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Clinical Epigenetics Jul 2023With the growing availability of cannabis and the popularization of additional routes of cannabis use beyond smoking, including edibles, the prevalence of cannabis use...
BACKGROUND
With the growing availability of cannabis and the popularization of additional routes of cannabis use beyond smoking, including edibles, the prevalence of cannabis use in pregnancy is rapidly increasing. However, the potential effects of prenatal cannabis use on fetal developmental programming remain unknown.
RESULTS
We designed this study to determine whether the use of edible cannabis during pregnancy is deleterious to the fetal and placental epigenome. Pregnant rhesus macaques consumed a daily edible containing either delta-9-tetrahydrocannabinol (THC) (2.5 mg/7 kg/day) or placebo. DNA methylation was measured in 5 tissues collected at cesarean delivery (placenta, lung, cerebellum, prefrontal cortex, and right ventricle of the heart) using the Illumina MethylationEPIC platform and filtering for probes previously validated in rhesus macaque. In utero exposure to THC was associated with differential methylation at 581 CpGs, with 573 (98%) identified in placenta. Loci differentially methylated with THC were enriched for candidate autism spectrum disorder (ASD) genes from the Simons Foundation Autism Research Initiative (SFARI) database in all tissues. The placenta demonstrated greatest SFARI gene enrichment, including genes differentially methylated in placentas from a prospective ASD study.
CONCLUSIONS
Overall, our findings reveal that prenatal THC exposure alters placental and fetal DNA methylation at genes involved in neurobehavioral development that may influence longer-term offspring outcomes. The data from this study add to the limited existing literature to help guide patient counseling and public health polices focused on prenatal cannabis use in the future.
Topics: Animals; Female; Pregnancy; Autism Spectrum Disorder; Autistic Disorder; DNA Methylation; Dronabinol; Macaca mulatta; Placenta; Prospective Studies
PubMed: 37415206
DOI: 10.1186/s13148-023-01519-4 -
International Journal of Molecular... Apr 2024Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal... (Review)
Review
Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia's genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.
Topics: Humans; Pre-Eclampsia; Female; Pregnancy; Placenta; Biomarkers; MicroRNAs; Hormones; Trophoblasts
PubMed: 38674114
DOI: 10.3390/ijms25084532 -
Environment International Aug 2023Human chorionic gonadotropin (hCG) is produced by the placenta and plays an essential role in the maintenance of pregnancy. Endocrine disrupting chemicals (EDCs) have...
BACKGROUND
Human chorionic gonadotropin (hCG) is produced by the placenta and plays an essential role in the maintenance of pregnancy. Endocrine disrupting chemicals (EDCs) have the potential to interfere with functions related to the production and secretion of hCG; however associations between exposure to EDCs and hCG concentrations in humans remain to be elucidated.
OBJECTIVES
To investigate the association of urinary, serum and plasma concentrations of EDCs during pregnancy with serum hCG concentrations.
METHODS
We utilized data form the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy (SELMA) study. We investigated the association of 26 EDCs measured in early pregnancy urine or blood with serum hCG concentrations using multi-variable adjusted linear regression models per EDC and Weighted Quantile Sum (WQS) regression with repeated holdout validation for the EDCs mixture.
RESULTS
In 2,039 included women, higher exposure to bisphenol A was associated with lower hCG (beta [95% CI]: -0.06 [-0.11 to -0.002]) while higher triclosan exposure was associated with a higher hCG (0.02 [0.003 to 0.04]). Higher exposure to several phthalates, including mono-ethyl and mono-butyl phthalates (MEP and MBP) as well as metabolites of di-2-ethylhexyl phthalate (DEHP) was associated with a lower hCG (beta [95% CI] for sum of DEHP metabolites: -0.13 [-0.19 to -0.07]). Likewise, higher exposure to several polychlorinated biphenyls (PCBs) was associated with a lower hCG. In the WQS regression, each quartile increase in the EDCs mixture was associated with -0.27 lower hCG (95% CI: -0.34 to -0.19).
