Poor maternal diet and psychosocial stress represent two environmental factors that can significantly impact maternal health during pregnancy. While various mouse models have been developed to study the relationship between maternal and offspring health and behaviour, few incorporate multiple sources of stress that mirror the complexity of human experiences. Maternal high-fat diet (HF) models in rodents are well-established, whereas use of psychosocial stress interventions in female mice are still emerging. The social instability stress (SIS) paradigm, serves as a chronic and unpredictable form of social stress. To evaluate the combined effects of a poor maternal diet and intermittent social stress on maternal health and behaviour, we developed a novel maternal stress model using adult female C57Bl/6 mice. We observed that all HF+ mice demonstrated rapid weight gain, elevated fasting blood glucose levels and impaired glucose tolerance independent of the presence (+) or absence (-) of SIS. Behavioural testing output revealed anxiety-like behaviours remained similar across all groups prior to pregnancy. However, integrated anxiety z-scores revealed a mixed anxious profile amongst HF+/SIS+ females prior to pregnancy. HF+/SIS+ females also did not show reduced plasma ACTH and corticosterone levels that were observed in our other HF+ and HF- stress groups after SIS exposure. Further, HF+/SIS+ females demonstrated significant postpartum maternal neglect, resulting in fewer numbers of live offspring. These findings suggest that prolonged maternal HF diet consumption, coupled with previous exposure to SIS, places a significant burden on the maternal stress response system, resulting in reduced parental investment and negative postpartum behaviour towards offspring.

OBJECTIVE: Few longitudinal studies have investigated the mediating role of inflammation during childhood in associations between prenatal maternal stress and adolescent mental health. The objective of this study was to examine the associations between prenatal maternal stress, concentrations of immune markers at age 9, and symptoms of generalized anxiety disorder (GAD) and depression during adolescence.
METHODS: This study included 3723 mother-child pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Prenatal maternal stress was examined using 55 items measured during pregnancy. Inflammation was assessed using serum concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP) when children were 9 years old. GAD and depression were assessed when children were 16 and 18 years of age, respectively. Analyses comprised of structural equation models.
RESULTS: Prenatal maternal stress was associated with higher concentrations of IL-6 in childhood, and with greater symptoms of depression and GAD in adolescence. However, we did not observe associations between prenatal maternal stress and CRP; also, CRP and IL-6 were not associated with depression and GAD. There was no evidence that CRP and IL-6 mediated the associations between prenatal maternal stress and either GAD or depression.
CONCLUSIONS: Prenatal maternal stress is associated with IL-6 levels in childhood, and with GAD and depression during adolescence. Future studies should examine immune activity at multiple points during development in relation to mental health into adulthood to determine whether inflammation at different points during development could increase risk for mental health problems among children whose mothers experienced significant stressors during pregnancy.

Prenatal stress (PNS) profoundly impacts maternal and offspring health, with enduring effects including microbiome alterations, neuroinflammation, and behavioral disturbances such as reductions in social behavior. Converging lines of evidence from preclinical and clinical studies suggest that PNS disrupts tryptophan (Trp) metabolic pathways and reduces gut Bifidobacteria, a known beneficial bacterial genus that metabolizes Trp. Specifically, previous work from our lab demonstrated that human prenatal mood disorders in mothers are associated with reduced Bifidobacterium dentium in infants at 13 months. Given that Bifidobacterium has been positively associated with neurodevelopmental and other health benefits and is depleted by PNS, we hypothesized that supplementing PNS-exposed pregnant dams with B. dentium would ameliorate PNS-induced health deficits. We measured inflammatory outputs, Trp metabolite levels and enzymatic gene expression in dams and fetal offspring, and social behavior in adult offspring. We determined that B. dentium reduced maternal systemic inflammation and fetal offspring neuroinflammation, while modulating tryptophan metabolism and increasing kynurenic acid and indole-3-propionic acid intergenerationally. Additional health benefits were demonstrated by the abrogation of PNS-induced reductions in litter weight. Finally, offspring of the B. dentium cohort demonstrated increased sociability in males primarily and increased social novelty primarily in females. Together these data illustrate that B. dentium can orchestrate interrelated host immune, metabolic and behavioral outcomes during and after gestation for both dam and offspring and may be a candidate for prevention of the negative sequelae of stress.

