Investigating maternal and neonatal health outcomes associated with continuing or ceasing dexamphetamine treatment for women with attention-deficit hyperactivity disorder during pregnancy: a retrospective cohort study.

PURPOSE: Attention-deficit hyperactivity disorder (ADHD) is becoming more commonly diagnosed in women, consequently, more women of reproductive age are taking ADHD medication, such as dexamphetamine. However, the safety associated with continuing or ceasing dexamphetamine during pregnancy is unclear. This study investigates outcomes associated with the continuation of dexamphetamine during pregnancy compared to those who ceased or were unexposed. METHODS: A population-based retrospective cohort of women from Western Australia who had been dispensed dexamphetamine during pregnancy and gave birth between 2003 and 2018. Women had either continued to take dexamphetamine throughout pregnancy (continuers, n = 547) or ceased dexamphetamine before the end of the second trimester (ceasers, n = 297). Additionally, a matched (1:1) comparison group of women who were dispensed an ADHD medication prior to pregnancy but not during pregnancy (unexposed) was included in the study (n = 844). Multivariable generalised linear models were used to compare maternal and neonatal health outcomes. RESULTS: Compared to continuers, ceasers had greater odds of threatened abortion (OR: 2.28; 95%CI: 1.00, 5.15; p = 0.049). The unexposed had some benefits compared to the continuers, which included lower risk of preeclampsia (OR: 0.58; 95%CI: 0.35, 0.97; p = 0.037), hypertension (OR: 0.32; 95%CI: 0.11, 0.93; p = 0.036), postpartum haemorrhage (OR: 0.57; 95%CI: 0.41, 0.80; p = 0.001), neonatal special care unit admittance (OR: 0.16; 95%CI: 0.12, 0.20; p < 0.001) and fetal distress (OR: 0.73; 95%CI: 0.54, 0.99; p = 0.042). CONCLUSION: Continuing dexamphetamine throughout pregnancy was not associated with an increase in adverse neonatal and maternal health outcomes compared to ceasing. Ceasing dexamphetamine during pregnancy was associated with increased odds of threatened abortion compared with continuing dexamphetamine. However, this is something that requires further investigation due to the small sample size, difficulties examining timing, and the inability to examine spontaneous abortions. The unexposed showed some benefits compared to the continuers, suggesting that where possible the cessation of dexamphetamine prior to pregnancy may be advisable.

Long-term exposure of mice to 890 ppm atmospheric CO2 alters growth trajectories and elicits hyperactive behaviours in young adulthood.

Atmospheric carbon dioxide (CO2 ) levels are currently at 418 parts per million (ppm), and by 2100 may exceed 900 ppm. The biological effects of lifetime exposure to CO2 at these levels is unknown. Previously we have shown that mouse lung function is altered by long-term exposure to 890 ppm CO2 . Here, we assess the broader systemic physiological responses to this exposure. Mice were exposed to either 460 or 890 ppm from preconception to 3 months of age, and assessed for effects on developmental, renal and osteological parameters. Locomotor, memory, learning and anxiety-like behaviours of the mice were also assessed. Exposure to 890 ppm CO2 increased birthweight, decreased female body weight after weaning, and, as young adults, resulted in reduced engagement in memory/learning tasks, and hyperactivity in both sexes in comparison to controls. There were no clear anxiety, learning or memory changes. Renal and osteological parameters were minimally affected. Overall, this study shows that exposure of mice to 890 ppm CO2 from preconception to young adulthood alters growth and some behaviours, with limited evidence of compensatory changes in acid-base balance. These findings highlight the potential for a direct effect of increased atmospheric CO2 on mammalian health outcomes. KEY POINTS: Long-term exposure to elevated levels of atmospheric CO2 is an uncontrolled experiment already underway. This is the first known study to assess non-respiratory physiological impacts of long-term (conception to young adulthood) exposure of mice to CO2 at levels that may arise in the atmosphere due to global emissions. Exposure to elevated CO2 , in comparison to control mice, altered growth patterns in early life and resulted in hyperactive behaviours in young adulthood. Renal and bone parameters, which are important to balance acid-base levels to compensate for increased CO2 exposure, remained relatively unaffected. This work adds to the body of evidence regarding the effects of carbon emissions on mammalian health and highlights a potential future burden of disease.

