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Article ; Online: DNA methylation profiles in the blood of newborn term infants born to mothers with obesity

Aya Sasaki / Kellie E. Murphy / Laurent Briollais / Patrick O. McGowan / Stephen G. Matthews

PLoS ONE, Vol 17, Iss

2022 Volume 5

Abstract: Maternal obesity is an important risk factor for childhood obesity and influences the prevalence of metabolic diseases in offspring. As childhood obesity is influenced by postnatal factors, it is critical to determine whether children born to women with ... ...

Abstract	Maternal obesity is an important risk factor for childhood obesity and influences the prevalence of metabolic diseases in offspring. As childhood obesity is influenced by postnatal factors, it is critical to determine whether children born to women with obesity during pregnancy show alterations that are detectable at birth. Epigenetic mechanisms such as DNA methylation modifications have been proposed to mediate prenatal programming. We investigated DNA methylation signatures in male and female infants from mothers with a normal Body Mass Index (BMI 18.5–24.9 kg/m2) compared to mothers with obesity (BMI≥30 kg/m2). BMI was measured during the first prenatal visit from women recruited into the Ontario Birth Study (OBS) at Mount Sinai Hospital in Toronto, ON, Canada. DNA was extracted from neonatal dried blood spots collected from heel pricks obtained 24 hours after birth at term (total n = 40) from women with a normal BMI and women with obesity matched for parity, age, and neonatal sex. Reduced representation bisulfite sequencing was used to identify genomic loci associated with differentially methylated regions (DMRs) in CpG-dense regions most likely to influence gene regulation. DMRs were predominantly localized to intergenic regions and gene bodies, with only 9% of DMRs localized to promoter regions. Genes associated with DMRs were compared to those from a large publicly available cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC; total n = 859). Hypergeometric tests revealed a significant overlap in genes associated with DMRs in the OBS and ALSPAC cohorts. PTPRN2, a gene involved in insulin secretion, and MAD1L1, which plays a role in the cell cycle and tumor suppression, contained DMRs in males and females in both cohorts. In males, KEGG pathway analysis revealed significant overrepresentation of genes involved in endocytosis and pathways in cancer, including IGF1R, which was previously shown to respond to diet-induced metabolic stress in animal models and in lymphocytes in the context of childhood obesity. These preliminary findings are consistent with Developmental Origins of Health and Disease paradigm, which posits that adverse prenatal exposures set developmental health trajectories.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: DNA methylation profiles in the blood of newborn term infants born to mothers with obesity.

Aya Sasaki / Kellie E Murphy / Laurent Briollais / Patrick O McGowan / Stephen G Matthews

PLoS ONE, Vol 17, Iss 5, p e

2022 Volume 0267946

Abstract	Maternal obesity is an important risk factor for childhood obesity and influences the prevalence of metabolic diseases in offspring. As childhood obesity is influenced by postnatal factors, it is critical to determine whether children born to women with obesity during pregnancy show alterations that are detectable at birth. Epigenetic mechanisms such as DNA methylation modifications have been proposed to mediate prenatal programming. We investigated DNA methylation signatures in male and female infants from mothers with a normal Body Mass Index (BMI 18.5-24.9 kg/m2) compared to mothers with obesity (BMI≥30 kg/m2). BMI was measured during the first prenatal visit from women recruited into the Ontario Birth Study (OBS) at Mount Sinai Hospital in Toronto, ON, Canada. DNA was extracted from neonatal dried blood spots collected from heel pricks obtained 24 hours after birth at term (total n = 40) from women with a normal BMI and women with obesity matched for parity, age, and neonatal sex. Reduced representation bisulfite sequencing was used to identify genomic loci associated with differentially methylated regions (DMRs) in CpG-dense regions most likely to influence gene regulation. DMRs were predominantly localized to intergenic regions and gene bodies, with only 9% of DMRs localized to promoter regions. Genes associated with DMRs were compared to those from a large publicly available cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC; total n = 859). Hypergeometric tests revealed a significant overlap in genes associated with DMRs in the OBS and ALSPAC cohorts. PTPRN2, a gene involved in insulin secretion, and MAD1L1, which plays a role in the cell cycle and tumor suppression, contained DMRs in males and females in both cohorts. In males, KEGG pathway analysis revealed significant overrepresentation of genes involved in endocytosis and pathways in cancer, including IGF1R, which was previously shown to respond to diet-induced metabolic stress in animal models and in lymphocytes in the context ...
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Antenatal Glucocorticoid Exposure Results in Sex-Specific and Transgenerational Changes in Prefrontal Cortex Gene Transcription that Relate to Behavioural Outcomes

