the target population during pregnancy and the first years of life. Severe iodine deficiency during pregnancy increases the risk of irreversible brain damage, intellectual disability, neurologic abnormalities, stunted growth, increased pregnancy loss, infant mortality, impairments in child development and cretinism. The potential effects of mild-to-moderate iodine deficiency are debated. Results from animal studies and observational human studies indicate that maternal mild-to-moderate iodine deficiency disturbs thyroid function in pregnancy and it also may affects fetal neurodevelopment. The effect of supplementation of iodine on thyroid function of pregnant women and their newborn, neurodevelopment of infants and cognitive performance of children have been investigated using iodine nutrition in pregnancy, based on median urinary iodine concentration. However they have found conflicting results regarding the benefits or harms of iodine supplementation in pregnancy. Although many epidemiological, interventional and clinical studies have supported the association between thyroid function in pregnant women and later psychomotor and mental development of their children, the effect of iodine supplementation in pregnant women on neurodevelopment of children is inconclusive. Even in areas with well-established universal salt iodization program, pregnancy could be at risk of having iodine deficiency and despite WHO/ICCIDD/UNICEF recommendation which believe that dietary iodine fortification during pregnancy depends primarily on the extent of pre-existing iodine deprivation, systematic dietary fortification needs to be implemented in this vulnerable group. However, iodine supplementation of mildly iodine deficient pregnant women may not have beneficial effects in their thyroid function or neurodevelopment of their children.

Asymmetric cortical development and prognosis in fetuses with isolated mild fetal ventriculomegaly: an observational prospective study

BackgroundAssessments of cortical development and identifying factors that may result in a poor prognosis for fetuses with isolated mild ventriculomegaly (IMVM) is a hot research topic. We aimed to perform a constant, detailed assessment of cortical development in IMVM fetuses using ultrasound and determine whether asymmetric cortical development occurred. Moreover, we aimed to estimate the prognosis of IMVM fetuses and compare the difference in the prognosis of IMVM fetuses presenting symmetric and asymmetric cortical maturation.MethodsIMVM was diagnosed by regular ultrasound, neurosonography and fetal MRI. Genetic and TORCH examinations were conducted to exclude common genetic abnormalities and TORCH infection of fetuses. Ultrasound examinations were conducted at an interval of 2–3 weeks to record sulcus development in IMVM fetuses using a scoring system. The neonatal behavioral neurological assessment (NBNA), the Ages and Stages Questionnaire, Third Edition (ASQ-3) and the Bayley Scales of Infant Development, First Edition (BSID-I) were performed after birth.ResultsForty fetuses with IMVM were included: twenty showed asymmetric cortical maturation and twenty showed symmetric cortical maturation. For IMVM fetuses presenting asymmetric cortical maturation, the mean gestational age (GA) at the first diagnosis of relatively delayed development was 24.23 weeks for the parieto-occipital sulcus, 24.71 weeks for the calcarine sulcus, and 26.43 weeks for the cingulate sulcus. All the sulci with delayed development underwent ‘catch-up growth’ and developed to the same grade as the sulci of the other hemisphere. The mean GA at which the two sides developed to the same grade was 29.40 weeks for the parieto-occipital sulcus, 29.30 weeks for the calcarine sulcus and 31.27 weeks for the cingulate sulcus. The NBNA, ASQ-3 and BSID-I scores of all patients were in the normal range.ConclusionsIMVM fetuses may show mild asymmetric cortical maturation in the second trimester, but the relatively delayed sulci undergo ‘catch-up growth’. The neurodevelopment of IMVM fetuses presenting asymmetric cortical maturation and ‘catch-up growth’ is not statistically significantly different from IMVM fetuses presenting symmetric cortical maturation.