The Role of 11ß-Hydroxy Steroid Dehydrogenase Type 2 in Glucocorticoid Programming of Affective and Cognitive Behaviours.

Developmental exposure to stress hormones, i.e. glucocorticoids, is central to the process of prenatal programming of later-life health. Glucocorticoid overexposure, through stress or exogenous glucocorticoids, results in a reduced birthweight, as well as affective and neuropsychiatric outcomes in adults, combined with altered hypothalamus-pituitary-adrenal (HPA) axis activity. As such, glucocorticoids are tightly regulated during development through the presence of the metabolizing enzyme 11ß-hydroxysteroid dehydrogenase type 2 (HSD2). HSD2 is highly expressed in 2 hubs during development, i.e. the placenta and the fetus itself, protecting the fetus from inappropriate glucocorticoid exposure early in gestation. Through manipulation of HSD2 expression in the mouse placenta and fetal tissues, we are able to determine the relative contribution of glucocorticoid exposure in each compartment. Feto-placental HSD2 deletion resulted in a reduced birthweight and the development of anxiety- and depression-like behaviours in adult mice. The placenta itself is altered by glucocorticoid overexposure, which causes reduced placental weight and vascular arborisation. Furthermore, altered flow and resistance in the umbilical vessels and modification of fetal heart function and development are observed. However, brain-specific HSD2 removal (HSD2BKO) also generated adult phenotypes of depressive-like behaviour and memory deficits, demonstrating the importance of fetal brain HSD2 expression in development. In this review we will discuss potential mechanisms underpinning early-life programming of adult neuropsychiatric disorders and the novel therapeutic potential of statins.

Pravastatin ameliorates placental vascular defects, fetal growth, and cardiac function in a model of glucocorticoid excess.

Fetoplacental glucocorticoid overexposure is a significant mechanism underlying fetal growth restriction and the programming of adverse health outcomes in the adult. Placental glucocorticoid inactivation by 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) plays a key role. We previously discovered that Hsd11b2(-/-) mice, lacking 11ß-HSD2, show marked underdevelopment of the placental vasculature. We now explore the consequences for fetal cardiovascular development and whether this is reversible. We studied Hsd11b2(+/+), Hsd11b2(+/-), and Hsd11b2(-/-) littermates from heterozygous (Hsd11b(+/-)) matings at embryonic day (E)14.5 and E17.5, where all three genotypes were present to control for maternal effects. Using high-resolution ultrasound, we found that umbilical vein blood velocity in Hsd11b2(-/-) fetuses did not undergo the normal gestational increase seen in Hsd11b2(+/+) littermates. Similarly, the resistance index in the umbilical artery did not show the normal gestational decline. Surprisingly, given that 11ß-HSD2 absence is predicted to initiate early maturation, the E/A wave ratio was reduced at E17.5 in Hsd11b2(-/-) fetuses, suggesting impaired cardiac function. Pravastatin administration from E6.5, which increases placental vascular endothelial growth factor A and, thus, vascularization, increased placental fetal capillary volume, ameliorated the aberrant umbilical cord velocity, normalized fetal weight, and improved the cardiac function of Hsd11b2(-/-) fetuses. This improved cardiac function occurred despite persisting indications of increased glucocorticoid exposure in the Hsd11b2(-/-) fetal heart. Thus, the pravastatin-induced enhancement of fetal capillaries within the placenta and the resultant hemodynamic changes correspond with restored fetal cardiac function. Statins may represent a useful therapeutic approach to intrauterine growth retardation due to placental vascular hypofunction.

Vitamin D deficiency and impaired placental function: potential regulation by glucocorticoids?

Maternal vitamin D deficiency has been implicated in a range of pregnancy complications including preeclampsia, preterm birth and intrauterine growth restriction. Some of these adverse outcomes arise from alterations in placental function. Indeed, vitamin D appears critical for implantation, inflammation, immune function and angiogenesis in the placenta. Despite these associations, absence of the placental vitamin D receptor in mice provokes little effect. Thus, interactions between maternal and fetal compartments are likely crucial for instigating adverse placental changes. Indeed, maternal vitamin D deficiency elicits changes in glucocorticoid-related parameters in pregnancy, which increase placental and fetal glucocorticoid exposure. As in utero glucocorticoid excess has a well-established role in eliciting placental dysfunction and fetal growth restriction, this review proposes that glucocorticoids are an important consideration when understanding the impact of vitamin D deficiency on placental function and fetal development.

