scholarly journals Toll-Like Receptor-4 Antagonist (+)-Naloxone Confers Sexually Dimorphic Protection From Inflammation-Induced Fetal Programming in Mice

Endocrinology ◽  
2019 ◽  
Vol 160 (11) ◽  
pp. 2646-2662 ◽  
Author(s):  
Peck Yin Chin ◽  
Camilla Dorian ◽  
David J Sharkey ◽  
Mark R Hutchinson ◽  
Kenner C Rice ◽  
...  
Keyword(s):  
Fetal Brain ◽  
Later Life ◽  
Female Offspring ◽  
Developmental Programming ◽  
In Utero ◽  
Cytokine Expression ◽  
Late Gestation ◽  
Toll Like Receptor ◽  
Fetal Sex ◽  
Lps Challenge

Abstract Inflammation elicited by infection or noninfectious insults during gestation induces proinflammatory cytokines that can shift the trajectory of development to alter offspring phenotype, promote adiposity, and increase susceptibility to metabolic disease in later life. In this study, we use mice to investigate the utility of a small molecule Toll-like receptor (TLR)4 antagonist (+)-naloxone, the nonopioid isomer of the opioid receptor antagonist (−)-naloxone, for mitigating altered fetal metabolic programming induced by a modest systemic inflammatory challenge in late gestation. In adult progeny exposed to lipopolysaccharide (LPS) challenge in utero, male but not female offspring exhibited elevated adipose tissue, reduced muscle mass, and elevated plasma leptin at 20 weeks of age. Effects were largely reversed by coadministration of (+)-naloxone following LPS. When given alone without LPS, (+)-naloxone elicited accelerated postweaning growth and elevated muscle and fat mass in adult male but not female offspring. LPS induced expression of inflammatory cytokines Il1a, Il1b, Il6, Tnf, and Il10 in fetal brain, placental, and uterine tissues, and (+)-naloxone suppressed LPS-induced cytokine expression. Fetal sex-specific regulation of cytokine expression was evident, with higher Il1a, Il1b, Il6, and Il10 induced by LPS in tissues associated with male fetuses, and greater suppression by (+)-naloxone of Il6 in females. These data demonstrate that modulating TLR4 signaling with (+)-naloxone provides protection from inflammatory diversion of fetal developmental programming in utero, associated with attenuation of gestational tissue cytokine expression in a fetal sex-specific manner. The results suggest that pharmacologic interventions targeting TLR4 warrant evaluation for attenuating developmental programming effects of fetal exposure to maternal inflammatory mediators.

Prenatal glucocorticoid exposure in the sheep alters renal development in utero: implications for adult renal function and blood pressure control

2011 ◽  
Vol 301 (2) ◽  
pp. R500-R509 ◽  
Author(s):  
Karen M. Moritz ◽  
Robert De Matteo ◽  
Miodrag Dodic ◽  
Andrew J. Jefferies ◽  
Debbie Arena ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Function ◽  
Arterial Pressure ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Salt Intake ◽  
Female Offspring ◽  
In Utero ◽  
Late Gestation ◽  
Elevated Arterial Pressure

Treatment of the pregnant ewe with glucocorticoids early in pregnancy results in offspring with hypertension. This study examined whether glucocorticoids can reduce nephron formation or alter gene expression for sodium channels in the late gestation fetus. Sodium channel expression was also examined in 2-mo-old lambs, while arterial pressure and renal function was examined in adult female offspring before and during 6 wk of increased dietary salt intake. Pregnant ewes were treated with saline (SAL), dexamethasone (DEX; 0.48 mg/h) or cortisol (CORT; 5 mg/h) over days 26–28 of gestation (term = 150 days). At 140 days of gestation, glomerular number in CORT and DEX animals was 40 and 25% less, respectively, compared with SAL controls. Real-time PCR showed greater gene expression for the epithelial sodium channel (α-, β-, γ-subunits) and Na+-K+-ATPase (α-, β-, γ-subunits) in both the DEX and CORT group fetal kidneys compared with the SAL group with some of these changes persisting in 2-mo-old female offspring. In adulthood, sheep treated with dexamethasone or cortisol in utero had elevated arterial pressure and an apparent increase in single nephron glomerular filtration rate, but global renal hemodynamics and excretory function were normal and arterial pressure was not salt sensitive. Our findings show that the nephron-deficit in sheep exposed to glucocorticoids in utero is acquired before birth, so it is a potential cause, rather than a consequence, of their elevated arterial pressure in adulthood. Upregulation of sodium channels in these animals could provide a mechanistic link to sustained increases in arterial pressure in cortisol- and dexamethasone-exposed sheep, since it would be expected to promote salt and water retention during the postnatal period.