Effects of Maternal Abdominal Surgery on Fetal Brain Development in the Rabbit Model

Introduction: Anesthesia during pregnancy can impair fetal neurodevelopment, but effects of surgery remain unknown. The aim is to investigate effects of abdominal surgery on fetal brain development. Hypothesis is that surgery impairs outcome. Methods: Pregnant rabbits were randomized at 28 days of gestation to 2 h of general anesthesia (sevoflurane group, n = 6) or to anesthesia plus laparoscopic appendectomy (surgery group, n = 13). On postnatal day 1, neurobehavior of pups was assessed and brains harvested. Primary outcome was neuron density in the frontal cortex, and secondary outcomes included neurobehavioral assessment and other histological parameters. Results: Fetal survival was lower in the surgery group: 54 versus 100% litters alive at birth (p = 0.0442). In alive litters, pup survival until harvesting was 50 versus 69% (p = 0.0352). No differences were observed for primary outcome (p = 0.5114) for surviving pups. Neuron densities were significantly lower in the surgery group in the caudate nucleus (p = 0.0180), but not different in other regions. No differences were observed for secondary outcomes. Conclusions did not change after adjustment for mortality. Conclusion: Abdominal surgery in pregnant rabbits at a gestational age corresponding to the end of human second trimester results in limited neurohistological changes but not in neurobehavioral impairments. High intrauterine mortality limits translation to clinical scenario, where fetal mortality is close to zero.

Lower iodine storage in the placenta is associated with gestational diabetes mellitus

BackgroundThe micronutrient iodine is essential for a healthy intrauterine environment and is required for optimal fetal growth and neurodevelopment. Evidence linking urinary iodine concentrations, which mainly reflects short-term iodine intake, to gestational diabetes mellitus (GDM) is inconclusive. Although the placental concentrations would better reflect the long-term gestational iodine status, no studies to date have investigated the association between the placental iodine load and the risk at GDM. Moreover, evidence is lacking whether placental iodine could play a role in biomarkers of insulin resistance and β-cell activity.MethodsWe assessed the incidence of GDM between weeks 24 and 28 of gestation for 471 mother-neonate pairs from the ENVIRONAGE birth cohort. In placentas, we determined the iodine concentrations. In maternal and cord blood, we measured the insulin concentrations, the Homeostasis Model Assessment (HOMA) for insulin resistance (IR) index, and β-cell activity. Logistic regression was used to estimate the odds ratios (OR) of GDM, and the population attributable factor (PAF) was calculated. Generalized linear models estimated the changes in insulin, HOMA-IR, and β-cell activity for a 5 μg/kg increase in placental iodine.ResultsHigher placental iodine concentrations decreased the risk at GDM (OR = 0.82; 95%CI 0.72 to 0.93; p = 0.003). According to the PAF, 54.2% (95%CI 11.4 to 82.3%; p = 0.0006) of the GDM cases could be prevented if the mothers of the lowest tertile of placental iodine would have placental iodine levels as those belonging to the highest tertile. In cord blood, the plasma insulin concentration was inversely associated with the placental iodine load (β = − 4.8%; 95%CI − 8.9 to − 0.6%; p = 0.026).ConclusionsHigher concentrations of placental iodine are linked with a lower incidence of GDM. Moreover, a lower placental iodine load is associated with an altered plasma insulin concentration, HOMA-IR index, and β-cell activity. These findings postulate that a mild-to-moderate iodine deficiency could be linked with subclinical and early-onset alterations in the normal insulin homeostasis in healthy pregnant women. Nevertheless, the functional link between gestational iodine status and GDM warrants further research.

Emotional regulation and psychomotor development after threatening preterm labor: a prospective study.