Pregnancy-induced changes in the circadian expression of hepatic clock genes: implications for maternal glucose homeostasis.

Adaptations in maternal carbohydrate metabolism are particularly important in pregnancy because glucose is the principal energy substrate used by the fetus. As metabolic homeostasis is intricately linked to the circadian system via the rhythmic expression of clock genes, it is likely that metabolic adaptations during pregnancy also involve shifts in maternal circadian function. We hypothesized that maternal adaptation in pregnancy involves changes in the hepatic expression of clock genes, which drive downstream shifts in circadian expression of glucoregulatory genes. Maternal liver and plasma (n = 6-8/group) were collected across 24-h periods (0800, 1200, 1600, 2000, 0000, 0400) from C57Bl/6J mice under isoflurane-nitrous oxide anesthesia prior to and on days 6, 10, 14 and 18 of pregnancy (term = day 19). Hepatic expression of clock genes and glucoregulatory genes was determined by RT-qPCR. Hepatic clock gene expression was substantially altered across pregnancy, most notably in late gestation when the circadian rhythmicity of several clock genes was attenuated (≤64% reduced amplitude on day 18). These changes were associated with a similar decline in rhythmicity of the key glucoregulatory genes Pck1, G6Pase, and Gk, and by day 18, Pck1 was no longer rhythmic. Overall, our data show marked adaptations in the liver clock during mouse pregnancy, changes that may contribute to the altered circadian variation in glucoregulatory genes near term. We propose that the observed reduction of daily oscillations in glucose metabolism ensure a sustained supply of glucose to meet the high demands of fetal growth.

Rescue of glucocorticoid-programmed adipocyte inflammation by omega-3 fatty acid supplementation in the rat.

BACKGROUND: Adverse fetal environments predispose offspring to pathologies associated with the metabolic syndrome. Previously we demonstrated that adult offspring of dexamethasone-treated mothers had elevated plasma insulin and pro-inflammatory cytokines, effects prevented by a postnatal diet enriched with omega (n)-3 fatty acids. Here we tested whether prenatal glucocorticoid excess also programmed the adipose tissue phenotype, and whether this outcome is rescued by dietary n-3 fatty acids. METHODS: Offspring of control and dexamethasone-treated mothers (0.75 µg/ml in drinking water, day 13 to term) were cross-fostered to mothers on a standard (Std) or high n-3 (Hn3) diet at birth. Offspring remained on these diets post-weaning, and serum and retroperitoneal fat were obtained at 6 months of age (n = 5-8 per group). Serum was analysed for blood lipids and fatty acid profiles, adipocyte cross sectional area was measured by unbiased stereological analysis and adipose expression of markers of inflammation, glucocorticoid sensitivity and lipid metabolism were determined by RT-qPCR analysis. RESULTS: Serum total fatty acid levels were elevated (P < 0.01) in male offspring of dexamethasone-treated mothers, an effect prevented by Hn3 consumption. Prenatal dexamethasone also programmed increased adipose expression of Il6, Il1b (both P < 0.05) and Tnfa (P < 0.001) mRNAs regardless of fetal sex, but again this effect was prevented (for Il6 and Il1b) by Hn3 consumption. Offspring of dexamethasone-treated mothers had increased adipose expression of Gr (P = 0.008) and Ppara (P < 0.05) regardless of sex or postnatal diet, while 11bHsd1 was upregulated in males only. The Hn3 diet increased Ppard expression and reduced adipocyte size in all offspring (both P < 0.05) irrespective of prenatal treatment. CONCLUSIONS: Prenatal glucocorticoid exposure programmed increased expression of inflammatory markers and enhanced glucocorticoid sensitivity of adipose tissue. Partial prevention of this phenotype by high n-3 consumption indicates that postnatal dietary manipulations can limit adverse fetal programming effects on adipose tissue.

Prenatal Opioid Exposure and Immune-Related Conditions in Children.