Andrea Constantinof / Vasilis G. Moisiadis / Alisa Kostaki / Moshe Szyf / Stephen G. Matthews

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 9

Abstract: Abstract Synthetic glucocorticoids (sGC) are administered to women at risk for pre-term delivery to reduce respiratory distress syndrome in the newborn. The prefrontal cortex (PFC) is important in regulating stress responses and related behaviours and ... ...

Abstract	Abstract Synthetic glucocorticoids (sGC) are administered to women at risk for pre-term delivery to reduce respiratory distress syndrome in the newborn. The prefrontal cortex (PFC) is important in regulating stress responses and related behaviours and expresses high levels of glucocorticoid receptors (GR). Further, antenatal exposure to sGC results in a hyperactive phenotype in first generation (F1) juvenile male and female offspring, as well as F2 and F3 juvenile females from the paternal lineage. We hypothesized that multiple courses of antenatal sGC modify gene expression in the PFC, that these effects are sex-specific and maintained across multiple generations, and that the gene sets affected relate to modified locomotor activity. We performed RNA sequencing on PFC of F1 juvenile males and females, as well as F2 and F3 juvenile females from the paternal lineage and used regression modelling to relate gene expression and behavior. Antenatal sGC resulted in sex-specific and generation-specific changes in gene expression. Further, the expression of 4 genes (C9orf116, Calb1, Glra3, and Gpr52) explained 20–29% of the observed variability in locomotor activity. Antenatal exposure to sGC profoundly influences the developing PFC; effects are evident across multiple generations and may drive altered behavioural phenotypes.
Keywords	Medicine ; R ; Science ; Q
Subject code	590
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prenatal Glucocorticoid Exposure Results in Changes in Gene Transcription and DNA Methylation in the Female Juvenile Guinea Pig Hippocampus Across Three Generations

Andrea Constantinof / Lisa Boureau / Vasilis G. Moisiadis / Alisa Kostaki / Moshe Szyf / Stephen G. Matthews

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 12

Abstract: Abstract Synthetic glucocorticoids (sGC) are administered to women at risk for pre-term delivery, to mature the fetal lung and decrease neonatal morbidity. sGC also profoundly affect the fetal brain. The hippocampus expresses high levels of ... ...

Abstract	Abstract Synthetic glucocorticoids (sGC) are administered to women at risk for pre-term delivery, to mature the fetal lung and decrease neonatal morbidity. sGC also profoundly affect the fetal brain. The hippocampus expresses high levels of glucocorticoid (GR) and mineralocorticoid receptor (MR), and its development is affected by elevated fetal glucocorticoid levels. Antenatal sGC results in neuroendocrine and behavioral changes that persist in three generations of female guinea pig offspring of the paternal lineage. We hypothesized that antenatal sGC results in transgenerational changes in gene expression that correlate with changes in DNA methylation. We used RNASeq and capture probe bisulfite sequencing to investigate the transcriptomic and epigenomic effects of antenatal sGC exposure in the hippocampus of three generations of juvenile female offspring from the paternal lineage. Antenatal sGC exposure (F0 pregnancy) resulted in generation-specific changes in hippocampal gene transcription and DNA methylation. Significant changes in individual CpG methylation occurred in RNApol II binding regions of small non-coding RNA (snRNA) genes, which implicates alternative splicing as a mechanism involved in transgenerational transmission of the effects of antenatal sGC. This study provides novel perspectives on the mechanisms involved in transgenerational transmission and highlights the importance of human studies to determine the longer-term effects of antenatal sGC on hippocampal-related function.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prenatal Glucocorticoid Exposure Modifies Endocrine Function and Behaviour for 3 Generations Following Maternal and Paternal Transmission