BACKGROUND: Stress hormones like catecholamine and cortisol are thought to reflect the magnitude of physical stress in adults and were studied in relationship to the cause of death and agony time. Intrauterine distress, intrapartum events, and modes of delivery can affect the fetal endocrine stress response, as reflected by biochemical analyses. The aim of the present study was to evaluate the role of catecholamines and cortisol as markers of ante-mortem fetal distress. The role of cortisol as a marker of circadian timing of delivery was also assessed.
METHODS: A 2-year prospective cohort-comparison inclusion of stillbirths and newborns took place with collection of antemortem data, labor parameters, neonatal outcome, post-mortem data and blood samples. Stillbirths were classified as acute or chronic on the basis of a multidisciplinary evaluation. Heart blood of stillbirths and cord blood of newborns were analyzed by high pressure liquid chromatography (HPLC) for adrenaline and noradrenaline and by immunoassay for cortisol determination.
RESULTS: Fifteen stillbirths and 46 newborns, as a comparison group, delivered by spontaneous vaginal birth, elective, and emergency cesarean sections were included. Stillbirths\' main cause of death was cord thrombosis. Levels of adrenaline and noradrenaline (median: 14,188 pg/ml and 230.5 pg/ml, respectively) were significantly higher (p < 0.001) in stillbirths than in newborns and were also higher in acute compared to chronic distress. Cortisol levels were significantly higher (p < 0.05) in spontaneous vaginal delivery (median: 18.2 μg/dl) compared to elective cesarean sections (median: 3.8 μg/dl). No difference in cortisol concentrations was detected between newborns delivered at morning and at afternoon/evening.
CONCLUSIONS: Our results suggest that the biochemical measurement of adrenaline and noradrenaline levels might reflect a marked physical stress response during the process of death in stillbirths. On the contrary, the elevation of cortisol levels could mirror the elevation in maternal cortisol level during vaginal delivery. For the post-mortem evaluation of stillbirths, the analysis of CA levels could provide additional data on the duration of distress, useful to integrate the forensic diagnosis.

UNASSIGNED: Prenatal stress (PS) can adversely affect cognitive and psychological functions in the offspring. This study aimed to determine the effect of PS and extremely low-frequency electromagnetic field (ELF-EMF) on spatial memory, serum corticosterone, brain-derived neurotrophic factor (BDNF) concentrations, and hippocampal BDNF levels in adult male offspring.
UNASSIGNED: Female Wistar rats were randomly divided into four groups (n=6): Control, Stress, ELF-EMF (exposure to ELF-EMF), and S+EMF (simultaneous exposure to stress and the ELF-EMF) groups. Animals received interven-tions for 21 days before and 21 days during pregnancy (a total of 42 days). On the offspring\'s 90th postnatal day (PND), spatial memory was tested using Morris Water Maze, serum Corticosterone and BDNF levels were measured by the ELISA method, and hippocampal BDNF levels were measured by Western blotting.
UNASSIGNED: PS did not affect spatial memory in the adult male offspring; however, it significantly (P<0.05) increased se-rum corticosterone levels compared to the control and EMF groups. Simultaneous induction of stress with ELF-EMF disrupted the memory acquisition phase. Serum and hippocampal BDNF levels increased signifi-cantly (P<0.05) in the EMF group compared to the stress group.
UNASSIGNED: Based on our findings, PS can increase serum corticosterone levels without affecting spatial memory. Howev-er, induction of ELF-EMF with stress has a destructive effect on spatial memory with no change in the corti-costerone levels. Compared to stress, prenatal exposure to ELF-EMF increases serum and hippocampal BDNF levels. Further studies are needed to determine the underlying mechanisms of these findings.

