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1.
Brain Behav Immun Health ; 39: 100807, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38988451

ABSTRACT

Poly I:C rat offspring are used to investigate the effects of in utero exposure to maternal immune activation (MIA) and have been suggested as a model of neurodevelopmental disorders (NDD). The behavioural symptoms of this model are diverse and can vary with external factors, including the choice of background strain and husbandry practices. Measuring whisker movements provides quantitative, robust measurements of sensory, motor and cognitive behaviours in rodents. In this study, whisker movements were investigated in 50-day-old male and female offspring of MIA-exposed rat dams and compared to age-matched offspring of control (vehicle) dams. Rat offspring were filmed using high-speed videography in a sequential object exploration task with smooth and textured objects. Poly I:C treatment effects were found in female offspring that did not increase whisker mean angular position during object exploration, especially for the smooth object, indicating an attentional deficit. Whisker tracking during object exploration is demonstrated here, for the first time, as a useful, quick and non-invasive tool to identify both treatment effects and sex differences in a model of MIA-induced NDDs.

2.
Neuronal Signal ; 7(2): NS20220064, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37332846

ABSTRACT

Maternal infection during pregnancy, leading to maternal immune activation (mIA) and cytokine release, increases the offspring risk of developing a variety of neurodevelopmental disorders (NDDs), including schizophrenia. Animal models have provided evidence to support these mechanistic links, with placental inflammatory responses and dysregulation of placental function implicated. This leads to changes in fetal brain cytokine balance and altered epigenetic regulation of key neurodevelopmental pathways. The prenatal timing of such mIA-evoked changes, and the accompanying fetal developmental responses to an altered in utero environment, will determine the scope of the impacts on neurodevelopmental processes. Such dysregulation can impart enduring neuropathological changes, which manifest subsequently in the postnatal period as altered neurodevelopmental behaviours in the offspring. Hence, elucidation of the functional changes that occur at the molecular level in the placenta is vital in improving our understanding of the mechanisms that underlie the pathogenesis of NDDs. This has notable relevance to the recent COVID-19 pandemic, where inflammatory responses in the placenta to SARS-CoV-2 infection during pregnancy and NDDs in early childhood have been reported. This review presents an integrated overview of these collective topics and describes the possible contribution of prenatal programming through placental effects as an underlying mechanism that links to NDD risk, underpinned by altered epigenetic regulation of neurodevelopmental pathways.

3.
Biomolecules ; 13(3)2023 03 07.
Article in English | MEDLINE | ID: mdl-36979424

ABSTRACT

Exposure to maternal immune activation (MIA) in utero significantly elevates the risk of developing schizophrenia and other neurodevelopmental disorders. To understand the biological mechanisms underlying the link between MIA and increased risk, preclinical animal models have focussed on specific signalling pathways in the brain that mediate symptoms associated with neurodevelopmental disorders such as cognitive dysfunction. Reelin signalling in multiple brain regions is involved in neuronal migration, synaptic plasticity and long-term potentiation, and has been implicated in cognitive deficits. However, how regulation of Reelin expression is affected by MIA across cortical development and associated cognitive functions remains largely unclear. Using a MIA rat model, here we demonstrate cognitive deficits in adolescent object-location memory in MIA offspring and reductions in Reln expression prenatally and in the adult prefrontal cortex. Further, developmental disturbances in gene/protein expression and DNA methylation of downstream signalling components occurred subsequent to MIA-induced Reelin dysregulation and prior to cognitive deficits. We propose that MIA-induced dysregulation of Reelin signalling contributes to the emergence of prefrontal cortex-mediated cognitive deficits through altered NMDA receptor function, resulting in inefficient long-term potentiation. Our data suggest a developmental window during which attenuation of Reelin signalling may provide a possible therapeutic target.


Subject(s)
Cognition Disorders , Cognitive Dysfunction , Rats , Animals , Brain , Signal Transduction , Cognition
4.
Front Neurosci ; 17: 1146710, 2023.
Article in English | MEDLINE | ID: mdl-36950133