Effects of in utero endotoxemia on the ovine fetal brain A model for schizophrenia

10.2741/e588 ◽  
2012 ◽  
Vol E4 (8) ◽  
pp. 2745-2753 ◽  
Author(s):  
Boris W Kramer
Keyword(s):  
Fetal Brain ◽  
In Utero ◽  
Ovine Fetal

scholarly journals Lycopene Inhibits Toll-Like Receptor 4-Mediated Expression of Inflammatory Cytokines in House Dust Mite-Stimulated Respiratory Epithelial Cells

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3127
Author(s):  
Jiyeon Choi ◽  
Joo Weon Lim ◽  
Hyeyoung Kim
Keyword(s):  
Epithelial Cells ◽  
A549 Cells ◽  
Cytokine Expression ◽  
Ros Production ◽  
Toll Like Receptor ◽  
Respiratory Epithelial Cells ◽  
Toll Like Receptor 4 ◽  
Mitochondrial Ros ◽  
Tlr4 Activation ◽  
Respiratory Epithelial

House dust mites (HDM) are critical factors in airway inflammation. They activate respiratory epithelial cells to produce reactive oxygen species (ROS) and activate Toll-like receptor 4 (TLR4). ROS induce the expression of inflammatory cytokines in respiratory epithelial cells. Lycopene is a potent antioxidant nutrient with anti-inflammatory activity. The present study aimed to investigate whether HDM induce intracellular and mitochondrial ROS production, TLR4 activation, and pro-inflammatory cytokine expression (IL-6 and IL-8) in respiratory epithelial A549 cells. Additionally, we examined whether lycopene inhibits HDM-induced alterations in A549 cells. The treatment of A549 cells with HDM activated TLR4, induced the expression of IL-6 and IL-8, and increased intracellular and mitochondrial ROS levels. TAK242, a TLR4 inhibitor, suppressed both HDM-induced ROS production and cytokine expression. Furthermore, lycopene inhibited the HDM-induced TLR4 activation and cytokine expression, along with reducing the intracellular and mitochondrial ROS levels in HDM-treated cells. These results collectively indicated that the HDM induced TLR4 activation and increased intracellular and mitochondrial ROS levels, thus resulting in the induction of cytokine expression in respiratory epithelial cells. The antioxidant lycopene could inhibit HDM-induced cytokine expression, possibly by suppressing TLR4 activation and reducing the intracellular and mitochondrial ROS levels in respiratory epithelial cells.

scholarly journals Neuroplacentology in congenital heart disease: placental connections to neurodevelopmental outcomes

2021 ◽  
Author(s):  
Rachel L. Leon ◽  
Imran N. Mir ◽  
Christina L. Herrera ◽  
Kavita Sharma ◽  
Catherine Y. Spong ◽  
...  
Keyword(s):  
Brain Development ◽  
Congenital Heart ◽  
Fetal Brain ◽  
In Utero ◽  
Structure And Function ◽  
Brain Growth ◽  
Neurodevelopmental Outcomes ◽  
Fetal Brain Development ◽  
And Function

Abstract Children with congenital heart disease (CHD) are living longer due to effective medical and surgical management. However, the majority have neurodevelopmental delays or disorders. The role of the placenta in fetal brain development is unclear and is the focus of an emerging field known as neuroplacentology. In this review, we summarize neurodevelopmental outcomes in CHD and their brain imaging correlates both in utero and postnatally. We review differences in the structure and function of the placenta in pregnancies complicated by fetal CHD and introduce the concept of a placental inefficiency phenotype that occurs in severe forms of fetal CHD, characterized by a myriad of pathologies. We propose that in CHD placental dysfunction contributes to decreased fetal cerebral oxygen delivery resulting in poor brain growth, brain abnormalities, and impaired neurodevelopment. We conclude the review with key areas for future research in neuroplacentology in the fetal CHD population, including (1) differences in structure and function of the CHD placenta, (2) modifiable and nonmodifiable factors that impact the hemodynamic balance between placental and cerebral circulations, (3) interventions to improve placental function and protect brain development in utero, and (4) the role of genetic and epigenetic influences on the placenta–heart–brain connection. Impact Neuroplacentology seeks to understand placental connections to fetal brain development. In fetuses with CHD, brain growth abnormalities begin in utero. Placental microstructure as well as perfusion and function are abnormal in fetal CHD.

