Bromine Inhalation in Pregnant Mice Induces Systemic and Pulmonary Hypertension, Fetal Growth Restriction, Heart Failure, and Death

Smoking is associated with multiple adverse pregnancy outcomes, including fetal growth restriction. The objective of this study was to determine whether cigarette smoke exposure during pregnancy in a mouse model affects the functional properties of maternal uterine, mesenteric, and renal arteries as a possible mechanism for growth restriction. C57Bl/CJ mice were exposed to whole body sidestream smoke for 4 h/day. Smoke particle exposure was increased from day 4 of gestation until late pregnancy ( day 16–19), with mean total suspended particle levels of 63 mg/m3, representative of moderate-to-heavy smoking in humans. Uterine, mesenteric, and renal arteries from late-pregnant and virgin mice were isolated and studied in a pressure-arteriograph system ( n = 23). Plasma cotinine was measured by ELISA. Fetal weights were significantly reduced in smoke-exposed compared with control fetuses (0.88 ± 0.1 vs. 1.0 ± 0.08 g, P < 0.02), while litter sizes were not different. Endothelium-mediated relaxation responses to methacholine were significantly impaired in both the uterine and mesenteric vasculature of pregnant mice exposed to cigarette smoke during gestation. This difference was not apparent in isolated renal arteries from pregnant mice exposed to cigarette smoke; however, relaxation was significantly reduced in renal arteries from smoke-exposed virgin mice. In conclusion, we found that passive cigarette smoke exposure is associated with impaired vascular relaxation of uterine and mesenteric arteries in pregnant mice. Functional maternal vascular perturbations during pregnancy, specifically impaired peripheral and uterine vasodilation, may contribute to a mechanism by which smoking results in fetal growth restriction.

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Nano Zinc Oxide Induced Fetal Mice Growth Restriction, Based on Oxide Stress and Endoplasmic Reticulum Stress

Nanomaterials ◽

10.3390/nano10020259 ◽

2020 ◽

Vol 10 (2) ◽

pp. 259 ◽

Cited By ~ 3

Author(s):

Bolu Chen ◽

Wuding Hong ◽

Pengfei Yang ◽

Yizhou Tang ◽

Yu Zhao ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Reproductive Toxicity ◽

Growth Restriction ◽

Oral Exposure ◽

Zno Nps ◽

Pregnant Mice ◽

Oxide Stress

ZnO NPs have been assessed to show adverse effects on reproductive organs, but the molecular mechanisms of reproductive toxicity have not been sufficiently studied. In this research, the dosage effects from the oral exposure of ZnO NPs (30 nm) to pregnant mice in gestation day 10.5 to 17.5 was analyzed. Pregnant mice exposed to ZnO NPs induced dam injury, mice fetal growth restriction, and the fetus number decreased. The pathological evaluation showed that ZnO NPs exposure caused placental spongiotrophoblast area decease and structural damage. The RT-qPCR and immunocytochemistry data indicated that ZnO NPs could induce placenta oxide stress, endoplasmic reticulum stress responses, apoptosis, and altered placental function. These findings indicated that ZnO NPs could induce dam injury and fetal growth restriction. Reproductive toxicity of ZnO NPs may be due to placental injury and function alteration caused by apoptosis, oxide stress, and endoplasmic reticulum stress after ZnO NPs exposure.

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Tadalafil Improves L-NG-Nitroarginine Methyl Ester-Induced Preeclampsia With Fetal Growth Restriction-Like Symptoms in Pregnant Mice

American Journal of Hypertension ◽

10.1093/ajh/hpx130 ◽

2017 ◽

Vol 31 (1) ◽

pp. 89-96 ◽

Cited By ~ 12

Author(s):

Kento Yoshikawa ◽

Takashi Umekawa ◽

Shintaro Maki ◽

Michiko Kubo ◽

Masafumi Nii ◽

...

