Neurodevelopmental Disorders In Offspring Research Articles

Maternal aging reduces female fecundity and alters offspring phenotype in a sex-specific manner.

Context The age of childbearing in women has increased, with more babies born to women over 30years old than to those in their 20s. However, increasing maternal age is associated with a range of pregnancy and perinatal complications, such as reduced chance of conception, and higher risk of miscarriage or fetal death. Further, epidemiological studies indicate that advanced maternal age is also linked to a higher incidence of metabolic and neurodevelopmental disorders in offspring, such as Type 1 diabetes and autism spectrum disorder (ASD). Aims Mature female mice recapitulate many of the fertility characteristics seen in older women, such as reduced egg number and quality, providing a robust experimental model. This study examined fertility and offspring phenotypes in female mice at the onset of reproductive aging. Methods Firstly, fecundity in mice was measured from 3 to 18months of age. Secondly, reproductive outcomes in aged female mice (12months old) were compared to those of young females (3months of age). Growth of the offspring was assessed, as well as metabolism, behaviour, and immune function in adulthood. Key results Female aging reduced pregnancy rate, litter size and pup survival to weaning. Maternal age did not affect adult offspring immune function; however, female offspring had higher body weights, and male littermates presented dysregulated glucose tolerance and hyperactivity. Conclusions Maternal age affects offspring survival and health in a sex-specific manner. Implications These findings expand our understanding of maternal programming of offspring health, particularly the effects of increased age at pregnancy.

Maternal autoimmune diseases and the risk of tics and Tourette's disorder in offspring: insights from Taiwan's real-world data.

Currently, tics and Tourette's disorder are burdensome neurological disorders that manifest in vocal and motor tics with onset during childhood. Previous studies have demonstrated that maternal autoimmune diseases may cause several neurodevelopmental disorders in offspring via maternal immune activation. However, the association between them has never been thoroughly researched. Thus, in this study, we aimed to explore whether maternal autoimmune diseases are associated with the risk of tics and Tourette's disorder in offspring in a real-world nationwide population-based cohort study. We analyzed offspring with or without autoimmune disease exposure between 2009 and 2016 from national population databases in Taiwan. Multivariate analysis, multiple Cox regression analyses, and stratified analyses were conducted in the study. In total, 76,411 offspring with autoimmune disease exposure and 1,211,936 offspring without maternal autoimmune disease exposure were selected and analyzed in this study. The incidence of childhood tics and Tourette's disorder was 2.35 [95% confidence interval (CI) 2.23-4.86] and 1.89 (95% CI 1.86-1.92) per 10,000 person-months in children exposed to maternal autoimmune disease and non-exposed children, respectively. The children whose mothers had an autoimmune disease had a 1.26-fold risk of tics and Tourette's disorder compared to children whose mothers did not have an autoimmune disease [crude hazard ratio: 1.26; 95% CI, 1.20-1.34, adjusted hazard ratio (aHR): 1.22; 95% CI, 1.15-1.29]. Offspring of mothers with rheumatoid arthritis (aHR: 1.46, 95% CI, 1.07-1.97), system lupus erythematosus (aHR: 1.57, 95% CI, 1.18-2.09), Sjogren's syndrome (aHR: 1.28, 95% CI, 1.09-1.50), ankylosing spondylitis (aHR: 1.49, 95% CI, 1.07-2.09), Graves' disease (aHR: 1.26, 95% CI, 1.15-1.37), Hashimoto's thyroiditis (aHR: 1.59, 95% CI, 1.29-1.98), and type I diabetes (aHR: 1.68, 95% CI, 1.13-2.50) had a significantly higher risk of developing tics and Tourette's disorder. Aside from maternal autoimmune diseases, mothers with urinary tract infections, diabetes mellitus, hyperlipidemia, anemia, a sleep disorder, endometriosis, and depression were also associated with childhood tics and Tourette's disorder. Maternal autoimmune diseases appeared to be associated with tics and Tourette's disorder in offspring, especially in mothers with the abovementioned diseases. Further research is warranted to investigate the possible pathogenetic mechanisms of these associations.

ATP8A2 expression is reduced in the mPFC of offspring mice exposed to maternal immune activation and its upregulation ameliorates synapse-associated protein loss and behavioral abnormalities.