scholarly journals Male Fetal Sex Affects Uteroplacental Angiogenesis in Growth Restriction Mouse Model†

2021 ◽  
Author(s):  
Jessica F Hebert ◽  
Jess A Millar ◽  
Rahul Raghavan ◽  
Amie Romney ◽  
Jason E Podrabsky ◽  
...  
Keyword(s):  
Mouse Model ◽  
Killer Cell ◽  
Receptor Activation ◽  
Growth Restriction ◽  
Late Gestation ◽  
Spiral Artery ◽  
Micro Computed Tomography ◽  
Fetal Sex ◽  
Maternal Genotype ◽  
Agt Gene

Abstract Abnormally increased angiotensin II activity related to maternal angiotensinogen (AGT) genetic variants, or aberrant receptor activation, is associated with small-for-gestational-age (SGA) babies and abnormal uterine spiral artery remodeling in humans. Our group studies a murine AGT gene titration transgenic (TG; 3-copies of the AGT gene) model, which has a 20% increase in AGT expression mimicking a common human AGT genetic variant (A[−6]G) associated with intrauterine growth restriction (IUGR) and spiral artery pathology. We hypothesized that aberrant maternal AGT expression impacts pregnancy-induced uterine spiral artery angiogenesis in this mouse model leading to IUGR. We controlled for fetal sex and fetal genotype (e.g., only 2-copy wild-type [WT] progeny from WT and TG dams were included). Uteroplacental samples from WT and TG dams from early (days 6.5 and 8.5), mid (d12.5), and late (d16.5) gestation were studied to assess uterine natural killer cell (uNK) phenotypes, decidual metrial triangle angiogenic factors, placental growth and capillary density, placental transcriptomics, and placental nutrient transport. Spiral artery architecture was evaluated at day 16.5 by contrast-perfused three-dimensional micro-computed tomography (3D microCT). Our results suggest that uteroplacental angiogenesis is significantly reduced in TG dams at day 16.5. Males from TG dams are associated with significantly reduced uteroplacental angiogenesis from early to late gestation compared with their female littermates and WT controls. Angiogenesis was not different between fetal sexes from WT dams. We conclude that male fetal sex compounds the pathologic impact of maternal genotype in this mouse model of growth restriction.

Fetal brain development of twins assessed in utero by ultrasound: implications for schizophrenia

1996 ◽  
Vol 19 (2-3) ◽  
pp. 141-149 ◽  
Author(s):  
John H. Gilmore ◽  
Diana O. Perkins ◽  
Mark A. Kliewer ◽  
Marvin L. Hage ◽  
Susan G. Silva ◽  
...  
Keyword(s):  
Brain Development ◽  
Fetal Brain ◽  
In Utero ◽  
Fetal Brain Development

scholarly journals Gestation Food Restriction and Refeeding Compensate Maternal Energy Status and Alleviate Metabolic Consequences in Juvenile Offspring in a Rabbit Model

Nutrients ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 310
Author(s):  
Rosa M. García-García ◽  
María Arias-Álvarez ◽  
Pilar Millán ◽  
María Rodríguez ◽  
Ana Sánchez-Rodríguez ◽  
...  
Keyword(s):  
Food Restriction ◽  
Rabbit Model ◽  
Later Life ◽  
Female Offspring ◽  
Energy Status ◽  
Juvenile Period ◽  
Body Reserves ◽  
Effect Of Food ◽  
Serum Aminotransferases ◽  
Similar Body