Keyword(s):

Methyl Ester ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Growth Restriction ◽

Pregnant Mice

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Metallothionein-I- and -II-deficient mice display increased susceptibility to cadmium-induced fetal growth restriction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00157.2013 ◽

2013 ◽

Vol 305 (6) ◽

pp. E727-E735 ◽

Cited By ~ 16

Author(s):

Johanna Selvaratnam ◽

Haiyan Guan ◽

James Koropatnick ◽

Kaiping Yang

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Structural Changes ◽

Molecular Mechanisms ◽

Glucose Transporter ◽

Cadmium Exposure ◽

Growth Restriction ◽

Glut1 Expression ◽

Pregnant Mice ◽

Underlying Mechanisms

Maternal cadmium exposure induces fetal growth restriction (FGR), but the underlying mechanisms remain largely unknown. The placenta is the main organ known to protect the fetus from environmental toxins such as cadmium. In this study, we examine the role of the two key placental factors in cadmium-induced FGR. The first is placental enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is known to protect the fetus from exposure to high cortisol levels and subsequently FGR, and the second the cadmium binding/sequestering proteins metallotheionein (MT)-I and -II. Using the MT-I/II −/− mouse model, pregnant mice were administered cadmium, following which pups and placentas were collected and examined. MT-I/II−/− pups exposed to cadmium were significantly growth restricted, but neither placental weight nor 11β-HSD2 was altered. Although cadmium administration did not result in any visible structural changes in the placenta, increased apoptosis was detected in MT-I/II−/− placentas following cadmium exposure, with a significant increase in levels of both p53 and caspase 3 proteins. Additionally, glucose transporter (GLUT1) was significantly reduced in MT-I/II−/− placentas of pups exposed to cadmium, whereas zinc transporter (ZnT-1) remained unaltered. Taken together, these results demonstrate that MT-I/II−/− mice are more vulnerable to cadmium-induced FGR. The present data also suggest that increased apoptosis and reduced GLUT1 expression in the placenta contribute to the molecular mechanisms underlying cadmium-induced FGR.

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Maternal circulating miRNAs that predict infant FASD outcomes influence placental maturation

Life Science Alliance ◽

10.26508/lsa.201800252 ◽

2019 ◽

Vol 2 (2) ◽

pp. e201800252 ◽

Cited By ~ 5

Author(s):

Alexander M Tseng ◽

Amanda H Mahnke ◽

Alan B Wells ◽

Nihal A Salem ◽

Andrea M Allan ◽

...

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Epithelial Mesenchymal Transition ◽

Prenatal Alcohol Exposure ◽

Alcohol Exposure ◽

Growth Restriction ◽

Circulating Mirnas ◽

Placental Development ◽

Mesenchymal Transition ◽

Pregnant Mice

Prenatal alcohol exposure (PAE), like other pregnancy complications, can result in placental insufficiency and fetal growth restriction, although the linking causal mechanisms are unclear. We previously identified 11 gestationally elevated maternal circulating miRNAs (HEamiRNAs) that predicted infant growth deficits following PAE. Here, we investigated whether theseHEamiRNAs contribute to the pathology of PAE, by inhibiting trophoblast epithelial–mesenchymal transition (EMT), a pathway critical for placental development. We now report for the first time that PAE inhibits expression of placental pro-EMT pathway members in both rodents and primates, and thatHEamiRNAs collectively, but not individually, mediate placental EMT inhibition.HEamiRNAs collectively, but not individually, also inhibited cell proliferation and the EMT pathway in cultured trophoblasts, while inducing cell stress, and following trophoblast syncytialization, aberrant endocrine maturation. Moreover, a single intravascular administration of the pooled murine-expressedHEamiRNAs, to pregnant mice, decreased placental and fetal growth and inhibited the expression of pro-EMT transcripts in the placenta. Our data suggest thatHEamiRNAs collectively interfere with placental development, contributing to the pathology of PAE, and perhaps also, to other causes of fetal growth restriction.

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Abstract 03: Ablation Of Endothelial Dysfunction Improves Blood Pressure And Fetal Growth Restriction In A Mouse Model Of Preeclampsia-like Hyperleptinemia

Hypertension ◽

10.1161/hyp.78.suppl_1.03 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Jessica L Faulkner ◽

Derrian Wright ◽

Simone Kennard ◽

Galina Antonova ◽

Iris Z Jaffe ◽

...

