Impaired Brain Development Research Articles

Single-nucleus chromatin accessibility and RNA sequencing reveal impaired brain development in prenatally e-cigarette exposed neonatal rats

SummaryAlthough emerging evidence reveals that vaping alters the function of the central nervous system, the effects of maternal vaping on offspring brain development remain elusive. Using a well-established in utero exposure model, we performed single-nucleus ATAC-seq (snATAC-seq) and RNA sequencing (snRNA-seq) on prenatally e-cigarette-exposed rat brains. We found that maternal vaping distorted neuronal lineage differentiation in the neonatal brain by promoting excitatory neurons and inhibiting lateral ganglionic eminence-derived inhibitory neuronal differentiation. Moreover, maternal vaping disrupted calcium homeostasis, induced microglia cell death, and elevated susceptibility to cerebral ischemic injury in the developing brain of offspring. Our results suggest that the aberrant calcium signaling, diminished microglial population, and impaired microglia-neuron interaction may all contribute to the underlying mechanisms by which prenatal e-cigarette exposure impairs neonatal rat brain development. Our findings raise the concern that maternal vaping may cause adverse long-term brain damage to the offspring.

A vaping risks education program for school students: Evaluation of the solve mystery toolkit

One in three grade 7 to 12 students in Canada report trying vaping or e-cigarettes. Despite consequences like nicotine addiction, impaired brain development, increased respiratory symptoms, and association with an increased risk of COVID-19 diagnosis, 48% of youth believe occasional vaping has little to no risk. There is a clear need for youth to learn about vaping consequences. We developed and piloted a novel free interactive educational program on vaping risks which has been used by over 800 grade 7 to 9 students. In post-program surveys, students reported a subjective increase in knowledge about the health consequences of vaping.

Systemic Maternal Human sFLT1 Overexpression Leads to an Impaired Foetal Brain Development of Growth-Restricted Foetuses upon Experimental Preeclampsia.

The pregnancy disorder preeclampsia (PE) is characterized by maternal hypertension, increased level of circulating antiangiogenic soluble fms-like tyrosine kinase-1 (sFLT1), and reduced placental perfusion, leading to foetal growth restriction (FGR) and preterm birth. All these adverse effects are associated with neurocognitive disorders in the offspring. However, the direct interplay between increased antiangiogenesis during PE and disturbed foetal brain development independent of prematurity has not been investigated yet. To examine foetal brain development in sFLT1-related PE, hsFLT1/rtTA-transgenic mice with systemic (maternal or maternal/fetoplacental) human sFLT1 (hsFLT1) overexpression since 10.5 days postconception (dpc) were used, and histological and molecular analyses of foetal brains were performed at 18.5 dpc. Consequences of elevated hsFLT1 on placental/foetal vascularization and hypoxia of placentas and foetal brains were analysed using the hypoxia markers pimonidazole and hemeoxygenase-1 (HO-1). Immunohistochemical analysis revealed increased hypoxia in placentas of PE-affected pregnancies. Moreover, an increase in HO-1 expression was observed upon elevated hsFLT1 in placentas and foetal brains. PE foetuses revealed asymmetrical FGR by increased brain/liver weight ratio. The brain volume was reduced combined with a reduction in the cortical/hippocampal area and an increase of the caudate putamen and its neuroepithelium, which was associated with a reduced cell density in the cortex and increased cell density in the caudate putamen upon hsFLT1 overexpression. Mild influences were observed on brain vasculature shown by free iron deposits and mRNA changes in Vegf signalling. Of note, both types of systemic hsFLT1 overexpression (indirect: maternal or direct: maternal/fetoplacental) revealed similar changes with increasing severity of impaired foetal brain development. Overall, circulating hsFLT1 in PE pregnancies impaired uteroplacental perfusion leading to disturbed foetal oxygenation and brain injury. This might be associated with a disturbed cell migration from the caudate putamen neuroepithelium to the cortex which could be due to disturbed cerebrovascular adaption.