Nutritional status during gestation can influence mother and offspring metabolism. Undernutrition in pregnancy affects women in both western and developing countries, and it is associated with a high prevalence of chronic diseases in later life. The present work was conducted in the rabbit model, as a longitudinal study, to examine the effect of food restriction during early and mid-gestation, and re-feeding ad libitum until the end of pregnancy on metabolic status and body reserves of mother and, its association with development and metabolism of fetuses and female offspring to the juvenile stage. Little changes in live body weight (LBW), compensatory feed intake, similar body reserves, and metabolism were observed in dams. Placenta biometry and efficiency were slightly affected, but fetal BW and phenotype were not modified. However, hyperinsulinemia, insulin resistance, and hypertriglyceridemia were demonstrated in pre-term fetuses. In the juvenile period, these changes were not evidenced, and a similar pattern of growth and serum metabolic parameters in offspring of food-restricted mothers were found, except in serum aminotransferases levels, which increased. These were associated with higher liver fibrosis. Maternal food restriction in the early and mid-pregnancy followed by re-feeding in our rabbit model established a compensatory energy status in dams and alleviated potential long-term consequences in growth and metabolism in the offspring, even if fetal metabolism was altered.

scholarly journals Maternal Obesity, Inflammation, and Developmental Programming

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Stephanie A. Segovia ◽  
Mark H. Vickers ◽  
Clint Gray ◽  
Clare M. Reynolds
Keyword(s):  
Maternal Obesity ◽  
Later Life ◽  
Developmental Programming ◽  
Health Concern ◽  
Low Grade ◽  
Critical Periods ◽  
Omega 3 ◽  
Child Bearing ◽  
Prevalence Of Obesity ◽  
Low Grade Inflammation

The prevalence of obesity, especially in women of child-bearing age, is a global health concern. In addition to increasing the immediate risk of gestational complications, there is accumulating evidence that maternal obesity also has long-term consequences for the offspring. The concept of developmental programming describes the process in which an environmental stimulus, including altered nutrition, during critical periods of development can program alterations in organogenesis, tissue development, and metabolism, predisposing offspring to obesity and metabolic and cardiovascular disorders in later life. Although the mechanisms underpinning programming of metabolic disorders remain poorly defined, it has become increasingly clear that low-grade inflammation is associated with obesity and its comorbidities. This review will discuss maternal metainflammation as a mediator of programming in insulin sensitive tissues in offspring. Use of nutritional anti-inflammatories in pregnancy including omega 3 fatty acids, resveratrol, curcumin, and taurine may provide beneficial intervention strategies to ameliorate maternal obesity-induced programming.

In utero brain destruction resulting in collapse of the fetal skull, microcephaly, scalp rugae, and neurologic impairment: The fetal brain disruption sequence

1984 ◽  
Vol 17 (2) ◽  
pp. 509-521 ◽  
Author(s):  
Laura J. Russell ◽  
David D. Weaver ◽  
Marilyn J. Bull ◽  
Marc Weinbaum ◽  
John M. Opitz
Keyword(s):  
Fetal Brain ◽  
In Utero ◽  
Neurologic Impairment

scholarly journals Maternal stress during pregnancy alters fetal cortico-cerebellar connectivity in utero and increases child sleep problems after birth

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marion I. van den Heuvel ◽  
Jasmine L. Hect ◽  
Benjamin L. Smarr ◽  
Tamara Qawasmeh ◽  
Lance J. Kriegsfeld ◽  
...  
Keyword(s):  
Prenatal Stress ◽  
Sleep Problems ◽  
Brain Connectivity ◽  
Fetal Brain ◽  
Brain Regions ◽  
In Utero ◽  
Resting State Functional Connectivity ◽  
Child Sleep ◽  
Maternal Prenatal Stress

AbstractChild sleep disorders are increasingly prevalent and understanding early predictors of sleep problems, starting in utero, may meaningfully guide future prevention efforts. Here, we investigated whether prenatal exposure to maternal psychological stress is associated with increased sleep problems in toddlers. We also examined whether fetal brain connectivity has direct or indirect influence on this putative association. Pregnant women underwent fetal resting-state functional connectivity MRI and completed questionnaires on stress, worry, and negative affect. At 3-year follow-up, 64 mothers reported on child sleep problems, and in the subset that have reached 5-year follow-up, actigraphy data (N = 25) has also been obtained. We observe that higher maternal prenatal stress is associated with increased toddler sleep concerns, with actigraphy sleep metrics, and with decreased fetal cerebellar-insular connectivity. Specific mediating effects were not identified for the fetal brain regions examined. The search for underlying mechanisms of the link between maternal prenatal stress and child sleep problems should be continued and extended to other brain areas.

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