Importance: Prenatal opioid exposure (POE) may alter with fetal development of the immune system, which may influence long-term health and susceptibility to immune-related conditions. Objective: To compare the risk of hospitalization and emergency department presentation for immune-related conditions in children with and without POE. Design, Setting, and Participants: This retrospective, population-based cohort study used linked administrative health records of all children born in Western Australia between January 1, 2003, and December 31, 2018 (N = 401 462). Exposure: Prenatal exposure to prescription opioids (overall and by trimester), neonatal abstinence syndrome diagnosis, and opioid indication (pain or opioid use disorder [OUD]). Main Outcomes and Measures: The main outcome was hospital admissions and emergency department presentations during which a child was diagnosed with an immune-related condition, including infections, conditions associated with an overactive immune system (eg, asthma, eczema, and allergy and anaphylaxis), and autoimmune diseases diagnosed before age 5 years or June 30, 2020. Data were analyzed between August 30, 2022, and February 27, 2023. Results: Neonates with POE (1656 [0.4%]; mean [SD] gestational age, 37.7 [2.1] weeks; 836 females [50.5%]; 820 males [49.5%]) were more likely to be born preterm, have low birth weight for gestational age, and be coexposed to cigarette smoke compared with nonexposed neonates. Perinatal opioid exposure was associated with an increased risk of perinatal infection (adjusted odds ratio [AOR], 1.62; 95% CI, 1.38-1.90) and eczema and dermatitis (AOR, 11.91; 95% CI, 9.84-14.41) compared with nonexposure. Neonatal abstinence syndrome was also associated with both conditions (AOR, 2.91 [95% CI, 2.36-3.57] and 31.11 [95% CI, 24.64-39.28], respectively). Prenatal opioid exposure was also associated with an increased risk of childhood asthma (adjusted hazard ratio [AHR], 1.44; 95% CI, 1.16-1.79), but not allergies and anaphylaxis. It was also associated with an increased risk of childhood eczema and dermatitis, but only in children with POE from opioids used to treat OUD (AHR, 1.47; 95% CI, 1.08-1.99) rather than pain. In contrast, POE from opioids used for pain was associated with an increased risk of infection (AHR, 1.44; 95% CI, 1.32-1.58), but POE to opioids used to treat OUD was not. Autoimmune conditions were rare and were not observed to be associated with POE. Conclusions and Relevance: In this cohort study, POE was associated with an increased risk of infection, eczema and dermatitis, and asthma, but not allergies and anaphylaxis or autoimmune conditions. These findings highlight the importance of further study of opioid-induced immune changes during pregnancy, the potential impact on long-term health in exposed children, and the mechanisms of opioid-induced immune dysregulation.

RISING STARS: The heat is on: how does heat exposure cause pregnancy complications?

The incidence and severity of heatwaves are increasing globally with concomitant health complications. Pregnancy is a critical time in the life course at risk of adverse health outcomes due to heat exposure. Dynamic physiological adaptations, which include altered thermoregulatory pathways, occur in pregnancy. If heat dissipation is ineffective, maternal and neonate health outcomes can be compromised. Indeed, epidemiological studies and animal models reveal that exposure to heat in pregnancy likely elicits an array of health complications including miscarriage, congenital anomalies, low birth weight, stillbirth, and preterm birth. Despite these associations, the reasons for why these complications occur are unclear. An array of physiological and endocrine changes in response to heat exposure in pregnancy likely underpin the adverse health outcomes, but currently, conclusive evidence is sparse. Accompanying these fundamental gaps in knowledge is a poor understanding of what exact climatic conditions challenge pregnant physiology. Moreover, the overlay of thermoregulatory-associated behaviours such as physical activity needs to be taken into consideration when assessing the risks to human health and identifying critical populations at risk. While the health impacts from heat are largely preventable through strategic interventions, for the related clinical practice, public health, and policy approaches to be effective, the gaps in basic science understanding urgently need to be addressed.

"Well, what can I do?": An examination of the role supervisors, peers and scientific societies can play in the multicultural student experience.

International graduate students are a multi-cultural and diverse demographic of researchers that are integral to higher education globally. Although their contributions to research and innovation are acknowledged, the experiences of international students overseas are influenced by structural inequalities and challenges, some similar, and some unique to their domestic colleagues, that are often compounded by a "deficit narrative". This paper was defined by the inaugural 'Pressure Cooker' workshop held at the Australian and New Zealand Placental Association (ANZPRA) conference in 2022, and discusses some of the major institutional and social structures that can define an international student's graduate degree trajectory. Further, we provide examples of collaborative programs and methods for academics, scientific societies and domestic graduate peer groups to promote an equitable and accessible environment for all researchers.