ABSTRACT

The adult brain is a complex structure with distinct functional sub-regions, which are generated from an initial pool of neural epithelial cells within the embryo. This transition requires a number of highly coordinated processes, including neurogenesis, i.e., the generation of neurons, and neuronal migration. These take place during a critical period of development, during which the brain is particularly susceptible to environmental insults. Neurogenesis defects have been associated with the pathogenesis of neurodevelopmental disorders (NDDs), such as autism spectrum disorder and schizophrenia. However, these disorders have highly complex multifactorial etiologies, and hence the underlying mechanisms leading to aberrant neurogenesis continue to be the focus of a significant research effort and have yet to be established. Evidence from epidemiological studies suggests that exposure to maternal infection in utero is a critical risk factor for NDDs. To establish the biological mechanisms linking maternal immune activation (MIA) and altered neurodevelopment, animal models have been developed that allow experimental manipulation and investigation of different developmental stages of brain development following exposure to MIA. Here, we review the changes to embryonic brain development focusing on neurogenesis, neuronal migration and cortical lamination, following MIA. Across published studies, we found evidence for an acute proliferation defect in the embryonic MIA brain, which, in most cases, is linked to an acceleration in neurogenesis, demonstrated by an increased proportion of neurogenic to proliferative divisions. This is accompanied by disrupted cortical lamination, particularly in the density of deep layer neurons, which may be a consequence of the premature neurogenic shift. Although many aspects of the underlying pathways remain unclear, an altered epigenome and mitochondrial dysfunction are likely mechanisms underpinning disrupted neurogenesis in the MIA model. Further research is necessary to delineate the causative pathways responsible for the variation in neurogenesis phenotype following MIA, which are likely due to differences in timing of MIA induction as well as sex-dependent variation. This will help to better understand the underlying pathogenesis of NDDs, and establish therapeutic targets.

5.
Brain Behav Immun ; 108: 162-175, 2023 02.
Article in English | MEDLINE | ID: mdl-36503051

ABSTRACT

Exposure to inflammatory stressors during fetal development is a major risk factor for neurodevelopmental disorders (NDDs) in adult offspring. Maternal immune activation (MIA), induced by infection, causes an acute increase in pro-inflammatory cytokines which can increase the risk for NDDs directly by inducing placental and fetal brain inflammation, or indirectly through affecting maternal care behaviours thereby affecting postnatal brain development. Which of these two potential mechanisms dominates in increasing offspring risk for NDDs remains unclear. Here, we show that acute systemic maternal inflammation induced by the viral mimetic polyinosinic:polycytidylic acid (poly I:C) on gestational day 15 of rat pregnancy affects offspring and maternal behaviour, offspring cognition, and expression of NDD-relevant genes in the offspring brain. Dams exposed to poly I:C elicited an acute increase in the pro-inflammatory cytokine tumour necrosis factor (TNF; referred to here as TNFα), which predicted disruption of key maternal care behaviours. Offspring of poly I:C-treated dams showed early behavioural and adult cognitive deficits correlated to the maternal TNFα response, but, importantly, not with altered maternal care. We also found interacting effects of sex and treatment on GABAergic gene expression and DNA methylation in these offspring in a brain region-specific manner, including increased parvalbumin expression in the female adolescent frontal cortex. We conclude that the MIA-induced elevation of TNFα in the maternal compartment affects fetal neurodevelopment leading to altered offspring behaviour and cognition. Our results suggest that a focus on prenatal pathways affecting fetal neurodevelopment would provide greater insights into the mechanisms underpinning the TNFα-mediated genesis of altered offspring behaviour and cognition following maternal inflammation.


Subject(s)
Neurodevelopmental Disorders , Prenatal Exposure Delayed Effects , Rats , Animals , Female , Pregnancy , Humans , Tumor Necrosis Factor-alpha/pharmacology , Behavior, Animal/physiology , Placenta/metabolism , Cytokines , Poly I-C/adverse effects , Maternal Behavior , Inflammation/metabolism , Disease Models, Animal
6.
Brain Behav Immun Health ; 25: 100514, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36177307

ABSTRACT

Schizophrenia and other neurodevelopmental disorders often have very heterogeneous symptoms, especially regarding cognition: while some individuals may exhibit deficient cognition, others are relatively unaffected. Studies using developmental animal models often ignore phenotypic heterogeneity in favour of traditional treatment/control comparisons. This may result in resilient or unaffected individuals masking the effects of susceptible individuals if grouped together. Here, we used maternal immune activation and limited bedding and nesting, respectively, as a two-hit neurodevelopmental model for schizophrenia. Both factors reduced cognitive function in a novel object recognition (NOR) task. While we found treatment group effects on cognitive phenotypes, behavioural clustering identified three subpopulations exposed to either insult: those exhibiting 'typical' cognitive performance on the NOR, an intermediate phenotype, or a marked deficit. These clusters included offspring from each treatment group, although both intermediate and marked deficit clusters were composed primarily of offspring from treated groups. Clustering allowed stratification within treatment groups into 'susceptible' and 'resilient' individuals, while also identifying conserved phenotypes across treatment groups. Using unbiased cluster analyses in preclinical models can better characterize phenotypes and enables a better understanding of both face and construct validity of phenotypic heterogeneity. The use of unbiased clustering techniques may help identify potential markers associated with individual susceptibility and resilience in neurodevelopmental disorder models.