Vasilis G. Moisiadis / Andrea Constantinof / Alisa Kostaki / Moshe Szyf / Stephen G. Matthews

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 15

Abstract: Abstract Fetal exposure to high levels of glucocorticoids programs long-term changes in the physiologic stress response and behaviours. However, it is not known whether effects manifest in subsequent generations of offspring following maternal (MT) or ... ...

Abstract	Abstract Fetal exposure to high levels of glucocorticoids programs long-term changes in the physiologic stress response and behaviours. However, it is not known whether effects manifest in subsequent generations of offspring following maternal (MT) or paternal (PT) transmission. We treated pregnant guinea pigs with three courses of saline or synthetic glucocorticoid (sGC) at a clinically relevant dose. Altered cortisol response to stress and behaviours transmitted to juvenile female and male F2 and F3 offspring from both parental lines. Behavioural effects of sGC in F1-F3 PT females associated with altered expression of genes in the prefrontal cortex and hypothalamic paraventricular nucleus (PVN). Exposure to sGC programmed large transgenerational changes in PVN gene expression, including type II diabetes, thermoregulation, and collagen formation gene networks. We demonstrate transgenerational programming to F3 following antenatal sGC. Transmission is sex- and generation-dependent, occurring through both parental lines. Paternal transmission to F3 females strongly implicates epigenetic mechanisms of transmission.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2017-09-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Automated tracking to measure behavioural changes in pigs for health and welfare monitoring

Stephen G. Matthews / Amy L. Miller / Thomas PlÖtz / Ilias Kyriazakis

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 12

Abstract: Abstract Since animals express their internal state through behaviour, changes in said behaviour may be used to detect early signs of problems, such as in animal health. Continuous observation of livestock by farm staff is impractical in a commercial ... ...

Abstract	Abstract Since animals express their internal state through behaviour, changes in said behaviour may be used to detect early signs of problems, such as in animal health. Continuous observation of livestock by farm staff is impractical in a commercial setting to the degree required to detect behavioural changes relevant for early intervention. An automated monitoring system is developed; it automatically tracks pig movement with depth video cameras, and automatically measures standing, feeding, drinking, and locomotor activities from 3D trajectories. Predictions of standing, feeding, and drinking were validated, but not locomotor activities. An artificial, disruptive challenge; i.e., introduction of a novel object, is used to cause reproducible behavioural changes to enable development of a system to detect the changes automatically. Validation of the automated monitoring system with the controlled challenge study provides a reproducible framework for further development of robust early warning systems for pigs. The automated system is practical in commercial settings because it provides continuous monitoring of multiple behaviours, with metrics of behaviours that may be considered more intuitive and have diagnostic validity. The method has the potential to transform how livestock are monitored, directly impact their health and welfare, and address issues in livestock farming, such as antimicrobial use.
Keywords	Medicine ; R ; Science ; Q
Subject code	360
Language	English
Publishing date	2017-12-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: ACE2 Is Expressed in Immune Cells That Infiltrate the Placenta in Infection-Associated Preterm Birth

Phetcharawan Lye / Caroline E. Dunk / Jianhong Zhang / Yanxing Wei / Jittanan Nakpu / Hirotaka Hamada / Guinever E. Imperio / Enrrico Bloise / Stephen G. Matthews / Stephen J. Lye

Cells, Vol 10, Iss 1724, p

2021 Volume 1724

Abstract: COVID-19 is associated with increased incidence of preterm birth (PTB). We assessed pathways by which SARS-CoV-2 could access the placenta. Placentae, from PTB with or without chorioamnionitis (ChA), or from term pregnancies ( n = 12/13/group) were ... ...