Development of human brain neuroimmune system under influence of alcohol

IntroductionExposure to alcohol causes imbalances in neuroimmune function and impaired brain development.ObjectivesAlcohol activates neuroimmune molecules, expressed and secreted by glial cells in the brain, alter neuronal function and stimulate alcoholic behavior.MethodsThe study involved women aged 25-41 years-did not drink alcohol 1 month before and during pregnancy – 1-st group; women with I-II degree of alcoholism 3-13 years – 2-nd group. Embryonic material were obtained 8-15 weeks of igestation. 2-nd group were divided into subgroups. Group Alcohol (A)-alcoholic women,s embrious, included 2 subgroups: A1-embryos 8-9 weeks, A2-10-11 weeks of gestation (n=12). The Control group (K) includ control samples K1-8–9, K2-10-11 weeks (n=14). The analysis of changes in morphometric parameters was used to identify quantitative changes among glioblasts, correlation between the degree of differentiation components and the degree of influence of alcohol. For this, the program AxioVision 4.8 was used Parameters of GABAA/benzodiazepine receptors were studied by the radio-receptor assay of [3H]-flunitrazepam with synaptoneurosomes.ResultsChanges in glioblasts tof human brain embryos and fetuses were revealed under conditions of chronic prenatal alcoholization with an increase in gestational age compared to the control subgroups: a significant increase in the average number of glioblasts, the length of the perimeters of the presynaptic terminal, postsynaptic density, presynaptic terminal areas were significantly less (p<0, 01) in the study group than in the control. Exposure to ethanol reduces the affinity of GABAA/benzodiazepine receptors, which affects neuronal plasticity associated with the development of glioblasts and neuroblasts during embryogenesis.ConclusionsChanges in microglial cause disruption of the neuronal activityDisclosureNo significant relationships.

Sight restoration in congenitally blind humans does not restore visual brain structure.

It is unknown whether impaired brain structure after congenital blindness is reversible if sight is restored later in life. Using structural magnetic resonance imaging, visual cortical surface area and cortical thickness were assessed in a large group of 21 sight-recovery individuals who had been born blind and who months or years later gained sight through cataract removal surgery. As control groups, we included 27 normally sighted individuals, 10 individuals with permanent congenital blindness, and 11 sight-recovery individuals with a late onset of cataracts. Congenital cataract-reversal individuals had a lower visual cortical surface area and a higher visual cortical thickness than normally sighted controls. These results corresponded to those of congenitally permanently blind individuals suggesting that impaired brain structure did not recover. Crucially, structural brain alterations in congenital-cataract reversal individuals were associated with a lower post-surgery visual acuity. No significant changes in visual cortex structure were observed in sight-recovery individuals with late onset cataracts. The results demonstrate that impaired structural brain development due to visual deprivation from birth is not fully reversible and limits functional recovery. Additionally, they highlight the crucial importance of prevention measures in the context of other types of aberrant childhood environments including low socioeconomic status and adversity.

Neonatal and Long-Term Prognosis of Monochorionic Diamniotic Pregnancies Complicated by Selective Growth Restriction.

Background: There are few data concerning the neonatal and long-term prognosis of monochorionic biamniotic twin pregnancies (MCBA) complicated by selective intrauterine growth restriction (sIUGR). The aim of the study is to assess the neurological outcomes at two years of age of these newborns and compares these outcomes to those of newborns resulting from intrauterine growth restriction (IUGR) pregnancies. Methods: The study focuses on a cross-sectional prospective cohort of patients treated between 2012 and 2019 in Marseille, France. The primary endpoint is the overall score of the Ages and Stages questionnaires (ASQ) at two years, which assesses the global neurodevelopment. The secondary endpoint is the assessment of neonatal morbi-mortality for both groups (composite endpoint). Results: In total, 251 patients were included in the analysis: 67 in the sIUGR group and 184 in the IUGR group. There was no statistically significant difference in the overall ASQ score at two years but there was the finest motor skills impairment in the IUGR group. The areas most often impaired were communication and fine motor skills. There were no significant differences between the neonatal morbi-mortality of the two groups (adjusted OR = 0.95, p = 0.9). Conclusions: Newborns from MCBA pregnancies with sIUGR appear to have similar overall neurological development to IUGR. Notably, IUGR seems to have the most moderate neurobehavioral disorder (fine motor) as a consequence of impaired antenatal brain development due to placenta insufficiency leading to chronic hypoxia.