7.
Front Cell Dev Biol ; 10: 802285, 2022.
Article in English | MEDLINE | ID: mdl-35846363

ABSTRACT

Homocysteine is a metabolite generated by methionine cycle metabolism, comprising the demethylated derivative of methionine. Homocysteine can be metabolised by the transsulphuration pathway to cystathionine, which requires vitamin B6, or can undergo remethylation to methionine. Homocysteine remethylation to methionine is catalysed by methionine synthase activity which requires vitamin B12, regenerating methionine to allow synthesis of the universal methyl donor S-adenosylmethionine required for methylation and gene transcription regulation. The methyl-group donated for homocysteine remethylation comes from 5-methyltetrahydrofolate generated by the folate cycle, which allows tetrahydrofolate to be returned to the active folate pool for nucleotide biosynthesis. Therefore the integrated actions of the methionine and folate cycles, required to metabolise homocysteine, also perpetuate methylation and nucleotide synthesis, vitally important to support embryonic growth, proliferation and development. Dysregulated activities of these two interdependent metabolic cycles, arising from maternal suboptimal intake of nutrient co-factors such as folate and vitamin B12 or gene polymorphisms resulting in reduced enzymatic activity, leads to inefficient homocysteine metabolic conversion causing elevated concentrations, known as hyperhomocysteinemia. This condition is associated with multiple adverse pregnancy outcomes including neural tube defects (NTDs). Raised homocysteine is damaging to cellular function, binding to proteins thereby impairing their function, with perturbed homocysteine metabolism impacting negatively on embryonic development. This review discusses the "cross-talk" of maternal-fetal homocysteine interrelationships, describes the placental transport of homocysteine, homocysteine impacts on pregnancy outcomes, homocysteine and methylation effects linking to NTD risk and proposes a putative pathway for embryonic provision of folate and vitamin B12, homocysteine-modulating nutrients that ameliorate NTD risk.

8.
Clin Sci (Lond) ; 136(15): 1117-1137, 2022 08 12.
Article in English | MEDLINE | ID: mdl-35852150

ABSTRACT

Maternal infection during pregnancy increases the offspring risk of developing a variety of neurodevelopmental disorders (NDDs), including schizophrenia. While the mechanisms remain unclear, dysregulation of placental function is implicated. We hypothesised that maternal infection, leading to maternal immune activation and stimulated cytokine production, alters placental and yolk sac amino acid transport, affecting fetal brain development and thus NDD risk. Using a rat model of maternal immune activation induced by the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)), we investigated placental and yolk sac expression of system L amino acid transporter subtypes which transport several essential amino acids including branched-chain amino acids (BCAA), maternal and fetal BCAA concentration, placental 14C-leucine transport activity and associated impacts on fetal growth and development. Poly(I:C) treatment increased acutely maternal IL-6 and TNFα concentration, contrasting with IL-1ß. Transcriptional responses for these pro-inflammatory cytokines were found in placenta and yolk sac following poly(I:C) treatment. Placental and yolk sac weights were reduced by poly(I:C) treatment, yet fetal body weight was unaffected, while fetal brain weight was increased. Maternal plasma BCAA concentration was reduced 24 h post-poly(I:C) treatment, yet placental, but not yolk sac, BCAA concentration was increased. Placental and yolk sac gene expression of Slc7a5, Slc7a8 and Slc43a2 encoding LAT1, LAT2 and LAT4 transporter subtypes, respectively, was altered by poly(I:C) treatment. Placental 14C-leucine transport was significantly reduced 24 h post-treatment, contrasting with a significant increase 6 days following poly(I:C) treatment. Maternal immune activation induces dysregulated placental transport of amino acids affecting fetal brain development, and NDD risk potential in offspring.


Subject(s)
Fetal Development , Placenta , Amino Acids/metabolism , Animals , Brain/metabolism , Cytokines/metabolism , Female , Leucine/metabolism , Leucine/pharmacology , Placenta/metabolism , Poly I-C/pharmacology , Pregnancy , Rats
9.
PLoS One ; 17(3): e0258372, 2022.
Article in English | MEDLINE | ID: mdl-35271586

ABSTRACT

Pregnant Muslim women are exempt from fasting during Ramadan; however a majority are reported to fast. The impact of this form of maternal intermittent fasting (IF) on fetal development and offspring health is not well defined. Using a rat model, we have shown previously that maternal IF results in fetal growth restriction accompanied by changes in placental nutrient transport function. The aim of this study was to assess cardiovascular, metabolic and renal function in adult offspring of IF-exposed dams. Food was withheld from Wistar rats from 17:00 to 09:00 daily throughout pregnancy; controls had ad libitum access to food. Birth weight was unaffected; however male IF pups grew more slowly up to 10 weeks of age (P < 0.01) whereas IF females matched their control counterparts. Systolic blood pressure (SBP), glucose tolerance and basal renal function at 14 weeks were not affected by IF exposure. When offered saline solutions (0.9-2.1%) to drink, females showed a greater salt preference than males (P < 0.01); however there were no differences between dietary groups. A separate group of pups was weaned onto a 4% NaCl diet. SBP increased in IF pups sooner, at 7 weeks (P < 0.01), than controls which became hypertensive from 10 weeks. Renal function did not appear to differ; however markers of renal injury were elevated in IF males (P < 0.05). Maternal IF does not affect resting cardiovascular, metabolic and renal function; but when challenged by dietary salt load male IF offspring are more prone to renal injury.