DISCUSSION
Higher exposure to several EDCs during pregnancy was associated with a lower hCG; and despite the small effect sizes, still indicating that the exposure may negatively affect production or secretion of hCG by the placenta. Our results provide the impetus for future experimental studies to investigate the placenta as a target organ for adverse effects of EDCs.
Topics: Pregnancy; Child; Humans; Female; Endocrine Disruptors; Diethylhexyl Phthalate; Polychlorinated Biphenyls; Longitudinal Studies; Phthalic Acids; Chorionic Gonadotropin; Environmental Pollutants; Environmental Exposure
PubMed: 37459690
DOI: 10.1016/j.envint.2023.108091 -
Reproduction (Cambridge, England) Jul 2023Healthy development of the placenta is dependent on trophoblast cell migration and reduced oxidative stress presence. This article describes how a phytoestrogen found in...
IN BRIEF
Healthy development of the placenta is dependent on trophoblast cell migration and reduced oxidative stress presence. This article describes how a phytoestrogen found in spinach and soy causes impaired placental development during pregnancy.
ABSTRACT
Although vegetarianism has grown in popularity, especially among pregnant women, the effects of phytoestrogens in placentation lack understanding. Factors such as cellular oxidative stress and hypoxia and external factors including cigarette smoke, phytoestrogens, and dietary supplements can regulate placental development. The isoflavone phytoestrogen coumestrol was identified in spinach and soy and was found to not cross the fetal-placental barrier. Since coumestrol could be a valuable supplement or potent toxin during pregnancy, we sought to examine its role in trophoblast cell function and placentation in murine pregnancy. After treating trophoblast cells (HTR8/SVneo) with coumestrol and performing an RNA microarray, we determined 3079 genes were significantly changed with the top differentially changed pathways related to the oxidative stress response, cell cycle regulation, cell migration, and angiogenesis. Upon treatment with coumestrol, trophoblast cells exhibited reduced migration and proliferation. Additionally, we observed increased reactive oxygen species accumulation with coumestrol administration. We then examined the role of coumestrol within an in vivo pregnancy by treating wildtype pregnant mice with coumestrol or vehicle from day 0 to 12.5 of gestation. Upon euthanasia, fetal and placental weights were significantly decreased in coumestrol-treated animals with the placenta exhibiting a proportional decrease with no obvious changes in morphology. Therefore, we conclude that coumestrol impairs trophoblast cell migration and proliferation, causes accumulation of reactive oxygen species, and reduces fetal and placental weights in murine pregnancy.
Topics: Pregnancy; Female; Mice; Humans; Animals; Placenta; Coumestrol; Phytoestrogens; Reactive Oxygen Species; Cell Line; Placentation; Trophoblasts; Oxidative Stress
PubMed: 37078791
DOI: 10.1530/REP-23-0017 -
Clinical Epigenetics Aug 2023Gestational diabetes mellitus (GDM), characterized by hyperglycemia that develops during pregnancy, increases the risk of fetal macrosomia, childhood obesity and...
BACKGROUND
Gestational diabetes mellitus (GDM), characterized by hyperglycemia that develops during pregnancy, increases the risk of fetal macrosomia, childhood obesity and cardiometabolic disorders later in life. This process has been attributed partly to DNA methylation modifications in growth and stress-related pathways. Nutrients involved with one-carbon metabolism (OCM), such as folate, choline, betaine, and vitamin B, provide methyl groups for DNA methylation of these pathways. Therefore, this study aimed to determine whether maternal OCM nutrient intakes and levels modified fetal DNA methylation and in turn altered fetal growth patterns in pregnancies with and without GDM.
RESULTS
In this prospective study at a single academic institution from September 2016 to June 2019, we recruited 76 pregnant women with and without GDM at 25-33 weeks gestational age and assessed their OCM nutrient intake by diet recalls and measured maternal blood OCM nutrient levels. We also collected placenta and cord blood samples at delivery to examine fetal tissue DNA methylation of the genes that modify fetal growth and stress response such as insulin-like growth factor 2 (IGF2) and corticotropin-releasing hormone (CRH). We analyzed the association between maternal OCM nutrients and fetal DNA methylation using a generalized linear mixed model. Our results demonstrated that maternal choline intake was positively correlated with cord blood CRH methylation levels in both GDM and non-GDM pregnancies (r = 0.13, p = 0.007). Further, the downstream stress hormone cortisol regulated by CRH was inversely associated with maternal choline intake (r = - 0.36, p = 0.021). Higher maternal betaine intake and serum folate levels were associated with lower cord blood and placental IGF2 DNA methylation (r = - 0.13, p = 0.049 and r = - 0.065, p = 0.034, respectively) in both GDM and non-GDM pregnancies. Further, there was an inverse association between maternal betaine intake and birthweight of infants (r = - 0.28, p = 0.015).