Differential Effects of Urban Particulate Matter on BV2 Microglial-Like and C17.2 Neural Stem/Precursor Cells

Air pollution affects the majority of the world’s population and has been linked to over 7 million premature deaths per year. Exposure to particulate matter (PM) contained within air pollution is associated with cardiovascular, respiratory, and neurological ill health. There is increasing evidence that exposure to air pollution in utero and in early childhood is associated with altered brain development. However, the underlying mechanisms for impaired brain development are not clear. While oxidative stress and neuroinflammation are documented consequences of PM exposure, cell-specific mechanisms that may be triggered in response to air pollution exposure are less well defined. Here, we assess the effect of urban PM exposure on two different cell types, microglial-like BV2 cells and neural stem/precursor-like C17.2 cells. We found that, contrary to expectations, immature C17.2 cells were more resistant to PM-mediated oxidative stress and cell death than BV2 cells. PM exposure resulted in decreased mitochondrial health and increased mitochondrial ROS in BV2 cells which could be prevented by MitoTEMPO antioxidant treatment. Our data suggest that not only is mitochondrial dysfunction a key trigger in PM-mediated cytotoxicity but that such deleterious effects may also depend on cell type and maturity.

Comparative metabolomics in the Pahenu2 classical PKU mouse identifies cerebral energy pathway disruption and oxidative stress.

Classical phenylketonuria (PKU, OMIM 261600) owes to hepatic deficiency of phenylalanine hydroxylase (PAH) that enzymatically converts phenylalanine (Phe) to tyrosine (Tyr). PKU neurologic phenotypes include impaired brain development, decreased myelination, early onset mental retardation, seizures, and late-onset features (neuropsychiatric, Parkinsonism). Phe over-representation is systemic; however, tissue response to hyperphenylalaninemia is not consistent. To characterize hyperphenylalaninemia tissue response, metabolomics was applied to Pahenu2 classical PKU mouse blood, liver, and brain. In blood and liver over-represented analytes were principally Phe, Phe catabolites, and Phe-related analytes (Phe-conjugates, Phe-containing dipeptides). In addition to Phe and Phe-related analytes, the metabolomic profile of Pahenu2 brain tissue evidenced oxidative stress responses and energy dysregulation. Glutathione and homocarnosine anti-oxidative responses are apparent Pahenu2 brain. Oxidative stress in Pahenu2 brain was further evidenced by increased reactive oxygen species. Pahenu2 brain presents an increased NADH/NAD ratio suggesting respiratory chain complex 1 dysfunction. Respirometry in Pahenu2 brain mitochondria functionally confirmed reduced respiratory chain activity with an attenuated response to pyruvate substrate. Glycolysis pathway analytes are over-represented in Pahenu2 brain tissue. PKU pathologies owe to liver metabolic deficiency; yet, Pahenu2 liver tissue shows neither energy disruption nor anti-oxidative response. Unique aspects of metabolomic homeostasis in PKU brain tissue along with increased reactive oxygen species and respiratory chain deficit provide insight to neurologic disease mechanisms. While some elements of assumed, long standing PKU neuropathology are enforced by metabolomic data (e.g. reduced tryptophan and serotonin representation), energy dysregulation and tissue oxidative stress expand mechanisms underlying neuropathology.

Comparison Study of ALPHA 1-Antitrypsin, And Some Elements in Iraqi Cord Blood new Born with their Mothers