ATP8A2 expression is reduced in the mPFC of offspring mice exposed to maternal immune activation and its upregulation ameliorates synapse-associated protein loss and behavioral abnormalities.

Prenatal inflammation impairs early CD11c-positive microglia induction and delays myelination in neurodevelopmental disorders

Histological chorioamnionitis (HCA) is a form of maternal immune activation (MIA) linked to an increased risk of neurodevelopmental disorders in offspring. Our previous study identified neurodevelopmental impairments in an MIA mouse model mimicking HCA. Thus, this study investigated the role of CD11c+ microglia, key contributors to myelination through IGF-1 production, in this pathology. In the mouse model, the CD11c+ microglial population was significantly lower in the MIA group than in the control group on postnatal day 3 (PN3d). Furthermore, myelination-related protein levels significantly decreased in the MIA group at PN8d. In humans, preterm infants with HCA exhibited higher IL-6 and IL-17A cord-serum levels and lower IGF-1 levels than those without HCA, followed by a higher incidence of delayed myelination on magnetic resonance imaging at the term-equivalent age. In silico analysis revealed that the transient induction of CD11c+ microglia during early development occurred similarly in mice and humans. Notably, a lack of high CD11c+ microglial population has been observed in children with neurodevelopmental disorders. This study reports impaired induction of CD11c+ microglia during postnatal development in a mouse model of MIA associated with delayed myelination. Our findings may inform strategies for improving outcomes in infants with HCA.

Neonatal Circulating Amino Acids and Lipid Metabolites Mediate the Association of Maternal Gestational Diabetes Mellitus with Offspring Neurodevelopment at 1 Year.

Background/Objectives: We aimed to identify neonatal circulating metabolic alterations associated with maternal gestational diabetes mellitus (GDM) and to explore whether these altered metabolites could mediate the association of GDM with offspring neurodevelopment. Additionally, we investigated whether neonatal circulating metabolites could improve the prediction of offspring neurodevelopmental disorders over traditional risk factors. Methods: The retrospective cohort study enrolled 1228 mother-child dyads in South China. GDM was diagnosed at 24-28 weeks of gestation. Neonatal circulating amino acids and lipid metabolites (carnitines) were measured from newborn heel blood 3-7 days postpartum. Offspring neurodevelopment was assessed at age 1 year using the Children Neuropsychological and Behavioral Examination Scale. Neurodevelopmental disorders were defined as developmental delay in any domain of the scale. Results: Twenty-one metabolites associated with GDM were identified, consisting of seven amino acids and fourteen carnitines. Among these metabolites, five (glycine, myristicylcarnitine, palmitoylcarnitine, octadecadienoylcarnitine, and 3-hydroxypalmitylcarnitine) mediated the negative association of GDM with offspring neurodevelopment at 1 year (mediation proportions: 3.91-10.66%). Furthermore, six metabolites (glycine, methionine, malonylcarnitine, isovalerylcarnitine, palmitoylcarnitine, and octadecadienoylcarnitine) significantly increased the predictive performance for offspring neurodevelopmental disorders at 1 year over five traditional risk factors including GDM, parity, infant sex, birth weight, and feeding patterns (area under curve: 0.762 vs. 0.718, p = 0.012). Conclusions: GDM was associated with a variety of amino acid and lipid metabolic alterations in neonatal circulation, among which certain metabolites mediated the association of GDM with adverse neurodevelopmental outcomes in offspring. Moreover, some neonatal circulating metabolites may serve as potential biomarkers that improved the prediction of offspring neurodevelopmental disorders over GDM and other traditional risk factors.

A Comprehensive Review of the Impact of Medications in Family Medicine on the Health of Pregnant Women and Children: Risks and Benefits