A threatened preterm labor (TPL) represents an adverse prenatal event that may affect fetal neurodevelopment, even in absence of prematurity. Indeed, late-preterm infants, without neurological complications, also exhibit neurodevelopment impairment with psychomotor delay as well as emotional regulation disturbances, considered early manifestations of neuropsychiatric disorders. The aim of this study is to examine the impact of TPL on infant's psychomotor development and temperament. This prospective cohort study recruited mothers who suffered from a TPL and a control group of mothers without TPL and full-term gestation (n = 61). TPL infants were classified into three groups depending on delivery time: Full-Term (n = 37), Late-Preterm (n = 66), and Very-Preterm (n = 38). Neurodevelopmental assessment was performed at 6months using the Ages & Stages Questionnaires for psychomotor development and the Infant Behaviour Questionnaire-Revised for temperament. After controlling for potential cofounders (multiple pregnancy and in vitro fertilization), Full-Term TPL infants, relative to the control group, exhibited development delay in Communication (p = 0.044) and Personal-social domains (p = 0.005) as well as temperament disturbances with higher Negative Affect (p = 0.013), lower Positive Affect (p = 0.010), and worse Emotional Regulation (p < 0.001) compared to Control. No differences were found between Full-Term and Late-Preterm TPL infants. TPL may represent a risk factor for neurodevelopmental disturbances in the offspring, affecting both psychomotor and emotional infant competences, even when infants were born at term.

Effects of Pregnancy Anesthesia on Fetal Nervous System

The effects of general anesthesia on the developing brain remain a great concern in the medical field and even in the public, and most researches in this area focus on infancy and childhood. In recent years, with the continuous development of medical technology, the number of operations during pregnancy is increasing, however, studies on general anesthesia during pregnancy are relatively lacking. The mid-trimester of pregnancy is a critical period, and is regarded as a safe period for surgery, but it is a fragile period for the development of the central nervous system and is particularly sensitive to the impact of the environment. Our research group found that general anesthesia may have adverse effects on fetal neurodevelopment during the mid-trimester. Therefore, in this review, we summarize the characteristics of anesthesia during pregnancy, and the related research of the anesthesia’s impacts on the development of central nervous system were introduced.

1133 Chronic intrauterine hypoxia shifts the balance of mitochondrial dynamics in the fetal guinea pig forebrain

Mitochondrial ATP production facilitates proper fetal neurodevelopment and is dependent on mitochondrial dynamics consisting of fission and fusion. We hypothesize in the setting of chronic intrauterine hypoxia, which is associated poor neurodevelopmental outcomes, that mitochondrial dynamics are dysregulated in a manner dependent on fetal sex and the timing of hypoxia onset. Using a guinea pig model of chronic intrauterine hypoxia, we characterized the expression of mitochondrial fission and fusion proteins in fetal forebrains after exposure to early or late-onset hypoxia (EO-HPX and LO-HPX, respectively). Pregnant guinea pigs were exposed to either normoxia (NMX) or hypoxia (ambient O2 10.5%) starting at 28 d (EO-HPX) or 50 d (LO-HPX) gestation until term (65d). Male and female fetuses were extracted from anesthetized sows and forebrains were excised (n=6). Protein expression of mitochondrial fission (Drp-1) and fusion (Mfn-2) proteins were measured by Western Blot. Results of the hypoxic effects are means +/- SEM, with statistical comparison to NMX by one-tailed T-Test. EO-HPX significantly increased Drp-1 expression levels in male fetal forebrains compared to NMX. There was no significant effect of LO-HPX on Drp-1 in the male fetal brain (Fig 1A). Both EO-HPX and LO-HPX increased Drp-1 expression in female forebrains compared to NMX (Fig1B). Mfn-2 was significantly lower in male fetal forebrain tissues exposed to EO-HPX as compared to NMX (Fig 2A). In contrast, LO-HPX had no significant effect on Mfn-2 in male fetuses compared to NMX. Neither EO-HPX nor LO-HPX had any effect on Mfn-2 in female forebrains compared to NMX (Fig 2B). Hypoxia exposure at mid-gestation shifted the balance of mitochondrial dynamics in a sex-dependent manner toward fission. Hypoxia both decreased fusion and increased fission in the male forebrain, In contrast, hypoxia had no effect on fusion but increased fission within females. . Therefore, altered mitochondrial functional capacity can be an underlying mechanism contributing to altered fetal brain development.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Thyroid Disrupting Effects of Old and New Generation PFAS.