Umbilical cord blood (UCB) consider as a waste product after obstetrical but when the medicine development, it was found that UCB abundant of life saving hematopoietic stem cell and contents of soluble growth factors which is necessary for proliferation. Alpha- antitrypsin (α1-AT) is mainly synthesized in the hepatocytes by the liver then secreted to the circulation Its function is Remove the acute inflammation through supperion cytokine production and inhibits different enzymes such as neutrophil elastase (NE) in the lungs, proteinase 3, trypsin, and cathepsin G. Lead (Pb) is one of the most toxic of the heavy metals. The children especially newborns are the most affected by Pb because of they grow up rapidly resulting impaired brain and nervous system development. Cadmium (Cd) is the metal of the 20th and its effect resulted when Cd binds to proteins rich in cystein like metallothionein which causing hepatotoxicity in the liver and through circulating accumulates in the kidney tissue via and causing nephrotoxicity. Selenium (Se) as a trace element is an essential and important for human health. The vital function of Se including thyroid hormone metabolism and anti-inflammatory, immunity, activates natural killer cells, increases activated T cells proliferation, tumor cytotoxicity and antioxidant defense. The research conducted to study of 92 specimen of mothers with their new born infants in (46 normal and 46 cesarean delivery) and examined the levels of α1-AT bu enzyme liked immune assay method. Also some heavy metals i.e. Pb, Cd in addition to the Se element were determined by atomic absorption spectroscopy. The correlation between α1-AT with Pb, Cd and Se was instigated. Conclusions: The levels of α1-AT in the UCB was higher than their maternal sera after normal delivery this mean the new infant need to observation and monitoring of α1-AT level after the birth till seventh days, while α1-AT level in the UCB was lower level than their mothers sera in cesarean delivery. Keywords: α1-AT, Pb, Cd, Se, cord blood and new born

Protocol for a Cross-Sectional Study: Effects of a Multiple Sclerosis Relapse Therapy With Methylprednisolone on Offspring Neurocognitive Development and Behavior (MS-Children).

IntroductionMultiple Sclerosis (MS) is the most common neuroimmunological disease in women of childbearing age. Current MS therapy consists of immunomodulatory relapse prevention with disease-modifying therapies (DMTs) and acute relapse therapy with the synthetic glucocorticoid (GC) methylprednisolone (MP). As most DMTs are not approved for use during pregnancy, treatment is usually discontinued, increasing the risk for relapses. While MP therapy during pregnancy is considered relatively save for the fetus, it may be detrimental for later cognitive and neuropsychiatric function. The underlying mechanism is thought to be an epigenetically mediated desensitization of GC receptors, the subsequent increase in stress sensitivity, and a GC-mediated impairment of brain development. The aim of this study is to investigate the associations of fetal MP exposure in the context of MS relapse therapy with later cognitive function, brain development, stress sensitivity, and behavior.Methods and AnalysisEighty children aged 8–18 years of mothers with MS will be recruited. Forty children, exposed to GC in utero will be compared to 40 children without fetal GC exposure. The intelligence quotient will serve as primary outcome. Secondary outcomes will include attention, motor development, emotional excitability, Attention-Deficit Hyperactivity Disorder-related symptoms, and behavioral difficulties. The Trier Social Stress Test will test stress sensitivity, EEG and MRI will assess functional and structural brain development. To determine underlying mechanisms, DNA methylation of the GC receptor gene and the H19/IGF2 locus and changes in the microbiome and the metabolome will be investigated. Primary and secondary outcomes will be analyzed using linear regression models. Time-variant outcomes of the stress test will be analyzed in two mixed linear models exploring overall activity and change from baseline.Ethics and DisseminationThis study was approved by the participating institutions' ethics committees and results will be presented in accordance with the STROBE 2007 Statement.Trial Registration https://clinicaltrials.gov/ct2/show/NCT04832269?id=ZKSJ0130

Pathophysiological Heterogeneity of the BBSOA Neurodevelopmental Syndrome.

The formation and maturation of the human brain is regulated by highly coordinated developmental events, such as neural cell proliferation, migration and differentiation. Any impairment of these interconnected multi-factorial processes can affect brain structure and function and lead to distinctive neurodevelopmental disorders. Here, we review the pathophysiology of the Bosch–Boonstra–Schaaf Optic Atrophy Syndrome (BBSOAS; OMIM 615722; ORPHA 401777), a recently described monogenic neurodevelopmental syndrome caused by the haploinsufficiency of NR2F1 gene, a key transcriptional regulator of brain development. Although intellectual disability, developmental delay and visual impairment are arguably the most common symptoms affecting BBSOAS patients, multiple additional features are often reported, including epilepsy, autistic traits and hypotonia. The presence of specific symptoms and their variable level of severity might depend on still poorly characterized genotype–phenotype correlations. We begin with an overview of the several mutations of NR2F1 identified to date, then further focuses on the main pathological features of BBSOAS patients, providing evidence—whenever possible—for the existing genotype–phenotype correlations. On the clinical side, we lay out an up-to-date list of clinical examinations and therapeutic interventions recommended for children with BBSOAS. On the experimental side, we describe state-of-the-art in vivo and in vitro studies aiming at deciphering the role of mouse Nr2f1, in physiological conditions and in pathological contexts, underlying the BBSOAS features. Furthermore, by modeling distinct NR2F1 genetic alterations in terms of dimer formation and nuclear receptor binding efficiencies, we attempt to estimate the total amounts of functional NR2F1 acting in developing brain cells in normal and pathological conditions. Finally, using the NR2F1 gene and BBSOAS as a paradigm of monogenic rare neurodevelopmental disorder, we aim to set the path for future explorations of causative links between impaired brain development and the appearance of symptoms in human neurological syndromes.