The impact of medications on the health of pregnant women and their children is a critical area of concern in medical research and obstetrics. During pregnancy, women often require treatment for various health conditions, including chronic illnesses like diabetes, hypertension, and mental health disorders. However, the use of medications during this sensitive period can pose risks, as some drugs may cross the placental barrier and affect fetal development. Certain medications have been associated with adverse outcomes, including congenital malformations, preterm birth, and low birth weight. The balance between effectively managing maternal health and minimizing potential harm to the fetus necessitates careful consideration and consultation between healthcare providers and expecting mothers. Children's health can also be significantly impacted by maternal medication use during pregnancy, with possible long-term consequences. Research indicates that in utero exposure to specific medications may increase the risk of developmental delays, behavioral issues, and lifelong health concerns. For example, the use of antiepileptic drugs or antidepressants during pregnancy has been linked to neurodevelopmental disorders in offspring. It is essential for healthcare providers to closely monitor and assess the risk-benefit ratio of medications prescribed to pregnant women, emphasizing the importance of individualized treatment plans and informed decision-making. Moreover, adequate education on the safe use of medications during pregnancy can help mitigate risks and ensure healthier outcomes for both mothers and their children.

6‐Chloronicotinic Acid Induces Toxicity in Mouse Neural Stem Cells via the C3ar1 Signaling

ABSTRACTNeural stem cells (NSCs) are essential for brain development due to their ability to proliferate and differentiate into various neural cell types. Neonicotinoid insecticides (NNIs), which have replaced traditional pesticides, are now widely used and frequently detected in environmental and biological samples. Prenatal exposure to NNIs has been associated with an increased risk of neurodevelopmental disorders in offspring, yet the causal relationship and the underpinning mechanism remain to be clarified. As one of the primary metabolites of chloropyridinyl neonicotinoids, 6‐chloronicotinic acid (6‐ClNA) has been identified as a potential neurotoxin, though its effects on NSCs have not been fully explored. Here, we demonstrate that 6‐ClNA exposure significantly disrupted NSC proliferation and differentiation in vitro. Transcriptomic analyses revealed that 6‐ClNA altered the expression of pathways related to proliferation, apoptosis, and inflammation, with notable activation of the C3ar1/C1qa signaling axis. Genetic ablation of C3ar1 using siRNA markedly restored NSC proliferation and neurosphere formation, as well as reduced apoptosis, suggesting a central role of C3ar1/C1qa in mediating 6‐ClNA's neurotoxic effects. These findings imply that early‐life exposure to NNIs may affect the fitness and function of NSCs, wherein the C3ar1 pathway plays an indispensable role.

Long-term, cell type-specific effects of prenatal stress on dorsal striatum and relevant behaviors in mice.

Maternal stress during pregnancy, or prenatal stress, is a risk factor for neurodevelopmental disorders in offspring, including autism spectrum disorder (ASD). In ASD, dorsal striatum displays abnormalities correlating with symptom severity, but there is a gap in knowledge about dorsal striatal cellular and molecular mechanisms that may contribute. Using a mouse model, we investigated how prenatal stress impacted striatal-dependent behavior in adult offspring. We observed enhanced motor learning and earlier response times on an interval timing task, with accompanying changes in time-related medium spiny neuron (MSN) activity. We performed adult dorsal striatal single-cell RNA sequencing following prenatal stress which revealed differentially expressed genes (DEGs) in multiple cell types; downregulated DEGs were enriched for ribosome and translational pathways consistently in MSN subtypes, microglia, and somatostatin neurons. DEGs in MSN subtypes over-represented ASD risk genes and were enriched for synapse-related processes. These results provide insights into striatal alterations relevant to neurodevelopmental disorders.

The relationship between excessive iodine during pregnancy and adverse pregnancy complications.

Iodine nutrition during pregnancy plays an important role in fetal development and maternal outcomes. Iodine deficiency has been proved to be associated with maternal thyroid dysfunction, adverse fetal outcomes and neurodevelopmental disorders in offspring. At present, there are few studies concentrate on the effects of iodine excess during pregnancy on thyroid function, maternal and neonatal outcomes, and the results are still controversial. The aim of this study was to evaluate the effects of excessive iodine status on thyroid function, glycolipid metabolism, and maternal and neonatal outcomes. A total of 595 pregnant women who gave birth at the First Affiliated Hospital of Nanjing Medical University from January 2023 to December 2023 were included in this study. Blood and urine samples were collected during the second trimester of pregnancy. Thyroid function include thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3) and urinary iodine concentrations (UIC) were measured. Maternal and neonatal outcomes were collected. Participants were divided into four groups based on UIC, with median UIC values of 100.5, 200, 314.2, and 655 μg/L, respectively. UIC was found to be positively associated with TSH, and negatively associated with FT3 and FT4. Fasting blood glucose (FBG) levels were elevated both in iodine deficiency and excess group. A U-shaped relationship between UIC and thyroid dysfunction were found. Iodine deficiency, excess iodine and even more than adequate iodine can lead to increased incidence of thyroid diseases such as isolated hypothyroxinaemia and overt hyperthyroidism. Importantly, iodine excess was found to be related with higher prevalence of umbilical cord around neck and eclampsia as well as higher blood glucose and low-density lipoprotein(LDL) level. Abnormal iodine status especially iodine excess during pregnancy was found to be related with higher prevalence of adverse mother and fetus outcomes, abnormal blood glucose and lipid level.