Per- and polyfluoroalkyl substances (PFAS) represent a group of synthetic compounds widely used in industry plants due to their low grade of degradation, surfactant properties, thermic and flame resistance. These characteristics are useful for the industrial production, however they are also potentially dangerous for human health and for the environment. PFAS are persistent pollutants accumulating in waters and soil and recoverable in foods due to their release by food packaging. Humans are daily exposed to PFAS because these compounds are ubiquitous and, when assimilated, they are difficult to be eliminated, persisting for years both in humans and animals. Due to their persistence and potential danger to health, some old generation PFAS have been replaced by newly synthesized PFAS with the aim to use alternative compounds presumably safer for humans and the environment. Yet, the environmental pollution with PFAS remains a matter of concern worldwide and led to large-scale epidemiological studies both on plants’ workers and on exposed people in the general population. In this context, strong concern emerged concerning the potential adverse effects of PFAS on the thyroid gland. Thyroid hormones play a critical role in the regulation of metabolism, and thyroid function is related to cardiovascular disease, fertility, and fetal neurodevelopment. In vitro, ex vivo data, and epidemiological studies suggested that PFASs may disrupt the thyroid hormone system in humans, with possible negative repercussions on the outcome of pregnancy and fetal-child development. However, data on the thyroid disrupting effect of PFAS remain controversial, as well as their impact on human health in different ages of life. Aim of the present paper is to review recent data on the effects of old and new generation PFAS on thyroid homeostasis. To this purpose we collected information from in vitro studies, animal models, and in vivo data on exposed workers, general population, and pregnant women.

Prenatal chlorpyrifos exposure in association with PPARγ H3K4me3 and DNA methylation levels and child development.

Chlorpyrifos, one of the most widely used pesticides, can penetrate the placenta and affect fetal growth and neurodevelopment. Epigenetic regulation of peroxisome proliferator-activated receptor gamma (PPARγ), such as DNA methylation and trimethylation of lysine 4 of H3 (H3K4me3), may provide a potential mechanism for how fetal growth and development are impacted by chlorpyrifos exposure. The aims of the study were to investigate whether prenatal chlorpyrifos exposure was associated with H3K4me3 and DNA methylation levels of the PPARγ gene in the placenta and the related effects on birth outcomes and neurodevelopment. Among 425 mother-infant pairs from the Taiwan Birth Panel Study, chlorpyrifos levels were measured in cord blood by using online SPE-LC/HESI/MS/MS; placental PPARγ H3K4me3 and DNA methylation levels were measured by ChIP-qPCR and pyrosequencing, respectively; the neonates' health outcomes were extracted from the medical records; and childhood neurodevelopment was evaluated by using the Comprehensive Developmental Inventory for Infants and Toddlers in 2-year-old children. Multivariable regression models were used to adjust for potential confounders. After controlling for potential confounders, each unit increase in the natural log-transformed prenatal chlorpyrifos exposure level was associated with an increase in the PPARγ DNA methylation level (adjusted β (aβ)=0.77, p=0.032) and poorer performance in the cognitive and language domains at 2 years old, especially in boys (aβ=-1.66, p=0.016, and aβ=-1.79, p=0.023, respectively). PPARγ H3K4me3 levels were positively associated with gestational age (aβ=0.16, p=0.011), birth weight (aβ=30.52, p=0.013), birth length (aβ=0.18, p=0.003 and aβ=0.15, p=0.042), and gross-motor performance (aβ=1.67, p=0.036). Our findings suggested that prenatal chlorpyrifos exposure affected PPARγ DNA methylation levels and performance in the cognitive and language domains.