CONCLUSIONS
In conclusion, we observed a complex interrelationship between maternal OCM nutrients and fetal DNA methylation levels regardless of GDM status, which may, epigenetically, program molecular pathways related to fetal growth and stress response.
Topics: DNA Methylation; Humans; Female; Diabetes, Gestational; Pregnancy; Fetus; Folic Acid; Promoter Regions, Genetic; Prospective Studies
PubMed: 37633918
DOI: 10.1186/s13148-023-01554-1 -
Medicina (Kaunas, Lithuania) Sep 2023Stroke during pregnancy and preeclampsia are two distinct but interrelated medical conditions, sharing a common denominator-blood control failure. Along with... (Review)
Review
Stroke during pregnancy and preeclampsia are two distinct but interrelated medical conditions, sharing a common denominator-blood control failure. Along with cardiovascular diseases, diabetes, dyslipidemia, and hypercoagulability, hypertension is undoubtedly a major risk factor associated with stroke. Even though men have higher age-specific stroke rates, women are facing higher life-long stroke risk, primarily due to longer life expectancy. Sex hormones, especially estrogen and testosterone, seem to play a key link in the chain of blood pressure control differences between the genders. Women affected with stroke are more susceptible to experience some atypical stroke manifestations, which might eventually lead to delayed diagnosis establishment, and result in higher morbidity and mortality rates in the population of women. Preeclampsia is a part of hypertensive disorder of pregnancy spectrum, and it is common knowledge that women with a positive history of preeclampsia are at increased stroke risk during their lifetime. Preeclampsia and stroke display similar pathophysiological patterns, including hypertension, endothelial dysfunction, dyslipidemia, hypercoagulability, and cerebral vasomotor reactivity abnormalities. High-risk pregnancies carrying the burden of hypertensive disorder of pregnancy have up to a six-fold higher chance of suffering from stroke. Resemblance shared between placental and cerebral vascular changes, adaptations, and sophisticated auto-regulatory mechanisms are not merely coincidental, but they reflect distinctive and complex cardiovascular performances occurring in the maternal circulatory system during pregnancy. Placental and cerebral malperfusion appears to be in the midline of both of these conditions; placental malperfusion eventually leads to preeclampsia, and cerebral to stoke. Suboptimal performances of the cardiovascular system are proposed as a primary cause of uteroplacental malperfusion. Placental dysfunction is therefore designated as a secondary condition, initiated by the primary disturbances of the cardiovascular system, rather than an immunological disorder associated with abnormal trophoblast invasion. In most cases, with properly and timely applied measures of prevention, stroke is predictable, and preeclampsia is a controllable condition. Understanding the differences between preeclampsia and stroke in pregnancy is vital for healthcare providers to enhance their clinical decision-making strategies, improve patient care, and promote positive maternal and pregnancy outcomes. Management approaches for preeclampsia and stroke require a multidisciplinary approach involving obstetricians, neurologists, and other healthcare professionals.