Subject(s)
Fasting , Prenatal Exposure Delayed Effects , Adult Children , Animals , Female , Humans , Kidney/physiology , Male , Placenta/metabolism , Pregnancy , Prenatal Exposure Delayed Effects/metabolism , Rats , Rats, Wistar , Sodium Chloride, Dietary/metabolism
10.
Neurosci Biobehav Rev ; 129: 389-421, 2021 10.
Article in English | MEDLINE | ID: mdl-34280428

ABSTRACT

Maternal immune activation (mIA) during pregnancy is hypothesised to disrupt offspring neurodevelopment and predispose offspring to neurodevelopmental disorders such as schizophrenia. Rodent models of mIA have explored possible mechanisms underlying this paradigm and provide a vital tool for preclinical research. However, a comprehensive analysis of the molecular changes that occur in mIA-models is lacking, hindering identification of robust clinical targets. This systematic review assesses mIA-driven transcriptomic and epigenomic alterations in specific offspring brain regions. Across 118 studies, we focus on 88 candidate genes and show replicated changes in expression in critical functional areas, including elevated inflammatory markers, and reduced myelin and GABAergic signalling proteins. Further, disturbed epigenetic markers at nine of these genes support mIA-driven epigenetic modulation of transcription. Overall, our results demonstrate that current outcome measures have direct relevance for the hypothesised pathology of schizophrenia and emphasise the importance of mIA-models in contributing to the understanding of biological pathways impacted by mIA and the discovery of new drug targets.


Subject(s)
Behavior, Animal , Prenatal Exposure Delayed Effects , Animals , Brain , Disease Models, Animal , Epigenesis, Genetic , Epigenomics , Female , Gene Expression , Poly I-C , Pregnancy , Prenatal Exposure Delayed Effects/genetics , Rodentia
11.
Clin Sci (Lond) ; 135(11): 1445-1466, 2021 06 11.
Article in English | MEDLINE | ID: mdl-34008846

ABSTRACT

During Ramadan, many pregnant Muslim women fast between dawn and sunset. Although the impacts of prolonged maternal intermittent fasting (IF) on fetal growth and placental function are under-researched, reported effects include reduced placental weight and birth weight. In the present study, pregnant Wistar rats were used to model repeated cycles of IF on fetal development and placental function and to examine sex-specific effects. In the IF group, food was withdrawn daily from 17:00 to 09:00 over 21 days of gestation, while the control group received food ad libitum. Both groups had free water access. IF dams consumed less food, had significantly reduced weight compared with controls, with reduced plasma glucose and amino acids. Both fetal sexes were significantly lighter in the IF group with reduced fetal plasma amino acids. Placental weights and morphology were unchanged. The profile of placental metabolites was altered in the IF group with sex-specific responses evident. Transplacental flux of 14C-methylaminoisobutyric acid (14C-MeAIB), a system A amino acid transporter substrate, was significantly reduced in both fetal sexes in the IF group. Sodium-dependent 14C-MeAIB uptake into isolated placental plasma membrane vesicles was unchanged. The gene expression of system A transporter Slc38a1, Slc38a2 and Slc38a4 was up-regulated in IF male placentas only. No changes were observed in placental SNAT1 and SNAT2 protein expression. Maternal IF results in detrimental impacts on maternal physiology and fetal development with changes in the placental and fetal metabolite profiles. Reduced placental system A transporter activity may be responsible for fetal growth restriction in both sexes.