The effect of stress in pregnant female Wistar rats on the behavior and lipid peroxidation (LP) in the neocortex, hippocampus and hypothalamus in the female F2 generation during the ovarian cycle was investigated. We subjected pregnant females to daily 1-hour immobilization stress from the 15th to the 19th days of pregnancy. Further, family groups were formed from prenatally stressed and control male and female rats of the F1 generation: group 1, the control female and male; group 2, the control female and the prenatally stressed male; group 3, the prenatally stressed female and the control male; group 4, the prenatally stressed female and male. The females of the F2 generation born from these couples were selected into four experimental groups in accordance with the family group. At the age of 3 months, behavior of rats was studied in the \"open field\" test in two stages of the ovarian cycle - estrus and diestrus. After 7-10 days, the rats were decapitated and the neocortex, hypothalamus and hippocampus were selected to determine the level of diene and triene conjugates, Schiff bases and the degree of lipid oxidation (Klein index). In F2 females with one prenatally stressed parent, there was no interstage difference in locomotor-exploratory activity and anxiety. If both F1 parents were prenatally stressed, female F2 rats retained interstage differences similar to the control pattern, while their locomotor-exploratory activity and time spent in the center of an \"open field\" decreased in absolute values. In the neocortex of F2 females in groups with prenatally stressed mothers, the level of primary LP products decreased and the level of Schiff bases increased in the estrus stage. In the hippocampus of F2 females in the groups with prenatally stressed fathers, the level of Schiff bases decreased in the estrus stage, and the level of primary LP products increased in group 2 and decreased in group 4. In the hypothalamus of F2 females in the groups with prenatally stressed mothers, the level of Schiff bases increased in the estrus stage and decreased in the diestrus; in addition, in group 3, the level of primary LP products in the estrus stage increased. Thus, we demonstrated the influence of prenatal stress of both F1 mother and F1 father on the behavior and the level of LP in the neocortex, hippocampus and hypothalamus in female rats of the F2 generation in estrus and diestrus.
Исследовано влияние стресса у беременных самок крыс Вистар на поведение и показатели перекисного окисления липидов (ПОЛ) в неокортексе, гиппокампе и гипоталамусе у поколения самок F2 в течение эстрального цикла. Беременных самок подвергали ежедневному 1-часовому иммобилизационному стрессу с 15-го по 19-й день беременности. Далее из рожденных пренатально стрессированных и контрольных самцов и самок крыс поколения F1 формировали семейные группы: группа 1 – контрольные самка и самец, группа 2 – контрольная самка и пренатально стрессированный самец, группа 3 – пренатально стрессированная самка и контрольный самец, группа 4 – пренатально стрессированные самка и самец. Рожденных от этих семейных пар самок поколения F2 отбирали в четыре экспериментальные группы в соответствии с семейной группой. В возрасте трех месяцев у крыс исследовали показатели поведения в тесте «открытое поле» в двух стадиях полового цикла – эструсе и диэструсе. Через 7–10 дней крыс декапитировали и производили отбор неокортекса, гипоталамуса и гиппокампа для определения уровня диеновых и триеновых конъюгатов, оснований Шиффа и степени окисленности липидов (индекса Клейна). У самок F2 с одним пренатально стрессированным родителем отсутствует межстадиальная разница в локомоторно-исследовательской активности и тревожности. Если оба родителя F1 являются пренатально стрессированными, самки крыс F2 сохраняют межстадиальные различия, схожие с контрольным паттерном, при этом по абсолютным значениям у них снижаются локомоторно-исследовательская активность и время нахождения в центре открытого поля. В неокортексе у самок F2 в группах с пренатально стрессированными матерями снижается уровень первичных продуктов ПОЛ и повышается уровень оснований Шиффа в стадии эструса. В гиппокампе у самок F2 в группах с пренатально стрессированными отцами снижается уровень оснований Шиффа в стадии эструса, а уровень первичных продуктов ПОЛ повышается в группе 2 и снижается в группе 4. В гипоталамусе у самок F2 в группах с пренатально стрессированными матерями уровень оснований Шиффа повышается в стадии эструса и снижается в диэструсе, кроме того, в группе 3 повышается уровень первичных продуктов ПОЛ в стадии эструса. Таким образом, выявлено влияние пренатального стресса как матери F1, так и отца F1 на показатели поведения и уровень ПОЛ в неокортексе, гиппокампе и гипоталамусе у самок крыс поколения F2 в эструсе и диэструсе.