Topics: Female; Pregnancy; Humans; Male; Pre-Eclampsia; Placenta; Hypertension; Stroke; Pregnancy Outcome; Thrombophilia; Dyslipidemias
PubMed: 37893425
DOI: 10.3390/medicina59101707 -
International Journal of Molecular... Oct 2023Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disorder clinically presented as Hashimoto thyroiditis (HT) and Graves' disease (GD). The... (Review)
Review
Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disorder clinically presented as Hashimoto thyroiditis (HT) and Graves' disease (GD). The pathogenesis of AITD is caused by an inappropriate immune response related to genetic, non-genetic, and environmental factors. Pregnancy is one of the factors that have a great influence on the function of the thyroid gland because of the increased metabolic demand and the effects of hormones related to pregnancy. During pregnancy, an adaptation of the maternal immune system occurs, especially of the innate immune system engaged in maintaining adaptive immunity in the tolerant state, preventing the rejection of the fetus. Pregnancy-related hormonal changes (estrogen, progesterone, hCG) may modulate the activity of innate immune cells, potentially worsening the course of AITD during pregnancy. This especially applies to NK cells, which are associated with exacerbation of HD and GD. On the other hand, previous thyroid disorders can affect fertility and cause adverse outcomes of pregnancy, such as placental abruption, spontaneous abortion, and premature delivery. Additionally, it can cause fetal growth retardation and may contribute to impaired neuropsychological development of the fetus. Therefore, maintaining the thyroid equilibrium in women of reproductive age and in pregnant women is of the highest importance.
Topics: Female; Humans; Pregnancy; Hashimoto Disease; Placenta; Thyroid Diseases; Autoimmune Diseases; Graves Disease; Immunity, Innate
PubMed: 37895126
DOI: 10.3390/ijms242015442 -
American Journal of Physiology.... Mar 2024Glucagon-like peptide 1 (GLP-1) regulates food intake, insulin production, and metabolism. Our recent study demonstrated that pancreatic α-cells-secreted (intraislet)...
Glucagon-like peptide 1 (GLP-1) regulates food intake, insulin production, and metabolism. Our recent study demonstrated that pancreatic α-cells-secreted (intraislet) GLP-1 effectively promotes maternal insulin secretion and metabolic adaptation during pregnancy. However, the role of circulating GLP-1 in maternal energy metabolism remains largely unknown. Our study aims to investigate systemic GLP-1 response to pregnancy and its regulatory effect on fetal growth. Using C57BL/6 mice, we observed a gradual decline in maternal blood GLP-1 concentrations. Subsequent administration of the GLP-1 receptor agonist semaglutide (Sem) to dams in late pregnancy revealed a modest decrease in maternal food intake during initial treatment. At the same time, no significant alterations were observed in maternal body weight or fat mass. Notably, Sem-treated dams exhibited a significant decrease in fetal body weight, which persisted even following the restoration of maternal blood glucose levels. Despite no observable change in placental weight, a marked reduction in the placenta labyrinth area from Sem-treated dams was evident. Our investigation further demonstrated a substantial decrease in the expression levels of various pivotal nutrient transporters within the placenta, including glucose transporter one and sodium-neutral amino acid transporter one, after Sem treatment. In addition, Sem injection led to a notable reduction in the capillary area, number, and surface densities within the labyrinth. These findings underscore the crucial role of modulating circulating GLP-1 levels in maternal adaptation, emphasizing the inhibitory effects of excessive GLP-1 receptor activation on both placental development and fetal growth. Our study reveals a progressive decline in maternal blood glucagon-like peptide 1 (GLP-1) concentration. GLP-1 receptor agonist injection in late pregnancy significantly reduced fetal body weight, even after restoration of maternal blood glucose concentration. GLP-1 receptor activation significantly reduced the placental labyrinth area, expression of some nutrient transporters, and capillary development. Our study indicates that reducing maternal blood GLP-1 levels is a physiological adaptation process that benefits placental development and fetal growth.
Topics: Animals; Female; Mice; Pregnancy; Blood Glucose; Fetal Development; Fetal Weight; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide-1 Receptor Agonists; Mice, Inbred C57BL; Placenta
PubMed: 38197791
DOI: 10.1152/ajpendo.00361.2023 -
Microbiome Feb 2024Bisphenol A (BPA) is an environmental contaminant with endocrine-disrupting properties that induce fetal growth restriction (FGR). Previous studies on pregnant ewes...
Gut microbiota contributes to bisphenol A-induced maternal intestinal and placental apoptosis, oxidative stress, and fetal growth restriction in pregnant ewe model by regulating gut-placental axis.