Subject(s)
Amino Acid Transport System A/metabolism , Amino Acid Transport Systems/metabolism , Fasting , Fetal Growth Retardation/metabolism , Placenta/metabolism , Animals , Female , Fetal Development/physiology , Fetus/metabolism , Pregnancy , Rats, Wistar
12.
Adv Nutr ; 12(1): 212-222, 2021 02 01.
Article in English | MEDLINE | ID: mdl-32892218

ABSTRACT

Supplementation with myo-inositol during the periconceptional period of pregnancy may ameliorate the recurrence risk of having a fetus affected by a neural tube defect (NTD; e.g., spina bifida). This could be of particular importance in providing a means for preventing NTDs that are unresponsive to folic acid. This review highlights the characteristics of inositol and describes the role of myo-inositol in the prevention of NTDs in rodent studies and the evidence for its efficacy in reducing NTD risk in human pregnancy. The possible reduction in NTD risk by maternal myo-inositol implies functional and developmentally important maternal-embryonic inositol interrelationships and also suggests that embryonic uptake of myo-inositol is crucial for embryonic development. The establishment of active myo-inositol cellular uptake mechanisms in the embryonic stages of human pregnancy, when the neural tube is closing, is likely to be an important determinant of normal development. We draw attention to the generation of materno-fetal inositol concentration gradients and relationships, and outline a transport pathway by which myo-inositol may be delivered to the early developing human embryo. These considerations provide novel insights into the mechanisms that may underpin inositol's ability to confer embryonic developmental benefit.


Subject(s)
Neural Tube Defects , Female , Folic Acid , Humans , Inositol , Neural Tube Defects/prevention & control , Pregnancy , Spinal Dysraphism , Yolk Sac
13.
Placenta ; 103: 188-198, 2021 01 01.
Article in English | MEDLINE | ID: mdl-33160252

ABSTRACT

INTRODUCTION: Amino acid transport across the placenta is crucial for fetal growth. In rodent models, the visceral yolk sac (referred to as yolk sac hereafter) is also likely to contribute to fetal amino acid provision. System L amino acid transporters mediate the transport of essential amino acids. System L activity is mediated by light chains LAT1 (Slc7a5) and LAT2 (Slc7a8) which form functional complexes by heterodimeric linkage to CD98 (Slc3a2). LAT4 (Slc43a2) is monomeric, possessing overlapping amino acid substrate specificity with LAT1 and LAT2. METHODS: This study investigates the expression of these LAT subtypes in fetus-matched rat placenta and yolk sac. RESULTS: Slc7a5, Slc7a8 and Slc43a2 transcripts were expressed in placenta and yolk sac with similar expression patterns between sexes. LAT1 expression was significantly higher in placenta than yolk sac. Conversely, LAT2 and LAT4 expression was significantly higher in yolk sac than placenta; CD98 expression was comparable. LAT1, LAT2, LAT4 and CD98 were distributed to rat placental labyrinth zone (LZ) and junctional zone (JZ). LAT1 and LAT4 demonstrated higher expression in LZ, whilst LAT2 was more intensely distributed to JZ. LAT1, LAT2, LAT4 and CD98 were expressed in yolk sac, with punctate LAT1 staining to endodermal cell cytoplasm, contrasting with the intense LAT2, LAT4 and CD98 endodermal cell basolateral distribution, accounting for greater LAT2 and LAT4 expression in yolk sac compared to placenta. CONCLUSION: LAT1, LAT2 and LAT4 are expressed in rat placenta and yolk sac implicating a combined role for these LAT subtypes in supporting fetal growth and development.


Subject(s)
Amino Acid Transport System L/genetics , Placenta/metabolism , Yolk Sac/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Amino Acid Transport System L/classification , Amino Acid Transport System L/metabolism , Amino Acid Transport System y+/genetics , Amino Acid Transport System y+/metabolism , Animals , Female , Fusion Regulatory Protein 1, Light Chains/genetics , Fusion Regulatory Protein 1, Light Chains/metabolism , Gene Expression Regulation, Developmental , Large Neutral Amino Acid-Transporter 1/genetics , Large Neutral Amino Acid-Transporter 1/metabolism , Male , Pregnancy , Rats , Rats, Wistar
14.
Exp Physiol ; 104(3): 421-433, 2019 03.
Article in English | MEDLINE | ID: mdl-30575177