MEMBANGKITKAN GENERASI MUDA BERINTEGRITAS SERTA MENINGKATKAN POLA HIDUP SEHAT BEBAS DARI NAPZA PADA SISWA (I) SMA NEGERI 13 TAKALAR

NAPZA stands for Narcotics, Psychotropics, and other Addictive Substances. The use of drugs is very dangerous for both mental and physical health of users. Drug users are at risk for impaired brain development, suicide and depression, memory loss, high risk for sexual behavior, addiction, impaired decision making, poor academic performance, violence, and motor vehicle accidents. Adolescent development is very vulnerable to the influence of the environment in everyday life. The transition period of adolescent development from children to adults is not only about age but also involves biological, cognitive, and socio-emotional changes. Changes in children's behavior, some in a positive direction and some in a negative direction. One of the negative behaviors is teenagers with habitual behavior of consuming alcohol. The many impacts experienced by drug abusers so that a treatment program is needed for those who have experienced drug abuse and anticipation for those who have not been entangled in using drugs, especially from the age of teenagers/students. This service is carried out on 12th grade high school students who are students of transition age to adolescence because in the next 3 years they will move into the teenage level. Through this service activity, it is expected to be able to provide understanding to SMAN 13 Takalar students about the dangers suffered by drug abuse, types and types of narcotics and how to overcome them. The method used provides a presentation of the correct understanding of drugs, discussions, questions and answers, the dangers and effective steps so that students can suppress negative behavior and abuse of drugs and harmful additives. In the activities carried out for approximately 4 hours, the children were very enthusiastic and became aware of the definition, forms, uses and dangers of drugs and committed not to use them in the future. Keywords: Education, prevention, deviant behavior

Association between morphine exposure and impaired brain development on term-equivalent age brain magnetic resonance imaging in very preterm infants

To investigate the relationship between morphine exposure in the first week of life and brain injury on term-equivalent age magnetic resonance imaging (MRI) in very preterm infants. A retrospective study included 106 infants with a birth weight of < 1500 g who were born at King Saud Medical City at ≤ 32 gestational weeks, were admitted to the neonatal intensive care unit, and underwent term-equivalent age or pre-discharge brain MRI. A univariate analysis in addition to modified log-Poisson regression with a robust variance estimator was applied, and the effect of early morphine exposure and cumulative dose in the first seven days on brain morphology and growth at term-equivalent age was determined using the Kidokoro score. Sixty-eight (64.2%) infants had received morphine in the first week of life (median cumulative dose: 1.68 mg/kg, interquartile range 0.48–2.52 mg/kg). Early initiation of morphine administration was significantly associated with high total white matter (adjusted relative risk [aRR] 1.32, 95% confidence interval [CI] 1.01–1.72) and cerebellum (aRR 1.36, 95% CI 1.03–1.81) scores and a small cerebellar volume (aRR 1.28, 95% CI 1.02–1.61). Morphine exposure in the first week of life was independently associated with white matter and cerebellar injury on term-equivalent age brain MRI in very preterm infants.

Does Bisphenol A Confer Risk of Neurodevelopmental Disorders? What We Have Learned from Developmental Neurotoxicity Studies in Animal Models.