BACKGROUND
Bisphenol A (BPA) is an environmental contaminant with endocrine-disrupting properties that induce fetal growth restriction (FGR). Previous studies on pregnant ewes revealed that BPA exposure causes placental apoptosis and oxidative stress (OS) and decreases placental efficiency, consequently leading to FGR. Nonetheless, the response of gut microbiota to BPA exposure and its role in aggravating BPA-mediated apoptosis, autophagy, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and OS of the maternal placenta and intestine are unclear in an ovine model of gestation.
RESULTS
Two pregnant ewe groups (n = 8/group) were given either a subcutaneous (sc) injection of corn oil (CON group) or BPA (5 mg/kg/day) dissolved in corn oil (BPA group) once daily, from day 40 to day 110 of gestation. The maternal colonic digesta and the ileum and placental tissue samples were collected to measure the biomarkers of autophagy, apoptosis, mitochondrial dysfunction, ERS, and OS. To investigate the link between gut microbiota and the BPA-induced FGR in pregnant ewes, gut microbiota transplantation (GMT) was conducted in two pregnant mice groups (n = 10/group) from day 0 to day 18 of gestation after removing their intestinal microbiota by antibiotics. The results indicated that BPA aggravates apoptosis, ERS and autophagy, mitochondrial function injury of the placenta and ileum, and gut microbiota dysbiosis in pregnant ewes. GMT indicated that BPA-induced ERS, autophagy, and apoptosis in the ileum and placenta are attributed to gut microbiota dysbiosis resulting from BPA exposure.
CONCLUSIONS
Our findings indicate the underlying role of gut microbiota dysbiosis and gut-placental axis behind the BPA-mediated maternal intestinal and placental apoptosis, OS, and FGR. The findings further provide novel insights into modulating the balance of gut microbiota through medication or probiotics, functioning via the gut-placental axis, to alleviate gut-derived placental impairment or FGR. Video Abstract.
Topics: Humans; Pregnancy; Sheep; Female; Animals; Mice; Placenta; Gastrointestinal Microbiome; Fetal Growth Retardation; Dysbiosis; Corn Oil; Oxidative Stress; Mitochondrial Diseases; Benzhydryl Compounds; Phenols
PubMed: 38365714
DOI: 10.1186/s40168-024-01749-5 -
Biology of Reproduction Aug 2023The present study aimed to investigate the regulation of placentas and uterus remodeling and involvement of estradiol in gestational diabetes mellitus. To achieve this,...
The present study aimed to investigate the regulation of placentas and uterus remodeling and involvement of estradiol in gestational diabetes mellitus. To achieve this, we established in vitro and in vivo models for gestational diabetes mellitus placentas by culturing human placental choriocarcinoma cells (BeWo) under hyperglycemic concentration and treating pregnant rats with streptozotocin. We evaluated the expression of angiogenesis-related proteins. The expression of the anti-angiogenic factor, excess placental soluble fms-like tyrosine kinase 1 was increased in our in vitro gestational diabetes mellitus model compared with the control. Moreover, the expressions of placental soluble fms-like tyrosine kinase 1 and the von Willebrand factor were also significantly elevated in the placenta of streptozotocin-treated rats. These data indicate the disruption of angiogenesis in the gestational diabetes mellitus placentas. The expression levels of connexin 43, a component of the gap junction and collagen type I alpha 2 chain, a component of the extracellular matrix, were decreased in the gestational diabetes mellitus uterus. These results suggest that uterus decidualization and placental angiogenesis are inhibited in gestational diabetes mellitus rats. Our results also showed upregulation of the expression of genes regulating estradiol synthesis as well as estrogen receptors in vivo models. Accordingly, the concentration of estradiol measured in the culture medium under hyperglycemic conditions, as well as in the serum and placenta of the streptozotocin-treated rats, was significantly elevated compared with the control groups. These results suggest that the dysregulated remodeling of the placenta and uterus may result in the elevation of estradiol and its signaling pathway in the gestational diabetes mellitus animal model to maintain pregnancy.
Topics: Pregnancy; Female; Rats; Animals; Humans; Placenta; Diabetes, Gestational; Vascular Endothelial Growth Factor Receptor-1; Streptozocin; Uterus; Estradiol; Vascular Endothelial Growth Factor A
PubMed: 37255320
DOI: 10.1093/biolre/ioad059