ABSTRACT

NEW FINDINGS: What is the central question of this study? Urotensin II is upregulated in patients in the later stages of chronic kidney disease (CKD), particularly in individuals requiring dialysis. Could treatment with a urotensin II receptor antagonist slow progression of renal disease? What is the main finding and its importance? In the rat, expression of urotensin II and its receptor increased, extending into cortical structures as CKD progressed towards end-stage renal failure. Subchronic treatment with a urotensin receptor antagonist slowed but did not prevent progression of CKD. This suggests that urotensin II contributes to the decline in renal function in CKD. ABSTRACT: Elevated serum and urine urotensin II (UII) concentrations have been reported in patients with end-stage chronic kidney disease (CKD). Similar increases in UII and its receptor, UT, have been reported in animal models of CKD, but only at much earlier stages of renal dysfunction. The aim of this study was to characterize urotensin system expression as renal disease progresses to end-stage failure in a ⅚ subtotal nephrectomy (SNx) rat model. Male Sprague-Dawley rats underwent SNx or sham surgery and were killed at 8 weeks postsurgery [early (E)] or immediately before end-stage renal failure [30 ± 3 weeks postsurgery; late (L)]. Systolic blood pressure, urinary albumin:creatinine ratio and glomerulosclerosis index were all increased in SNx-E rats compared with sham-E by 8 weeks postsurgery. These changes were associated with an increase in renal immunoreactive UII staining but little change in UT expression. As CKD progressed to end-stage disease in the SNx-L group, markers of renal function deteriorated further, in association with a marked increase in immunoreactive UII and UT staining. Subchronic administration of a UT antagonist, SB-611812, at 30 mg kg-1  day-1 for 13 weeks, in a separate group of SNx rats resulted in a 2 week delay in the increase in both systolic blood pressure and urinary albumin:creatinine ratio observed in vehicle-treated SNx but did not prevent the progression of renal dysfunction. The urotensin system is upregulated as renal function deteriorates in the rat; UT antagonism can slow but not prevent disease progression, suggesting that UII plays a role in CKD.


Subject(s)
Kidney/metabolism , Renal Insufficiency, Chronic/metabolism , Urotensins/metabolism , Animals , Blood Pressure/physiology , Disease Progression , Glomerular Filtration Rate/physiology , Male , Nephrectomy/methods , Rats , Rats, Sprague-Dawley
15.
BMC Pregnancy Childbirth ; 18(1): 421, 2018 Oct 25.
Article in English | MEDLINE | ID: mdl-30359228

ABSTRACT

BACKGROUND: Although exempt, many pregnant Muslim women partake in the daily fast during daylight hours during the month of Ramadan. In other contexts an impoverished diet during pregnancy impacts on birth weight. The aim of this systematic review was to determine whether Ramadan fasting by pregnant women affects perinatal outcomes. Primary outcomes investigated were perinatal mortality, preterm birth and small for gestational age (SGA) infants. Secondary outcomes investigated were stillbirth, neonatal death, maternal death, hypertensive disorders of pregnancy, gestational diabetes, congenital abnormalities, serious neonatal morbidity, birth weight, preterm birth and placental weight. METHODS: Systematic review and meta-analysis of observational studies and randomised controlled trials was conducted in EMBASE, MEDLINE, CINAHL, Web of Science, Google Scholar, the Health Management Information Consortium and Applied Social Sciences Index and Abstracts. Studies from any year were eligible. Studies reporting predefined perinatal outcomes in pregnancies exposed to Ramadan fasting were included. Cohort studies with no comparator group or that considered fasting outside pregnancy were excluded, as were studies assuming fasting practice based solely upon family name. Quality of included studies was assessed using the ROBINS-I tool for assessing risk of bias in non-randomised studies. Analyses were performed in STATA. RESULTS: From 375 records, 22 studies of 31,374 pregnancies were included, of which 18,920 pregnancies were exposed to Ramadan fasting. Birth weight was reported in 21 studies and was not affected by maternal fasting (standardised mean difference [SMD] 0.03, 95% CI 0.00 to 0.05). Placental weight was significantly lower in fasting mothers (SMD -0.94, 95% CI -0.97 to -0.90), although this observation was dominated by a single large study. No data were presented for perinatal mortality. Ramadan fasting had no effect on preterm delivery (odds ratio 0.99, 95% CI 0.72 to 1.37) based on 5600 pregnancies (1193 exposed to Ramadan fasting). CONCLUSIONS: Ramadan fasting does not adversely affect birth weight although there is insufficient evidence regarding potential effects on other perinatal outcomes. Further studies are needed to accurately determine whether Ramadan fasting is associated with adverse maternal or neonatal outcome.


Subject(s)
Fasting/physiology , Pregnancy Outcome/epidemiology , Birth Weight/physiology , Female , Humans , Infant, Newborn , Islam , Perinatal Mortality , Pregnancy
16.
Drug Metab Dispos ; 46(11): 1817-1826, 2018 11.
Article in English | MEDLINE | ID: mdl-30097436