Psychological stress during pregnancy is known to have a range of long-lasting negative consequences on the development and health of offspring. Here, we tested whether a measure of prenatal early-life stress was associated with a biomarker of physiological development at birth, namely epigenetic gestational age, using foetal cord-blood DNA-methylation data. Longitudinal cohorts from the Netherlands (Generation R Study [Generation R], n = 1,396), the UK (British Avon Longitudinal Study of Parents and Children [ALSPAC], n = 642), and Norway (Mother, Father and Child Cohort Study [MoBa], n1 = 1,212 and n2 = 678) provided data on prenatal maternal stress and genome-wide DNA methylation from cord blood and were meta-analysed (pooled n = 3,928). Measures of epigenetic age acceleration were calculated using three different gestational epigenetic clocks: \"Bohlin\", \"EPIC overlap\" and \"Knight\". Prenatal stress exposure, examined as an overall cumulative score, was not significantly associated with epigenetically-estimated gestational age acceleration or deceleration in any of the clocks, based on the results of the pooled meta-analysis or those of the individual cohorts. No significant associations were identified with specific domains of prenatal stress exposure, including negative life events, contextual (socio-economic) stressors, parental risks (e.g., maternal psychopathology) and interpersonal risks (e.g., family conflict). Further, no significant associations were identified when analyses were stratified by sex. Overall, we find little support that prenatal psychosocial stress is associated with variation in epigenetic age at birth within the general paediatric population.

Prenatal stress (PNS), which alters the hypothalamic-pituitary-adrenal axis function in the offspring, predisposes to insulin resistance (IR) in later life and is associated with numerous disorders, including cognitive and memory impairments. At present, our main goal is to assess the effects of chronic piromelatine (Pir) administration, a melatonin analogue, on PNS-provoked IR in the periphery and the hippocampus in male and female offspring. Pregnant Sprague-Dawley rats were exposed to chronic stress (one short-term stressor on a daily basis and one long-term stressor on a nightly basis) from the first gestation week until birth. Vehicle or Pir 20 mg/kg were administered intraperitoneally for 21 days. Plasma glucose, serum insulin levels, and the homeostasis model assessment of insulin resistance (HOMA-IR) were determined as markers of peripheral IR. For the hippocampal IR assessment, insulin receptors (IRs) and glucose transporter 4 (GLUT4) were examined. Prenatally stressed offspring of both sexes indicated enhanced plasma glucose and serum insulin concentrations, increased HOMA-IR, and decreased hippocampal GLUT4 only in male rats. The PNS-induced changes were corrected by chronic treatment with Pir. The present results suggest that the melatoninergic compound Pir exerts beneficial effects on altered glucose/insulin homeostasis in PNS-exposed offspring.

Prenatal maternal stressors ranging in severity from everyday occurrences/hassles to the experience of traumatic events negatively impact neurodevelopment, increasing the risk for the onset of psychopathology in the offspring. Notably, the timing of prenatal stress exposure plays a critical role in determining the nature and severity of subsequent neurodevelopmental outcomes. In this review, we evaluate the empirical evidence regarding temporal windows of heightened vulnerability to prenatal stress with respect to motor, cognitive, language, and behavioural development in both human and animal studies. We also explore potential temporal windows whereby several mechanisms may mediate prenatal stress-induced neurodevelopmental effects, namely, excessive hypothalamic-pituitary-adrenal axis activity, altered serotonin signalling and sympathetic-adrenal-medullary system, changes in placental function, immune system dysregulation, and alterations of the gut microbiota. While broadly defined developmental windows are apparent for specific psychopathological outcomes, inconsistencies arise when more complex cognitive and behavioural outcomes are considered. Novel approaches to track molecular markers reflective of the underlying aetiologies throughout gestation to identify tractable biomolecular signatures corresponding to critical vulnerability periods are urgently required.

Stress during pregnancy is often linked with increased incidents of neurodevelopmental disorders, including cognitive impairment. Here, we report that stress during pregnancy leads to alterations in the intestinal flora, which negatively affects the cognitive function of offspring. Cognitive impairment in stressed offspring can be reproduced by transplantation of cecal contents of stressed pregnant rats (ST) to normal pregnant rats. In addition, gut microbial dysbiosis results in an increase of β-guanidinopropionic acid in the blood, which leads to an activation of the adenosine monophosphate-activated protein kinase (AMPK) and signal transducer and activator of transcription 3 (STAT3) in the fetal brain. Moreover, β-guanidinopropionic acid supplementation in pregnant rats can reproduce pregnancy stress-induced enhanced glial differentiation of the fetal brain, resulting in impaired neural development. Using probiotics to reconstruct maternal microbiota can correct the cognitive impairment in the offspring of pregnant stressed rats. These findings suggest that microbial reconstitution reverses gestational stress-induced cognitive impairment and synaptic deficits in male rat offspring.