Discussing maternal human papillomavirus infection and offspring neurodevelopmental disorders.

Discussing maternal human papillomavirus infection and offspring neurodevelopmental disorders.

Maternal asthma during pregnancy and the likelihood of neurodevelopmental disorders in offspring.

Asthma is the most common chronic disease during pregnancy. Maternal asthma has been associated with a multitude of unwanted pregnancy outcomes, in some studies also with neurodevelopmental disorders. Here we investigated associations between maternal asthma and neurodevelopmental disorders. We studied a retrospective population-based cohort of 1 271 439 mother-child pairs from singleton live births in Finland between the years 1996-2018. We used multiple high-cover registers for data collection. Adjusted unconditional Cox regression models were used to investigate associations between maternal asthma, asthma medication used during pregnancy, and offspring's neurodevelopmental disorder diagnoses. We identified 106 163 mother-child pairs affected by maternal asthma. We found that maternal asthma was associated with offspring neurodevelopmental disorders, but the differences in absolute prevalence between the control and exposure groups were small. Attention-deficit hyperactivity disorder (ADHD) was found in 4114 (3.9%) offspring with maternal asthma and in 32 122 (3.0%) controls (adjusted hazard ratio (HR): 1.49; 95% CI 1.44-1.54); autism in 1617 (1.5%) offspring vs 13 701 (1.3%) controls (HR: 1.33; 95% CI 1.26-1.40); motor-developmental disorder in 1569 (1.5%) offspring vs 12 147 (1.1%) controls (HR: 1.37; 95% CI 1.30-1.45); language disorder in 3057 (2.9%) offspring vs 28 421 (2.7%) controls (HR: 1.13; 95% CI 1.08-1.17), learning disabilities in 849 (0.8%) offspring vs 6534 (0.6%) controls (HR: 1.51; 95% CI 1.41-1.62); mixed developmental disorder in 1633 (1.5%) offspring vs 14 434 (1.3%) controls (HR 1.20; 95% CI, 1.14-1.26); and intellectual disability in 908 (0.9%) vs 9155 (0.9%) controls (HR: 1.12; 95% CI 1.04-1.20). No substantial differences were found between allergic and non-allergic asthma phenotypes, and neither allergic tendency nor respiratory infection was associated with a similar likelihood of neurodevelopmental disorders. Maternal asthma and allergic and non-allergic phenotypes showed weak associations with the offspring's neurodevelopmental disorders. The association is concerned especially with learning disabilities, ADHD, motor development, and autism.

Maternal COVID-19 infection associated with offspring neurodevelopmental disorders.

Maternal COVID-19 infection increases the incidence of neurodevelopmental disorders (NDDs) in offspring, although the underlying mechanisms have not been elucidated. This study demonstrated that COVID-19 infection during pregnancy disrupted the balance of maternal and fetal immune environments, driving alterations in astrocytes, endothelial cells, and excitatory neurons. A risk score was established using 47 unique genes in the single-cell transcriptome of gestational mothers. The high risk score in CD4 proliferating T cell level served as an indicator for increased risk of offspring NDDs. Summary-based Mendelian randomization and phenome-wide association study analyses were conducted to identify the causal association of the transcriptional changes with the increased risk of offspring NDDs. Additionally, 10 drugs were identified as potential therapeutic candidates. Our findings support a model where the maternal COVID-19 infection changed the levels of CD4 proliferating T cells, leading to the alterations of astrocytes, endothelial cells, and excitatory neurons in offspring, contributing to the increased risk of NDDs in these individuals.