ABSTRACT

Abacavir is a preferred antiretroviral drug for preventing mother-to-child human immunodeficiency virus transmission; however, mechanisms of its placental transfer have not been satisfactorily described to date. Because abacavir is a nucleoside-derived drug, we hypothesized that the nucleoside transporters, equilibrative nucleoside transporters (ENTs, SLC29A) and/or Na+-dependent concentrative nucleoside transporters (CNTs, SLC28A), may play a role in its passage across the placenta. To test this hypothesis, we performed uptake experiments using the choriocarcinoma-derived BeWo cell line, human fresh villous fragments, and microvillous plasma membrane (MVM) vesicles. Using endogenous substrates of nucleoside transporters, [3H]-adenosine (ENTs, CNT2, and CNT3) and [3H]-thymidine (ENTs, CNT1, and CNT3), we showed significant activity of ENT1 and CNT2 in BeWo cells, whereas experiments in the villous fragments and MVM vesicles, representing a model of the apical membrane of a syncytiotrophoblast, revealed only ENT1 activity. When testing [3H]-abacavir uptakes, we showed that of the nucleoside transporters, ENT1 plays the dominant role in abacavir uptake into placental tissues, whereas contribution of Na+-dependent transport, most likely mediated by CNTs, was observed only in BeWo cells. Subsequent experiments with dually perfused rat term placentas showed that Ent1 contributes significantly to overall [3H]-abacavir placental transport. Finally, we quantified the expression of SLC29A in first- and third-trimester placentas, revealing that SLC29A1 is the dominant isoform. Neither SLC29A1 nor SLC29A2 expression changed over the course of placental development, but there was considerable interindividual variability in their expression. Therefore, drug-drug interactions and the effect of interindividual variability in placental ENT1 expression on abacavir disposition into fetal circulation should be further investigated to guarantee safe and effective abacavir-based combination therapies in pregnancy.


Subject(s)
Anti-HIV Agents/metabolism , Dideoxynucleosides/metabolism , Equilibrative Nucleoside Transporter 1/metabolism , Nucleoside Transport Proteins/metabolism , Placenta/metabolism , Adenosine/metabolism , Animals , Biological Transport/physiology , Cell Line, Tumor , Equilibrative-Nucleoside Transporter 2/metabolism , Female , Humans , Membrane Transport Proteins/metabolism , Nucleosides/metabolism , Pregnancy , Rats , Rats, Wistar
17.
Int J Obes (Lond) ; 42(6): 1202-1210, 2018 06.
Article in English | MEDLINE | ID: mdl-29899523

ABSTRACT

INTRODUCTION: Alkaline phosphatase is implicated in intestinal lipid transport and in the development of obesity. Placental alkaline phosphatase is localised to the microvillous plasma membrane of the placental syncytiotrophoblast at the maternal-fetal interface, but its role is unclear. We investigated the relations of placental alkaline phosphatase activity and mRNA expression with maternal body composition and offspring fat mass in humans. METHODS: Term human placentas from the UK Birthright cohort (n = 52) and the Southampton Women's Survey (SWS) (n = 95) were studied. In the Birthright cohort, alkaline phosphatase activity was measured in placental microvillous plasma membrane vesicles. In the SWS, alkaline phosphatase mRNA was measured using Nanostring. Alkaline phosphatase gene expression was compared to other lipid-related genes. RESULTS: In Birthright samples placental microvillous plasma membrane alkaline phosphatase activity was positively associated with maternal triceps skinfold thickness and BMI (ß = 0.04 (95% CI: 0.01-0.06) and ß = 0.02 (0.00-0.03) µmol/mg protein/min per SD, P = 0.002 and P = 0.05, respectively) after adjusting for potential confounders. In SWS samples placental alkaline phosphatase mRNA expression in term placenta was positively associated with maternal triceps skinfold (ß = 0.24 (0.04, 0.44) SD/SD, P = 0.02), had no association with neonatal %fat mass (ß = 0.01 (-0.20 to 0.21) SD/SD, P = 0.93) and was negatively correlated with %fat mass at ages 4 (ß = -0.28 (-0.52 to -0.04) SD/SD, P = 0.02), 6-7 (ß = -0.25 (-0.49 to -0.02) SD/SD, P = 0.03) years. When compared with placental expression of other genes, alkaline phosphatase expression was positively related to genes including the lysophosphatidylcholine transporter MFSD2A (major facilitator superfamily domain containing 2A, P < 0.001) and negatively related to genes including the fatty acid transport proteins 2 and 3 (P = 0.001, P < 0.001). CONCLUSIONS: Our findings suggest relationships between placental alkaline phosphatase and both maternal and childhood adiposity. The inverse relationship between placental alkaline phosphatase gene expression and childhood %fat mass suggests that placental alkaline phosphatase may help to protect the foetus from the adverse effects of maternal obesity.