11ß-hydroxysteroid dehydrogenases and the brain: from zero to hero, a decade of progress.

Glucocorticoids have profound effects on brain development and adult CNS function. Excess or insufficient glucocorticoids cause myriad abnormalities from development to ageing. The actions of glucocorticoids within cells are determined not only by blood steroid levels and target cell receptor density, but also by intracellular metabolism by 11ß-hydroxysteroid dehydrogenases (11ß-HSD). 11ß-HSD1 regenerates active glucocorticoids from their inactive 11-keto derivatives and is widely expressed throughout the adult CNS. Elevated hippocampal and neocortical 11ß-HSD1 is observed with ageing and causes cognitive decline; its deficiency prevents the emergence of cognitive defects with age. Conversely, 11ß-HSD2 is a dehydrogenase, inactivating glucocorticoids. The major central effects of 11ß-HSD2 occur in development, as expression of 11ß-HSD2 is high in fetal brain and placenta. Deficient feto-placental 11ß-HSD2 results in a life-long phenotype of anxiety and cardiometabolic disorders, consistent with early life glucocorticoid programming.

Prenatal excess glucocorticoid exposure and adult affective disorders: a role for serotonergic and catecholamine pathways.

Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal 'programming' of adult affective behaviours such as depression and anxiety. Indeed, the glucocorticoid metabolising enzyme 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), which is highly expressed in the placenta and the developing fetus, acts as a protective barrier from the high maternal glucocorticoids which may alter developmental trajectories. The programmed changes resulting from maternal stress or bypass or from the inhibition of 11ß-HSD2 are frequently associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Hence, circulating glucocorticoid levels are increased either basally or in response to stress accompanied by CNS region-specific modulations in the expression of both corticosteroid receptors (mineralocorticoid and glucocorticoid receptors). Furthermore, early-life glucocorticoid exposure also affects serotonergic and catecholamine pathways within the brain, with changes in both associated neurotransmitters and receptors. Indeed, global removal of 11ß-HSD2, an enzyme that inactivates glucocorticoids, increases anxiety- and depressive-like behaviour in mice; however, in this case the phenotype is not accompanied by overt perturbation in the HPA axis but, intriguingly, alterations in serotonergic and catecholamine pathways are maintained in this programming model. This review addresses one of the potential adverse effects of glucocorticoid overexposure in utero, i.e. increased incidence of affective behaviours, and the mechanisms underlying these behaviours including alteration of the HPA axis and serotonergic and catecholamine pathways.

Exploring sex differences in fetal programming for childhood emotional disorders.

In examining maternal depression, placental 11ß-HSD2 mRNA expression and offspring cortisol regulation as a potential fetal programming pathway in relation to later child emotional disorders, it has become clear that sex differences may be important to consider. This study reports on data obtained from 209 participants in the Mercy Pregnancy and Emotional Wellbeing Study (MPEWS) recruited before 20 weeks of pregnancy. Maternal depressive disorders were diagnosed using the SCID-IV and maternal childhood trauma using the Childhood Trauma Questionnaire. Placental 11ß-HSD2 mRNA was measured using qRT-PCR. For assessment of stress-induced cortisol reactivity, salivary cortisol samples were taken at 12 months of age. At 4 years of age, measurement of Childhood Emotional Disorders (depression and anxiety) was based on maternal report using the Preschool Age Psychiatric Assessment (PAPA) and internalizing symptoms using the Child Behavior Checklist (CBCL). Maternal depression in pregnancy and postpartum, and infant cortisol reactivity, was associated with internalizing symptoms for females only. For female offspring only, increased 12-month cortisol reactivity was also associated with increased emotional disorders at 4 years of age; however, there was no association with placental 11ß-HSD2 mRNA expression. In females only, the combination of lower placental 11ß-HSD2 mRNA expression and higher cortisol reactivity at 12 months of age predicted increased internalising problems. These findings suggest there may be sex differences in prenatal predictors and pathways for early childhood depression and anxiety symptoms and disorder.

Mouse Lung Structure and Function after Long-Term Exposure to an Atmospheric Carbon Dioxide Level Predicted by Climate Change Modeling.