Maternal obesity and developmental programming of neuropsychiatric disorders: An inflammatory hypothesis

Maternal obesity is associated with the development of a variety of neuropsychiatric disorders; however, the mechanisms behind this association are not fully understood. Comparison between maternal immune activation and maternal obesity reveals similarities in associated impairments and maternal cytokine profile. Here, we present a summary of recent evidence describing how inflammatory processes contribute towards the development of neuropsychiatric disorders in the offspring of obese mothers. This includes discussion on how maternal cytokine levels, fatty acids and placental inflammation may interact with foetal neurodevelopment through changes to microglial behaviour and epigenetic modification. We also propose an exosome-mediated mechanism for the disruption of brain development under maternal obesity and discuss potential intervention strategies.

Research Progresses on the Relationship Between the Phthalates Exposure and Children’s Neurodevelopmental Disorders

Neurodevelopment, a complex multifactorial process, is influenced by genetic factors, environmental factors and the interaction between them. Among various environmental factors, prenatal or postnatal phthalate exposure are gradually attracting great attention. The plasticizers phthalate are widely used in various products. Since they do not form covalent bonds with the polymer matrix, they may leach or outgas into the environment and enter the human body, even affect the development of the fetus or newborn through the placenta or breast milk. In recent years, increasing evidences have shown that maternal phthalate exposure can interfere with the development of fetal central nervous system, resulting in neurodevelopmental disorders in postnatal children. However, the specific relationship between maternal phthalate exposure and fetal neurodevelopment and its mechanism have not been clearly studied. At present, the known possible mechanisms include disruption of thyroid homeostasis, alteration of calcium signal transduction, disturbance of lipid metabolism, interfering with the action of sex hormones, influence of the Rho-GTPase pathway, induction of epigenetic and oxidative stress, etc. As the problem has gradually become the focus of attention all over the world, new research results are still emerging. In order to provide references for further study of the etiology and pathogenesis, the latest research progresses and mechanisms of phthalate exposure on neurodevelopment were reviewed in the following article.

Endocrine disrupting chemicals (EDCs) and placental function: Impact on fetal brain development.

Pregnancy is a critical time of vulnerability for the development of the fetal brain. Exposure to environmental pollutants at any point in pregnancy can negatively impact many aspects of fetal development, especially the organization and differentiation of the brain. The placenta performs a variety of functions that can help protect the fetus and sustain brain development. However, disruption of any of these functions can have negative impacts on both the pregnancy outcome and fetal neurodevelopment. This review presents current understanding of how environmental exposures, specifically to endocrine disrupting chemicals (EDCs), interfere with placental function and, in turn, neurodevelopment. Some of the key differences in placental development between animal models are presented, as well as how placental functions such as serving as a xenobiotic barrier and exchange organ, immune interface, regulator of growth and fetal oxygenation, and a neuroendocrine organ, could be vulnerable to environmental exposure. This review illustrates the importance of the placenta as a modulator of fetal brain development and suggests critical unexplored areas and possible vulnerabilities to environmental exposure.

The Effects of Maternal Interleukin-17A on Social Behavior, Cognitive Function, and Depression-Like Behavior in Mice with Altered Kynurenine Metabolites.

Viral infection and chronic maternal inflammation during pregnancy are correlated with a higher prevalence of autism spectrum disorder (ASD). However, the pathoetiology of ASD is not fully understood; moreover, the key molecules that can cross the placenta following maternal inflammation and contribute to the development of ASD have not been identified. Recently, the pro-inflammatory cytokine, interleukin-17A (IL-17A) was identified as a potential mediator of these effects. To investigate the impact of maternal IL-17A on offspring, C57BL/6J dams were injected with IL-17A-expressing plasmids via the tail vein on embryonic day 12.5 (E12.5), and maternal IL-17A was expressed continuously throughout pregnancy. By adulthood, IL-17A-injected offspring exhibited behavioral abnormalities, including social and cognitive defects. Additionally, maternal IL-17A promoted metabolism of the essential amino acid tryptophan, which produces several neuroactive compounds and may affect fetal neurodevelopment. We observed significantly increased levels of kynurenine in maternal serum and fetal plasma. Thus, we investigated the effects of high maternal concentration of kynurenine on offspring by continuously administering mouse dams with kynurenine from E12.5 during gestation. Obviously, maternal kynurenine administration rapidly increased kynurenine levels in the fetal plasma and brain, pointing to the ability of kynurenine to cross the placenta and change the KP metabolites which are affected as neuroactive compounds in the fetal brain. Notably, the offspring of kynurenine-injected mice exhibited behavioral abnormalities similar to those observed in offspring of IL-17A-conditioned mice. Several tryptophan metabolites were significantly altered in the prefrontal cortex of the IL-17A-conditioned and kynurenine-injected adult mice, but not in the hippocampus. Even though we cannot exclude the possibility or other molecules being related to ASD pathogenesis and the presence of a much lower degree of pathway activation, our results suggest that increased kynurenine following maternal inflammation may be a key factor in changing the balance of KP metabolites in fetal brain during neuronal development and represents a therapeutic target for inflammation-induced ASD-like phenotypes.