Prenatal and early childhood infections requiring hospitalization and risk of neurodevelopmental disorders in offspring: a population-based birth cohort study in Taiwan.

In utero and early childhood infections have been associated with an increased risk of neurodevelopmental disorders; however, the observed associations may be confounded by familial predispositions. This study examined the neurodevelopmental disorders attributable to maternal infections during pregnancy and early childhood infections during the first year of life, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), tic disorders, and mental retardation (MR). We performed population and sibling comparison analyses to account for unmeasured familial confounding factors. We conducted a register-based cohort study with 2,885,662 individuals (comprising 1,864,660 full siblings) born in Taiwan between 2001 and 2018 and followed up until 2021. We employed Cox regression analysis to assess the association between in utero and early childhood infections requiring hospitalization and the subsequent risk of neurodevelopmental disorders. In the population analyses, an offspring exposed to maternal infection had an increased risk for ASD (hazard ratio (HR) = 1.19, 95% confidence interval (CI): 1.13-1.26), ADHD (HR = 1.14, 95% CI: 1.11-1.18), and MR (HR = 1.21, 95% CI: 1.13-1.30). These associations attenuated toward null in the sibling analyses. Individuals exposed to early childhood infection had an increased risk for ASD (HR = 1.13, 95% CI: 1.10-1.16), ADHD (HR = 1.16, 95% CI: 1.15-1.18), tic disorders (HR = 1.12, 95% CI: 1.09-1.15), and MR (HR = 1.64, 95% CI: 1.60-1.69) in the population analyses; these associations were also significant for ASD (HR = 1.14, 95% CI: 1.07-1.21) and MR (HR = 1.52, 95% CI: 1.44-1.62) in the sibling analyses. The association between maternal infection during pregnancy and offspring neurodevelopmental risk is largely due to familial confounding factors. Conversely, infection in early childhood may be attributable to it being a sensitive period and may play a role in the subsequent risk of ASD and MR.

Association of Parental Prenatal Mental Health on Offspring Neurodevelopmental Disorders: A Systematic Review and Meta-Analysis.

Parental prenatal mood and anxiety disorders (PMAD) are linked to child neurodevelopmental disorders (NDDs), but evaluations of the magnitude and mechanisms of this association are limited. This study estimates the strength of the association and whether it is impacted by genetic and environmental factors. A systematic search of PubMed, CENTRAL, PsycINFO, OVID, and Google Scholar was performed for articles published from January 1988 to January 2024. Of 2,170 articles screened, 64 met the inclusion criteria. Meta-analyses were conducted on 20 studies, and 44 were included in the narrative synthesis. We conducted random-effects meta-analyses, along with tests for heterogeneity (I2) and publication bias (Egger's test). The review followed PRISMA and MOOSE guidelines. Maternal PMADs were associated with a significantly increased risk of ADHD (OR 1.91, 95% CI 1.45-2.52) and ASD (OR 1.57, 95% CI 1.37-1.81) in children. Paternal PMADs were also associated with the risk of NDDs, with combined odds for ASD and ADHD (OR 1.24, 95% CI 1.15-1.34). Several studies suggested that the link between parental PMADs and offspring NDDs might be impacted by both genetic and environmental factors, including the impact of ongoing parental depression on child behavior. Parental PMADs are significantly associated with an increased risk of NDDs in children. These associations may be influenced by both genetic predispositions and environmental factors. Understanding these pathways is important for informing interventions aimed at mitigating mental health risks in families and supporting child development.

Prenatal Nutritional Factors and Neurodevelopmental Disorders: A Narrative Review.