BACKGROUND: Climate change models predict that atmospheric carbon dioxide [CO2] levels will be between 700 and 900 ppm within the next 80 y. Despite this, the direct physiological effects of exposure to slightly elevated atmospheric CO2 (as compared with ∼410 ppm experienced today), especially when exposures extend from preconception to adulthood, have not been thoroughly studied. OBJECTIVES: In this study we aimed to assess the respiratory structure and function effects of long-term exposure to 890 ppm CO2 from preconception to adulthood using a mouse model. METHODS: We exposed mice to CO2 (∼890 ppm) from prepregnancy, through the in utero and early life periods, until 3 months of age, at which point we assessed respiratory function using the forced oscillation technique, and lung structure. RESULTS: CO2 exposure resulted in a range of respiratory impairments, particularly in female mice, including higher tissue elastance, longer chord length, and lower lung compliance. Importantly, we also assessed the lung function of the dams that gave birth to our experimental subjects. Even though these mice had been exposed to the same level of increased CO2 for a similar amount of time (∼8wk), we measured no impairments in lung function. This suggests that the early life period, when lungs are undergoing rapid growth and development, is particularly sensitive to CO2. DISCUSSION: To the best of our knowledge, this study, for the first time, shows that long-term exposure to environmentally relevant levels of CO2 can impact respiratory function in the mouse. https://doi.org/10.1289/EHP7305.

Maternal, Placental, and Fetal Responses to Intermittent Heat Exposure During Late Gestation in Mice.

Physiological adaptations during heat exposure are critical in pregnancy. Maternal thermoregulation has to accommodate the increased metabolic load of the developing fetus. Here, we assess the consequences of intermittent heat exposure, as occurs in heat waves, for maternal adaptations during pregnancy, and chronic feto-placental outcomes. Following timed mating, C57BL/6J mice were allocated to either standard animal housing temperature conditions (SH) or housing at a temperature within the thermoneutral zone (TNZ). A subset of the TNZ group was exposed to 37 °C for 8 h a day from E15.5 to E17.5 to simulate a heat wave (HW). Maternal weight gain, food intake, rectal temperature, and nesting behaviors were measured across gestation. Fetal and placental tissues were collected at E18.5. With heat exposure, maternal rectal temperature increased while food intake and nest complexity decreased. Maternal daily weight gain initially decreased due to heat exposure, but on the last day of exposure, it was comparable to the other experimental groups. These maternal responses during heat exposure impacted on the fetus, with restrictions in placental and fetal development evident just before birth. Thus, the vascular portion of the placenta, and the relative fetal head size, was smaller. Furthermore, SH and TNZ animals demonstrated distinct differences in food intake and nesting behavior during pregnancy, reinforcing the need for caution in extrapolating from animal models to humans when housing occurs outside of thermoneutral zone conditions. This study highlights the direct effects of temperature conditions on health in pregnancy and provides a foundation for future studies to investigate fetal health consequences that are associated with intermittent heat exposure.

Maternal vitamin D deficiency during rat gestation elicits a milder phenotype compared to the mouse model: Implications for the placental glucocorticoid barrier.

Maternal vitamin D deficiency disturbs fetal development and programmes neurodevelopmental complications in offspring, possibly through increased fetal glucocorticoid exposure. We aimed to determine whether prenatal exposure to excess glucocorticoids underlies our rat model of early-life vitamin D deficiency, leading to altered adult behaviours. Vitamin D deficiency reduced the expression of the glucocorticoid-inactivating enzyme Hsd11b2 in the female placenta, but did not alter maternal glucocorticoid levels, feto-placental weights, or placental expression of other glucocorticoid-related genes at mid-gestation. This differs to the phenotype previously observed in vitamin D deficient mice, and highlights important modelling considerations.

Vitamin D is crucial for maternal care and offspring social behaviour in rats.