Associations between maternal thyroid function in pregnancy and child neurodevelopmental outcomes at 20 months in the Seychelles Child Development Study, Nutrition Cohort 2 (SCDS NC2).

Maternal thyroid hormones facilitate optimal foetal neurodevelopment; however, the exact role of the thyroid hormones on specific cognitive outcomes is unknown. The present study aimed to investigate associations between maternal thyroid function and neurodevelopmental outcomes in the Seychelles Child Development Study (SCDS) Nutrition 2 cohort (n 1328). Maternal free thyroid hormones (fT3, fT4 and fTSH) were assessed at 28 weeks' gestation with a range of child cognitive outcomes analysed at 20 months. Dietary iodine intake was analysed for a subset of women through a Food Frequency Questionnaire. Linear regression analysis was used to test associations between serum concentrations of maternal thyroid hormones and child neurodevelopment outcomes. Thyroid hormones were analysed as continuous data and categorised as quintiles. 95% of mothers had optimal thyroid function based on fTSH concentrations. Overall, the present study shows that maternal thyroid function is not associated with neurodevelopmental outcomes in this high fish-eating population. However, a positive association, using quintiles for fT3, was reported for the Mental Developmental Index, between Q3 v. Q4 (β 0⋅073; P 0⋅043) and for Q3 v. Q5 (β value 0⋅086; P 0⋅018). To conclude, mothers in our cohort, who largely have optimal thyroid function and iodine intakes, appear able to regulate thyroid function throughout pregnancy to meet neurodevelopmental needs. However, it is possible that minor imbalances of fT3, as indicated from our secondary analysis, may impact offspring neurodevelopment. Further investigation of the relationship between maternal thyroid function and infant neurodevelopment is warranted, particularly in populations with different dietary patterns and thereby iodine intakes.

Purines and Pyrimidines: Metabolism, Function and Potential as Therapeutic Options in Neurodegenerative Diseases.

Various neurodegenerative disorders have various molecular origins but some common molecular mechanisms. In the current scenario, there are very few treatment regimens present for advanced neurodegenerative diseases. In this context, there is an urgent need for alternate options in the form of natural compounds with an ameliorating effect on patients. There have been individual scattered experiments trying to identify potential values of various intracellular metabolites. Purines and Pyrimidines, which are vital molecules governing various aspects of cellular biochemical reactions, have been long sought as crucial candidates for the same, but there are still many questions that go unanswered. Some critical functions of these molecules associated with neuromodulation activities have been identified. They are also known to play a role in foetal neurodevelopment, but there is a lacuna in understanding their mechanisms. In this review, we have tried to assemble and identify the importance of purines and pyrimidines, connecting them with the prevalence of neurodegenerative diseases. The leading cause of this class of diseases is protein misfolding and the formation of amyloids. A direct correlation between loss of balance in cellular homeostasis and amyloidosis is yet an unexplored area. This review aims at bringing the current literature available under one umbrella serving as a foundation for further extensive research in this field of drug development in neurodegenerative diseases.