Abstract	COVID-19 is associated with increased incidence of preterm birth (PTB). We assessed pathways by which SARS-CoV-2 could access the placenta. Placentae, from PTB with or without chorioamnionitis (ChA), or from term pregnancies ( n = 12/13/group) were collected. Peripheral blood was collected from healthy pregnant women ( n = 6). Second trimester placental explants (16–20 weeks, n = 5/group) were treated with lipopolysaccharide (LPS, to mimic bacterial infection) and ACE2, CCL2, IL-6/8 and TNFα mRNA was assessed. ChA-placentae exhibited increased ACE2 and CCL2 mRNA expression ( p < 0.05). LPS increased cytokine and ACE2 mRNA in placental explants. Placental ACE2 protein localized to syncytiotrophoblast, fetal endothelium, extravillous trophoblast and in immune cells-subsets (M1/M2 macrophage and neutrophils) within the villous stroma. Significantly increased numbers of M1 macrophage and neutrophils were present in the ChA-placenta ( p < 0.001). Subsets of peripheral immune cells from pregnant women express the ACE2 mRNA and protein. A greater fraction of granulocytes was positive for ACE2 protein expression compared to lymphocytes or monocytes. These data suggest that in pregnancies complicated by ChA, ACE2 positive immune cells in the maternal circulation have the potential to traffic SARS-CoV-2 virus to the placenta and increase the risk of vertical transmission to the placenta/fetus.
Keywords	SARS-CoV-2 ; COVID-19 ; ACE2 ; chorioamnionitis ; preterm birth ; M1 ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Breast Cancer Resistance Protein (BCRP/ ABCG2 ) Inhibits Extra Villous Trophoblast Migration

Phetcharawan Lye / Enrrico Bloise / Lubna Nadeem / Chun Peng / William Gibb / Tania M. Ortiga-Carvalho / Stephen J. Lye / Stephen G. Matthews

Cells, Vol 8, Iss 10, p

The Impact of Bacterial and Viral Infection

2019 Volume 1150

Abstract: Extravillous trophoblasts (EVT) migration into the decidua is critical for establishing placental perfusion and when dysregulated, may lead to pre-eclampsia (PE) and intrauterine growth restriction (IUGR). The breast cancer resistance protein (BCRP; ... ...

Abstract	Extravillous trophoblasts (EVT) migration into the decidua is critical for establishing placental perfusion and when dysregulated, may lead to pre-eclampsia (PE) and intrauterine growth restriction (IUGR). The breast cancer resistance protein (BCRP; encoded by ABCG2 ) regulates the fusion of cytotrophoblasts into syncytiotrophoblasts and protects the fetus from maternally derived xenobiotics. Information about BCRP function in EVTs is limited, however placental exposure to bacterial/viral infection leads to BCRP downregulation in syncitiotrophoblasts. We hypothesized that BCRP is involved in the regulation of EVT function and is modulated by infection/inflammation. We report that besides syncitiotrophoblasts and cytotrophoblasts, BCRP is also expressed in EVTs. BCRP inhibits EVT cell migration in HTR8/SVneo (human EVT-like) cells and in human EVT explant cultures, while not affecting cell proliferation. We have also shown that bacterial—lipopolysaccharide (LPS)—and viral antigens—single stranded RNA (ssRNA)—have a profound effect in downregulating ABCG2 and BCRP levels, whilst simultaneously increasing the migration potential of EVT-like cells. Our study reports a novel function of BCRP in early placentation and suggests that exposure of EVTs to maternal infection/inflammation could disrupt their migration potential via the downregulation of BCRP. This could negatively influence placental development/function, contribute to existing obstetric pathologies, and negatively impact pregnancy outcomes and maternal/neonatal health.
Keywords	breast cancer resistance protein (bcrp/ abcg2 ) ; extra villous trophoblast ; first trimester placenta ; migration ; infection ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Is perinatal neuroendocrine programming involved in the developmental origins of metabolic disorders?