Keyword(s):

Blood Pressure ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Vascular Function ◽

Vascular Dysfunction ◽

Fold Change ◽

Growth Restriction ◽

Mesenteric Arteries ◽

Pregnant Mice ◽

Placental Efficiency

Placental ischemia, an initiating event of preeclampsia (PE), increases plasma leptin levels. We recently developed a model of midgestation (gestation day (GD)11-18) leptin infusion mimicking the midgestation rise in leptin levels of PE patients. Our previous work demonstrates that deletion of endothelial mineralocorticoid receptors (ECMR) improves markers of vascular dysfunction in leptin-infused female mice. We hypothesized vascular function improvement with ECMR deletion ablates hypertension and fetal growth restriction in pregnant leptin-infused mice. Pregnant ECMR +/+ (WT) and ECMR -/- (KO) mice were infused with vehicle or leptin by osmotic pump (lep, 0.9mg/kg/day, s.c.) on GD11-18 while implanted with radiotelemeters for conscious blood pressure (BP) measurement and wire myography of thoracic aorta and 2 nd order mesenteric arteries at GD18 (*=P<0.05). Leptin infusion did not decrease maternal weight in any groups. Leptin decreased pup weight (0.86±0.04g WT vs 0.52±0.11 WT+lep*) and placental efficiency (pup/placenta ratio) (9.7±0.7 WT vs 7.9±0.6 WT+lep*) in WT pregnant mice. ECMR deletion prevented leptin-mediated decreases in pup weight (0.91±0.06g KO vs 1.0±0.07 KO+lep) and placental efficiency (9.6±0.5 KO vs 9.4±1.2 KO+lep). Mean arterial pressure (BP) increased in leptin-infused WT (102±3mmHg WT vs 120±12 WT+lep*), but not KO (107±2 KO vs 106±8 KO+lep), mice from GD11-18. Leptin infusion reduced acetylcholine-mediated relaxation in both aorta and mesenteric arteries of WT* and constriction to KCl in mesenteric arteries in WT*, but not KO, pregnant mice (2-way ANOVA, repeated measures). Leptin increased plasma endothelin-1 (ET-1, 1.1±0.3 pg/ml WT vs 4.4±1.8 WT+lep*), placental mRNA expression of prepro-ET-1 (1.9±0.3-fold change from WT*) and ET-1 converting enzyme-1 (1.6±0.3-fold change from WT*) in pregnant WT mice. Leptin infusion also increased adrenal aldosterone-synthase protein (1.4±0.4 WT ratio/β actin vs 3.2±0.3 WT+lep*) and angiotensin II type 1 receptor b (3.5±0.8-fold change from WT*) mRNA in pregnant mice. Collectively, these data indicate that leptin infusion induces hypertension and fetal growth restriction in pregnant mice due to vascular dysfunction and increased ECMR activation in pregnant mice.

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Fetal growth restriction and pulmonary hypertension in premature infants with bronchopulmonary dysplasia

Journal of Perinatology ◽

10.1038/jp.2012.164 ◽

2013 ◽

Vol 33 (7) ◽

pp. 553-557 ◽

Cited By ~ 121

Author(s):

J Check ◽

N Gotteiner ◽

X Liu ◽

E Su ◽

N Porta ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Bronchopulmonary Dysplasia ◽

Premature Infants ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Growth Restriction

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Antenatal pomegranate juice rescues hypoxia-induced fetal growth restriction in pregnant mice while reducing placental cell stress and apoptosis

Placenta ◽

10.1016/j.placenta.2018.04.009 ◽

2018 ◽

Vol 66 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Baosheng Chen ◽

Mark S. Longtine ◽

Joan K. Riley ◽

D. Michael Nelson

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Cell Stress ◽

Growth Restriction ◽

Pomegranate Juice ◽

Placental Cell ◽

Pregnant Mice

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Neonatal pulmonary hypertension after severe early-onset fetal growth restriction: post hoc reflections on the Dutch STRIDER study

European Journal of Pediatrics ◽

10.1007/s00431-021-04355-x ◽

2022 ◽

Author(s):

Anouk Pels ◽

Wes Onland ◽

Rolf M. F. Berger ◽

Arno F. J. van Heijst ◽

Enrico Lopriore ◽

...