Early life vitamin D plays a prominent role in neurodevelopment and subsequent brain function, including schizophrenic-like outcomes and increasing evidence for an association with autism spectrum disorder (ASD). Here, we investigate how early life vitamin D deficiency during rat pregnancy and lactation alters maternal care and influences neurodevelopment and affective, cognitive and social behaviours in male adult offspring. Sprague-Dawley rats were placed on either a vitamin D control (2195 IU/kg) or deficient diet (0 IU/kg) for five weeks before timed mating, and diet exposure was maintained until weaning of offspring on postnatal day (PND) 23. MRI scans were conducted to assess brain morphology, and plasma corticosterone levels and neural expression of genes associated with language, dopamine and glucocorticoid exposure were characterised at PND1, PND12 and 4 months of age. Compared to controls, vitamin D-deficient dams exhibited decreased licking and grooming of their pups but no differences in pup retrieval. Offspring neurodevelopmental markers were unaltered, but vitamin D-deficient pup ultrasonic vocalisations were atypical. As adults, males that had been exposed to vitamin D deficiency in early life exhibited decreased social behaviour, impaired learning and memory outcomes and increased grooming behaviour, but unaltered affective behaviours. Accompanying these behavioural changes was an increase in lateral ventricle volume, decreased cortical FOXP2 (a protein implicated in language and communication) and altered neural expression of genes involved in dopamine and glucocorticoid-related pathways. These data highlight that early life levels of vitamin D are an important consideration for maternal behavioural adaptations as well as offspring neuropsychiatry.

Viscosity and haemodynamics in a late gestation rat feto-placental arterial network.

The placenta is a transient organ which develops during pregnancy to provide haemotrophic support for healthy fetal growth and development. Fundamental to its function is the healthy development of vascular trees in the feto-placental arterial network. Despite the strong association of haemodynamics with vascular remodelling mechanisms, there is a lack of computational haemodynamic data that may improve our understanding of feto-placental physiology. The aim of this work was to create a comprehensive 3D computational fluid dynamics model of a substructure of the rat feto-placental arterial network and investigate the influence of viscosity on wall shear stress (WSS). Late gestation rat feto-placental arteries were perfused with radiopaque Microfil and scanned via micro-computed tomography to capture the feto-placental arterial geometry in 3D. A detailed description of rat fetal blood viscosity parameters was developed, and three different approaches to feto-placental haemodynamics were simulated in 3D using the finite volume method: Newtonian model, non-Newtonian Carreau-Yasuda model and Fåhræus-Lindqvist effect model. Significant variability in WSS was observed between different viscosity models. The physiologically-realistic simulations using the Fåhræus-Lindqvist effect and rat fetal blood estimates of viscosity revealed detailed patterns of WSS throughout the arterial network. We found WSS gradients at bifurcation regions, which may contribute to vessel enlargement, and sprouting and pruning during angiogenesis. This simulation of feto-placental haemodynamics shows the heterogeneous WSS distribution throughout the network and demonstrates the ability to determine physiologically-relevant WSS magnitudes, patterns and gradients. This model will help advance our understanding of vascular physiology and remodelling in the feto-placental network.

Prevention of programmed hyperleptinemia and hypertension by postnatal dietary omega-3 fatty acids.

Fetal programming is now recognized as a key determinant of the adult phenotype, with major implications for adult-onset diseases including hypertension. Two mediators of fetal programming are maternal nutrition and fetal glucocorticoid exposure. Recent studies show that postnatal dietary manipulations can exacerbate programming effects, but whether programming effects can be attenuated by postnatal dietary manipulations, and thus provide a possible therapeutic strategy, is unknown. In this study, we tested the hypothesis that a postnatal diet enriched with long-chain omega-3 fatty acids attenuates programmed hyperleptinemia and hypertension. Pregnant rats were treated with dexamethasone (Dex) from d 13 to term, and offspring were cross-fostered to mothers on either a standard diet or a diet high in omega-3 fatty acids and remained on these diets postweaning. Maternal Dex reduced birthweight and delayed the onset of puberty in offspring. Hyperleptinemia (associated with elevated leptin mRNA expression in adipose tissue) and hypertension were evident in offspring by 6 months of age in Dex-exposed animals consuming a standard diet, but these effects were completely blocked by a high omega-3 diet. These results demonstrate for the first time that manipulation of postnatal diet can limit adverse outcomes of fetal programming, with programmed hyperleptinemia and hypertension prevented by a postnatal diet enriched with omega-3 fatty acids. This raises the possibility that dietary supplementation with omega-3 fatty acids may provide a viable therapeutic option for preventing and/or reducing adverse programming outcomes in humans.