Substantial evidence indicates that bisphenol A (BPA), a ubiquitous environmental chemical used in the synthesis of polycarbonate plastics and epoxy resins, can impair brain development. Clinical and epidemiological studies exploring potential connections between BPA and neurodevelopmental disorders in humans have repeatedly identified correlations between early BPA exposure and developmental disorders, such as attention deficit/hyperactivity disorder and autism spectrum disorder. Investigations using invertebrate and vertebrate animal models have revealed that developmental exposure to BPA can impair multiple aspects of neuronal development, including neural stem cell proliferation and differentiation, synapse formation, and synaptic plasticity—neuronal phenotypes that are thought to underpin the fundamental changes in behavior-associated neurodevelopmental disorders. Consistent with neuronal phenotypes caused by BPA, behavioral analyses of BPA-treated animals have shown significant impacts on behavioral endophenotypes related to neurodevelopmental disorders, including altered locomotor activity, learning and memory deficits, and anxiety-like behavior. To contextualize the correlations between BPA and neurodevelopmental disorders in humans, this review summarizes the current literature on the developmental neurotoxicity of BPA in laboratory animals with an emphasis on neuronal phenotypes, molecular mechanisms, and behavioral outcomes. The collective works described here predominantly support the notion that gestational exposure to BPA should be regarded as a risk factor for neurodevelopmental disorders.

Pengaruh Postural Control Exercise Pada Anak Cerebral Palsy Spastik Hemiplegi

ABSTRACT&#x0D; Cerebral palsy is a motor problem as a result of non-progressive brain lesions in impaired brain development. In children who suffer from Cerebral Palsy experience damage to the brain that is permanent. The characteristic of Cerebral Palsy with the Spastic Hemiplegic type is characterized by the appearance of problems in the upper and lower limbs of one side of the body. The intervention given in this case is a postural control exercise which aims to improve the child's ability to control body position with the aim of stability and orientation. This research method is experimental, the research design uses case studies and data collection techniques use Pre and Post Tests. The sampling technique used was accidental sampling. Examination of posture using a posture assessment scale and functional examination of activities using the GMFM form. After six sessions of therapy, the results showed an improvement in posture and an increase in the functional score of children's activities, although not significant. Postural control exercise programmed to patients is able to improve posture and increase the functional ability of children's activities.

Assessment of Stunting Status and Stunting Prevention Efforts in Toddlers in Penajam District, North Penajam Paser Regency

North Penajam Paser Regency (PPU) is one of the 100 priority districts/cities for stunting intervention in Indonesia. The prevalence of stunting in PPU Regency is 27%, while the prevalence in East Kalimantan is 28.3%, and nationally, 36.4%. Stunting has an impact on impaired brain growth, physical growth, and development. The purpose of community service is to analyze the characteristics of stunting toddlers and stunting prevention through posyandu activities. The method of implementing descriptive-analytic through secondary data collection activities for stunted toddlers is described. Posyandu activities for toddlers through health checks, providing nutrition education to toddlers in the villages of Penajam, Gunung Steleng, Nipah Nipah, and Nenang. Literature study on the prevention of stunting under five by the local government of PPU Regency. The results showed that there were 92 stunting toddlers, 53 boys, and 39 girls, with 68 short toddlers and 24 very short toddlers, most of whom were &gt;24 -60 months old, i.e. 59 toddlers. Stunting prevention includes health checks for children under five, education on stunting prevention at posyandu and strengthening of stunting prevention/control policies with Regent Regulations. More optimal efforts are needed in implementing the Regent's regulation for the prevention of stunting under five.

General anaesthesia for nonobstetric surgery during pregnancy

Nonobstetric surgery may be required in up to 1% of pregnancies. Most common procedures are urgent abdominal surgeries requiring general anaesthesia. Maintaining normal maternal physiology during anaesthesia is vital. Left lateral tilt position prevents aortocaval compression and preserves normal venous return. Preparation for a difficult airway is required in all obstetric patients due to the known anatomical and physiological changes. Aspiration prophylaxis and a rapid sequence induction are traditionally recommended to avoid the (probably overestimated) risk of aspiration. Although the minimum alveolar concentration (MAC) of volatile anaesthetic agents is reduced by 30 to 40%, awareness occurs more frequently in the obstetric population. Maternal outcomes from surgery are comparable with those of nonpregnant women, but increased incidences of foetal loss, preterm delivery, low birth weight and caesarean section have been reported. Although animal studies have observed impaired foetal brain development after antenatal exposure to anaesthesia, the translational value of these studies remain controversial. Clinical evidence is nearly absent. Withholding urgent/essential procedures is certainly more threatening than proceeding with the surgery. To increase the safety of mother and foetus, nonurgent or nonessential procedures should be postponed until after delivery, and if procedures cannot wait, locoregional anaesthesia should be used if possible. Where general anaesthesia cannot be avoided, the duration of exposure should be kept to a minimum. This narrative review summarises the literature of the past 20 years concerning the anaesthetic management and outcomes of nonobstetric surgery under general anaesthesia during pregnancy.