Subject(s)
Alkaline Phosphatase/metabolism , Isoenzymes/metabolism , Obesity/metabolism , Prenatal Exposure Delayed Effects/physiopathology , Tumor Suppressor Proteins/metabolism , Adult , Biological Transport , Body Composition , Child Development , Cohort Studies , Female , GPI-Linked Proteins/metabolism , Humans , Infant, Newborn , Obesity/physiopathology , Pregnancy , Symporters , Term Birth
18.
Integr Comp Biol ; 58(1): 127-139, 2018 07 01.
Article in English | MEDLINE | ID: mdl-29790957

ABSTRACT

Immersion in well-designed outdoor environments can foster the habits of mind that enable critical and authentic scientific questions to take root in students' minds. Here we share two design cases in which careful, collaborative, and intentional design of outdoor learning environments for informal inquiry provide people of all ages with embodied opportunities to learn about the natural world, developing the capacity for understanding ecology and the ability to empathize, problem-solve, and reflect. Embodied learning, as facilitated by and in well-designed outdoor learning environments, leads students to develop new ways of seeing, new scientific questions, new ways to connect with ideas, with others, and new ways of thinking about the natural world. Using examples from our collaborative practises as experiential learning designers, we illustrate how creating the habits of mind critical to creating scientists, science-interested, and science-aware individuals benefits from providing students spaces to engage in embodied learning in nature. We show how public landscapes designed in creative partnerships between educators, scientists, designers, and the public have potential to amplify science learning for all.


Subject(s)
Problem-Based Learning/methods , Science/education , Community Participation , North Carolina , Students
19.
Placenta ; 64 Suppl 1: S9-S15, 2018 04.
Article in English | MEDLINE | ID: mdl-29370939

ABSTRACT

There is now a basic understanding of the driving forces and mechanisms underlying rates of solute exchange across the placenta but there are still major gaps in knowledge. Here we summarise this basic understanding, whilst highlighting gaps in knowledge. We then focus on two particular areas where more knowledge is needed: (1) the electrical potential difference (PD) across the placenta and (2) the paracellular permeability of the placenta to hydrophilic solutes. In many species a PD has been recorded between a catheter in a maternal blood vessel and one in a fetal vessel. However, the key question is whether this PD is the same as that across the placental exchange barrier. We addressed this in the human placenta using microelectrodes to measure the PD in isolated villi in vitro; the transtrophoblast PD so measured had a median value of -3 mV (range 0-15 mV). There have been no subsequent studies to validate this measurement. The syncytiotrophoblast of haemochorial placentas lacks any obvious extracellular water filled paracellular space between the syncytial nuclei. However, in mouse, rat, guinea pig and human there is an inverse relationship between the rate of diffusion of inert hydrophilic solutes across the placenta and their molecular size. The simplest explanation is that a paracellular route exists but its morphological identity is still uncertain. Areas of syncytial denudation could provide a paracellular route but this has not been proven. Answers to these and similar questions are required to fully understand the exchange physiology of the normal placenta and how this is affected in pathology.


Subject(s)
Maternal-Fetal Exchange/physiology , Placenta/metabolism , Trophoblasts/metabolism , Animals , Female , Humans , Permeability , Pregnancy
20.
PLoS One ; 12(11): e0187291, 2017.
Article in English | MEDLINE | ID: mdl-29125872

ABSTRACT

BACKGROUND: Placental malaria is a major cause of low birthweight, principally due to impaired fetal growth. Intervillositis, a local inflammatory response to placental malaria, is central to the pathogenesis of poor fetal growth as it impairs transplacental amino acid transport. Given the link between inflammation and autophagy, we investigated whether placental malaria-associated intervillositis increased placental autophagy as a potential mechanism in impaired fetal growth. METHODS: We examined placental biopsies collected after delivery from uninfected women (n = 17) and from women with Plasmodium falciparum infection with (n = 14) and without (n = 7) intervillositis. Western blotting and immunofluorescence staining coupled with advanced image analysis were used to quantify the expression of autophagic markers (LC3-II, LC3-I, Rab7, ATG4B and p62) and the density of autophagosomes (LC3-positive puncta) and lysosomes (LAMP1-positive puncta). RESULTS: Placental malaria with intervillositis was associated with higher LC3-II:LC3-I ratio, suggesting increased autophagosome formation. We found higher density of autophagosomes and lysosomes in the syncytiotrophoblast of malaria-infected placentas with intervillositis. However, there appear to be no biologically relevant increase in LC3B/LAMP1 colocalization and expression of Rab7, a molecule involved in autophagosome/lysosome fusion, was lower in placental malaria with intervillositis, indicating a block in the later stage of autophagy. ATG4B and p62 expression showed no significant difference across histological groups suggesting normal autophagosome maturation and loading of cargo proteins into autophagosomes. The density of autophagosomes and lysosomes in the syncytiotrophoblast was negatively correlated with placental amino acid uptake. CONCLUSIONS: Placental malaria-associated intervillositis is associated with dysregulated autophagy that may impair transplacental amino acid transport, possibly contributing to poor fetal growth.


Subject(s)
Autophagy , Malaria, Falciparum/immunology , Placenta/immunology , Pregnancy Complications, Infectious/immunology , Female , Humans , Lysosomes/immunology , Malaria, Falciparum/complications , Phagosomes/immunology , Pregnancy
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