David IW Phillips / Stephen G Matthews

World Journal of Diabetes, Vol 2, Iss 12, Pp 211-

2011 Volume 216

Abstract: The discovery that small size at birth and during infancy are associated with a higher risk of diabetes and related metabolic disease in later life has pointed to the importance of developmental factors in these conditions. The birth size associations ... ...

Abstract	The discovery that small size at birth and during infancy are associated with a higher risk of diabetes and related metabolic disease in later life has pointed to the importance of developmental factors in these conditions. The birth size associations are thought to reflect exposure to adverse environmental factors during early development but the mechanisms involved are still not fully understood. Animal and human work has pointed to the importance of changes in the set-point of a number of key hormonal systems controlling growth and development. These include the IGF-1/GH axis, gonadal hormones and, in particular, the systems mediating the classical stress response. Several studies show that small size at birth is linked with increased activity of the hypothalamic-pituitary-adrenal axis and sympathoadrenal system in adult life. More recent human studies have shown associations between specific adverse experiences during pregnancy, such as famine or the consumption of adverse diets, and enhanced stress responses many decades later. The mediators of these neuroendocrine responses are biologically potent and are likely to have a direct influence on the risk of metabolic disease. These neuroendocrine changes may also have an evolutionary basis being part of broader process, termed phenotypic plasticity, by which adverse environmental cues experienced during development modify the structure and physiology of the adult towards a phenotype adapted for adversity. The changes are clearly advantageous if they lead to a phenotype which is well-adapted for the adult environment, but may lead to disease if there is subsequent overnutrition or other unexpected environmental conditions.
Keywords	Neuroendocrine fetal programming ; Metabolic disease ; Diabetes ; Hypothalamic-pituitary-adrenal axis ; Stress responses ; Birth weight ; Diseases of the endocrine glands. Clinical endocrinology ; RC648-665 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Internal medicine ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	610
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Baishideng Publishing Group Co., Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Effects of sertraline and fluoxetine on p-glycoprotein at barrier sites

Amita Kapoor / Majid Iqbal / Sophie Petropoulos / Hay Lam Ho / William Gibb / Stephen G Matthews

PLoS ONE, Vol 8, Iss 2, p e

in vivo and in vitro approaches.

2013 Volume 56525

Abstract: Retention of substances from systemic circulation in the brain and testes are limited due to high levels of P-glycoprotein (P-gp) in the luminal membranes of brain and testes capillary endothelial cells. From a clinical perspective, P-gp rapidly extrudes ...

Abstract	Retention of substances from systemic circulation in the brain and testes are limited due to high levels of P-glycoprotein (P-gp) in the luminal membranes of brain and testes capillary endothelial cells. From a clinical perspective, P-gp rapidly extrudes lipophilic therapeutic agents, which then fail to reach efficacious levels. Recent studies have demonstrated that acute administration of selective serotonin reuptake inhibitors (SSRI) can affect P-gp function, in vitro and in vivo. However, little is known concerning the time-course of these effects or the effects of different SSRI in vivo.The P-gp substrate, tritiated digoxin ([(3)H] digoxin), was co-administered with fluoxetine or sertraline to determine if either compound increased drug accumulation within the brains and testes of mice due to inhibition of P-gp activity. We undertook parallel studies in endothelial cells derived from brain microvessels to determine the dose-response and time-course of effects.In vitro, sertraline resulted in rapid and potent inhibition of P-gp function in brain endothelial cells, as determined by cellular calcein accumulation. In vivo, a biphasic effect was demonstrated. Brain accumulation of [(3)H] digoxin was increased 5 minutes after treatment with sertraline, but by 60 minutes after sertraline treatment, brain accumulation of digoxin was reduced compared to control. By 240 minutes after sertraline treatment brain digoxin accumulation was elevated compared to control. A similar pattern of results was obtained in the testes. There was no significant effect of fluoxetine on P-gp function, in vitro or in vivo.Acute sertraline administration can modulate P-gp activity in the blood-brain barrier and blood-testes barrier. This clearly has implications for the ability of therapeutic agents that are P-gp substrates, to enter the brain when co-administered with SSRI.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2013-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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