According to the DSM-5, neurodevelopmental disorders represent a group of heterogeneous conditions, with onset during the developmental period, characterized by an alteration of communication and social skills, learning, adaptive behavior, executive functions, and psychomotor skills. These deficits determine an impairment of personal, social, scholastic, or occupational functioning. Neurodevelopmental disorders are characterized by an increased incidence and a multifactorial etiology, including genetic and environmental components. Data largely explain the role of genetic and environmental factors, also through epigenetic modifications such as DNA methylation and miRNA. Despite genetic factors, nutritional factors also play a significant role in the pathophysiology of these disorders, both in the prenatal and postnatal period, underscoring that the control of modifiable factors could decrease the incidence of neurodevelopmental disorders. The preventive role of nutrition is widely studied as regards many chronic diseases, such as diabetes, hypertension, and cancer, but actually we also know the effects of nutrition on embryonic brain development and the influence of prenatal and preconceptional nutrition in predisposition to various pathologies. These factors are not limited only to a correct caloric intake and a good BMI, but rather to an adequate and balanced intake of macro and micronutrients, the type of diet, and other elements such as exposure to heavy metals. This review represents an analysis of the literature as regards the physiopathological mechanisms by which food influences our state of health, especially in the age of development (from birth to adolescence), through prenatal and preconceptional changes, underlying how controlling these nutritional factors should improve mothers' nutritional state to significantly reduce the risk of neurodevelopmental disorders in offspring. We searched key words such as "maternal nutrition and neurodevelopmental disorders" on Pubmed and Google Scholar, selecting the main reviews and excluding individual cases. Therefore, nutrigenetics and nutrigenomics teach us the importance of personalized nutrition for good health. So future perspectives may include well-established reference values in order to determine the correct nutritional intake of mothers through food and integration.

Associations of prenatal exposure to individual and mixed organophosphate esters with ADHD symptom trajectories in preschool children: The modifying effects of maternal Vitamin D

Associations of prenatal exposure to individual and mixed organophosphate esters with ADHD symptom trajectories in preschool children: The modifying effects of maternal Vitamin D

Risk of Neurodevelopmental Disorders in Offspring of Parents with Major Depressive Disorder: A Birth Cohort Study.

Studies have reported inconsistent results regarding associations between parental depression and offspring neurodevelopmental disorders, such as developmental delay and autism spectrum disorder (ASD). In all, 7,593 children who were born between 1996 and 2010 in Taiwan and had at least one parent with major depressive disorder and 75,930 birth-year- and sex-matched children of parents without major depressive disorder were followed from 1996 or time of birth to the end of 2011. Intergroup differences in neurodevelopmental conditions-including ASD, attention-deficit hyperactivity disorder (ADHD), tic disorder, developmental delay, and intellectual disability (ID)-were assessed. Compared with the children in the control group, the children of parents with major depression were more likely [hazard ratio (HR), 95% confidence interval (CI)] to develop ADHD (1.98, 1.80-2.18), ASD (1.52, 1.16-1.94), tic disorder (1.40, 1.08-1.81), developmental delay (1.32, 1.20-1.45), and ID (1.26, 1.02-1.55). Parental depression was associated with offspring neurodevelopmental disorders, specifically ASD, ADHD, developmental delay, ID, and tic disorder. Therefore, clinicians should closely monitor the neurodevelopmental conditions of children of parents with depression.

Associations of prenatal exposure to PM2.5 and its components with offsprings' neurodevelopmental and behavioral problems: A prospective cohort study from China

Associations of prenatal exposure to PM2.5 and its components with offsprings' neurodevelopmental and behavioral problems: A prospective cohort study from China

Prenatal immune activation in mice induces long-term alterations in brain mitochondrial function

Prenatal exposure to infections is a risk factor for neurodevelopmental disorders in offspring, and alterations in mitochondrial function are discussed as a potential underlying factor. Here, using a mouse model of viral-like maternal immune activation (MIA) based on poly(I:C) (POL) treatment at gestational day (GD) 12, we show that adult offspring exhibit behavioral deficits, such as reduced levels of social interaction. In addition, we found increased nicotinamidadenindinucleotid (NADH)- and succinate-linked mitochondrial respiration and maximal electron transfer capacity in the prefrontal cortex (PFC) and in the amygdala (AMY) of males and females. The increase in respiratory capacity resulted from an increase in mitochondrial mass in neurons (as measured by complex IV activity and transcript expression), presumably to compensate for a reduction in mitochondrion-specific respiration. Moreover, in the PFC of control (CON) male offspring a higher excess capacity compared to females was observed, which was significantly reduced in the POL-exposed male offspring, and, along with a higher leak respiration, resulted in a lower mitochondrial coupling efficiency. Transcript expression of the uncoupling proteins (UCP4 and UCP5) showed a reduction in the PFC of POL male mice, suggesting mitochondrial dysfunction. In addition, in the PFC of CON females, a higher expression of the antioxidant enzyme superoxide dismutase (SOD1) was observed, suggesting a higher antioxidant capacity as compared to males. Finally, transcripts analysis of genes involved in mitochondrial biogenesis and dynamics showed reduced expression of fission/fusion transcripts in PFC of POL offspring of both sexes. In conclusion, we show that MIA causes alterations in neuronal mitochondrial function and mass in the PFC and AMY of adult offspring with some effects differing between males and females.