Keyword(s):

At Risk ◽

Pulmonary Hypertension ◽

Bronchopulmonary Dysplasia ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Early Onset ◽

Growth Restriction ◽

Persistent Pulmonary Hypertension ◽

Pathophysiological Mechanism ◽

Co Morbidity

AbstractThe aim was to reflect on the unexpected finding of persistent pulmonary hypertension of the neonate (PPHN) and pulmonary hypertension in infants born within the Dutch STRIDER trial, its definition and possible pathophysiological mechanisms. The trial randomly assigned pregnant women with severe early-onset fetal growth restriction to sildenafil 25 mg three times a day versus placebo. Sildenafil use did not reduce perinatal mortality and morbidity, but did result in a higher rate of neonatal pulmonary hypertension (PH). The current paper reflects on the used definition, prevalence, and possible pathophysiology of the data on pulmonary hypertension. Twenty infants were diagnosed with pulmonary hypertension (12% of 163 live born infants). Of these, 16 infants had PPHN shortly after birth, and four had pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia. Four infants with PPHN in the early neonatal period subsequently developed pulmonary hypertension associated with bronchopulmonary dysplasia in later life. Infants with pulmonary hypertension were at lower gestational age at delivery, had a lower birth weight and a higher rate of neonatal co-morbidity. The infants in the sildenafil group showed a significant increase in pulmonary hypertension compared to the placebo group (relative risk 3.67; 95% confidence interval 1.28 to 10.51, P = 0.02).Conclusion: Pulmonary hypertension occurred more frequent among infants of mothers allocated to antenatal sildenafil compared with placebo. A possible pathophysiological mechanism could be a “rebound” vasoconstriction after cessation of sildenafil. Additional studies and data are necessary to understand the mechanism of action. What is Known:• In the Dutch STRIDER trial, persistent pulmonary hypertension in the neonate (PPHN) was more frequent among infants after antenatal sildenafil exposure versus placebo. What is New:• The current analysis focuses on the distinction between PPHN and pulmonary hypertension associated with sepsis or bronchopulmonary dysplasia and on timing of diagnosis and aims to identify the infants at risk for developing pulmonary hypertension.• The diagnosis pulmonary hypertension is complex, especially in infants born after severe early-onset fetal growth restriction. The research field could benefit from an unambiguous consensus definition and standardized screening in infants at risk is proposed.

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Pregnancy with Heart Disease: Maternal Outcomes and Risk Factors for Fetal Growth Restriction

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16122075 ◽

2019 ◽

Vol 16 (12) ◽

pp. 2075 ◽

Cited By ~ 2

Author(s):

Thang Nguyen Manh ◽

Nhon Bui Van ◽

Huyen Le Thi ◽

Long Vo Hoang ◽

Hao Nguyen Si Anh ◽

...

Keyword(s):

Risk Factors ◽

Heart Failure ◽

Heart Disease ◽

Fetal Growth ◽

Cardiac Disease ◽

Fetal Growth Restriction ◽

Septal Defect ◽

Growth Restriction ◽

Maternal Outcomes ◽

Valve Regurgitation

Caring for children and mothers suffering from cardiac disease is highly challenging, with issues including late diagnosis as well as inadequate infrastructure and supply of drugs. We aimed to evaluate maternal outcomes among pregnant women suffering from heart disease with a live birth, and explored the risk factors for fetal growth restriction among these patients. A retrospective study was performed at the National Hospital of Obstetrics and Gynecology (Hanoi, Vietnam) over a 3-year period from 2014 to 2016. A total of 284 patients were enrolled in the study. Overall, most women were aged below 35 years and were diagnosed with heart disease before pregnancy. Of the women experiencing rheumatic heart disease, the prevalence of mitral valve regurgitation was the highest (40.14%), while the figure for aortic valve regurgitation was the lowest (4.23%). Of women with congenital heart defects, the most common defects were ventricular septal defect (VSD) and atrial septal defect (ASD) (19.37% and 16.55%, respectively), while 5.28% of mothers were diagnosed with tetralogy of Fallot and 1.76% with patent ductus arteriosus. Noted clinical presentations of the patients included palpitation (63.38%), breathlessness (23.59%), leg edema (8.45%), and chest pain (8.1%). The common complications in the study population included 16.90% of women having heart failure and 19.37% having arrhythmias. The incidence of fetal growth restriction was 9.15%. Hypertension (odds ratio (OR): 59.75, 95% confidence interval (CI): 9.1–392.17), the heart disease types (ASD (OR: 4.27, 95% CI: 1.19–15.29) and tetralogy of Fallot (OR: 6.82, 95% CI: 1.21–38.55)), and the complications (heart failure (OR: 10.34, 95% CI: 2.75–38.87) and pulmonary edema (OR: 107.16, 95% CI: 4.96–2313.93)) were observed as risk factors for intrauterine growth restriction. This study provides a cornerstone to promote further studies and to motivate people to apply evidence-based medical care for mothers with diagnosed cardiac disease in the antenatal and postnatal periods.

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