Behavioral profile of vitamin B12 deficiency: A reflection of impaired brain development, neuronal stress and altered neuroplasticity.

Our understanding of brain biology and function is one of the least characterized and therefore, there are no effective treatments for most of neurological disorders. The influence of vitamins, and particularly vitamin B12, in neurodegenerative disease is demonstrated but largely unresolved. Behaviors are often quantified to attest brain dysfunction alone or in parallel with neuro-imaging to identify regions involved. Nevertheless, attention should be paid to extending observations made in animal models to humans, since, first, behavioral tests have to be adjusted in each model to address the initial question and second, because brain analysis should not be conducted for a whole organ but rather to specific sub-structures to better define function. Indeed, cognitive functions such as psychiatric disorders and learning and memory are often cited as the most impacted by a vitamin B12 deficiency. In addition, differential dysfunctions and mechanisms could be defined according sub-populations and ages. Vitamin B12 enters the cell bound to Transcobalamin, through the Transcobalamin Receptor and serves in two cell compartments, the lipid metabolism in the mitochondrion and the one-carbon metabolism involved in methylation reactions. Dysfunctions in these mechanisms can lead to two majors outcomes; axons demyelinisation and upregulation of cellular stress involving mislocalization of RNA binding proteins such as the ELAVL1/HuR or the dysregulation of pro- or anti-oxidant NUDT15, TXNRD1, VPO1 and ROC genes. Finally, it appears that apart from developmental problems that have to be identified and treated as early as possible, other therapeutic approaches for behavioral dysfunctions should investigate cellular methylation, oxidative and endoplasmic reticulum stress and mitochondrial function.

Plastic pollution: why is it a public health problem?

Plastic pollution: why is it a public health problem?

Perinatal exposure to the thyroperoxidase inhibitors methimazole and amitrole perturbs thyroid hormone system signaling and alters motor activity in rat offspring

Disruption of the thyroid hormone system during development can impair brain development and cause irreversible damage. Some thyroid hormone system disruptors act by inhibiting the thyroperoxidase (TPO) enzyme, which is key to thyroid hormone synthesis. For the potent TPO-inhibiting drug propylthiouracil (PTU) this has been shown to result in thyroid hormone system disruption and altered brain development in animal studies. However, an outstanding question is which chemicals beside PTU can cause similar effects on brain development and to what degree thyroid hormone insufficiency must be induced to be able to measure adverse effects in rats and their offspring. To start answering these questions, we performed a perinatal exposure study in pregnant rats with two TPO-inhibitors: the drug methimazole (MMI) and the triazole herbicide amitrole. The study involved maternal exposure from gestational day 7 through to postnatal day 22, to MMI (8 and 16 mg/kg body weight/day) or amitrole (25 and 50 mg/kg body weight/day). Both MMI and amitrole reduced serum T4 concentrations in a dose-dependent manner in dams and offspring, with a strong activation of the hypothalamic-pituitary-thyroid axis. This reduction in serum T4 led to decreased thyroid hormone-mediated gene expression in the offspring’s brains and caused adverse effects on brain function, seen as hyperactivity and decreased habituation in preweaning pups. These dose-dependent effects induced by MMI and amitrole are largely the same as those observed with PTU. This demonstrates that potent TPO-inhibitors can induce effects on brain development in rats and that these effects are driven by T4 deficiency. This knowledge will aid the identification of TPO-inhibiting thyroid hormone system disruptors in a regulatory context and can serve as a starting point in search of more sensitive markers of developmental thyroid hormone system disruption.