P-253 Development of embryos from aged mothers transferred to the uterus of young mice

Abstract Study question Is the development of embryos from advanced maternal age (AMA) mice, similar to those from young maternal age (YMA) mice when transferred to young uteri? Summary answer AMA mouse embryos are characterized by altered organ morphology, particularly of the brain, which may predispose to neurodevelopmental disorders. What is known already Human and animal studies have linked AMA pregnancy to elevated risk of neurodevelopmental disorders and behavioural alterations in offspring, primarily attributed to compromised uterine (maternal) conditions. In human, it was also suggested that postnatal care of older mother may influence offspring behaviour. Animal studies revealed that behavioural alterations of AMA offspring are programmed during pregnancy and so they persist in litters fostered by young mouse. It remains unclear whether an embryo of older mother will undergo normal development after embryo transfer to younger female’s uterus. Study design, size, duration Embryos for Advanced Maternal Age, AMA (n = 105) and control Young Maternal Age, YMA (n = 44) groups were collected from thirty females 8-14 months old and six females 3-5 months old, respectively and transferred to pseudo-pregnant mice for further development. At embryonic day 16 (E16) foetuses were collected, fixed for histology and evaluated using Theiler and Kaufman’s classification of mouse development, where E16 corresponds to Theiler stage 24 (TS24) Participants/materials, setting, methods CBA x C57BL6 hybrid mice were used throughout the experiment. At E16, embryo survival rate (number of foetuses collected / number of transferred embryos) was scored for both groups. Foetuses were assessed for visible abnormalities and underwent histological evaluation of organs accordingly to TS 24. Parameters such as size/diameter, signs of vacuolization, cell density and layers of cerebral cortex in brain of foetuses were analysed. Values were considered different when p < 0.05, Mean±SD; Mann-Whitney test. Main results and the role of chance At E16, the survival of AMA embryos did not differ significantly from YMA control (39/105; 37% vs. 20/44; 45%, respectively) however, 5% of AMA foetuses (2/39) displayed oedema or cerebral haemorrhage. Histological analysis revealed alterations in the head/brain of AMA in comparison to YMA foetuses, such as smaller head size (head area in mid-sagittal section: 25.25±4.87 vs. 31.39±3.79 mm2, p < 0.05), thinner cerebral cortex (435.78±12.95 vs. 515.22±17.78µm, p < 0.005), reduced ratio of cortical plate (CP) to cerebral cortex thickness (0.20±0.03 vs. 0.26±0.009, p < 0.05) and an increased ratio of ventricular zone (VZ) to cerebral cortex thickness (0.29±0.002 vs. 0.24±0.002, p < 0.05). Moreover, decreased cellular density in CP layer (10378.86 vs. 12066.40 cells/mm2, P < 0.05) was noted. AMA brains were characterised by high degree of cellular vacuolisation, particularly in medulla oblongata, suggestive for spongiosis (1550.27 vs. 571.92 vacuoles/mm2, p < 0.05). These brain alterations may cause neurodevelopmental disorders in offspring. AMA foetuses had: smaller bronchial diameter (31.52 vs. 36.62µm, p < 0.05), no ossification centres and reduced skin wrinkling, corresponding to TS23 (that is previous developmental stage). These observations may suggest a delayed development of AMA foetuses. Limitations, reasons for caution The results of controlled animal experiments play a key role in developing conceptual models and formulating hypothesis about target species. However, extrapolation of these results to humans requires caution because species-specific developmental features may differ. Wider implications of the findings Our study demonstrates that advanced maternal age (AMA) impacts oocyte/embryo programming in mice. Morphological changes in AMA-conceived foetuses suggest potential risks for neurodevelopmental and other health issues in offspring, even when carried in the uterus of a young female, emphasizing the far-reaching effects of AMA on progeny health. Trial registration number not applicable