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1.
Ecotoxicol Environ Saf ; 207: 111281, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32919195

RESUMO

Epidemiological studies of human and animal experiments indicated that gestational exposure to atmospheric pollutants could be followed by the abnormal placental development. However, the effects of this exposure on the placental transportation for nutrients have not been systematically investigated. In this study, fine particulate matters (PM2.5) samples were collected in Taiyuan and pregnant rodent models were administered with 3 mg/kg b.w. PM2.5 by oropharyngeal aspiration every other day starting on embryonic day 0.5 (E0.5). Then the pregnant mice were sacrificed and their placentas were collected at different time points. The results showed that maternal PM2.5 exposure (MPE) disrupted the expression of proliferating cell nuclear antigen (PCNA) at all time points and inhibited the cell proliferation in placenta. Following that, the capacity for placental nutrient transport was impaired. The changes at E18.5 were observed most significantly, showing the altered mRNA expression of amino acid, long-chain polyunsaturated fatty acid (LCPUFA), glucose and folate transporters. In addition, the glycogen content was elevated at E18.5, and the triglyceride content was increased at E13.5 and E15.5 and decreased at E18.5 in the placenta after MPE. In a word, the adverse effect induced by MPE revealed that MPE led tothe disruption on the nutrient supply to the developing fetus via modulating the abundance of placental nutrient transporters (PNT).


Assuntos
Poluentes Atmosféricos/toxicidade , Exposição Materna/efeitos adversos , Nutrientes/metabolismo , Material Particulado/toxicidade , Placenta/efeitos dos fármacos , Poluentes Atmosféricos/metabolismo , Aminoácidos/metabolismo , Animais , Transporte Biológico , Proliferação de Células/efeitos dos fármacos , Ácidos Graxos/metabolismo , Feminino , Glucose/metabolismo , Glicogênio/metabolismo , Humanos , Troca Materno-Fetal/efeitos dos fármacos , Camundongos , Material Particulado/metabolismo , Placenta/metabolismo , Placenta/patologia , Gravidez
2.
Life Sci ; 261: 118314, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32835699

RESUMO

AIMS: Placental tissues from patients with preeclampsia (PE) and in the lipopolysaccharide (LPS)-induced PE-like model were used to investigate the implication of placental inflammation and apoptosis in PE. Whether the beneficial effects of nicotine are related to inhibition of placental inflammation and apoptosis in the PE-like model were investigated. MAIN METHODS: Placental apoptosis was detected in PE patients and the PE-like rat model by TUNEL staining. Changes in the number of CD68+ macrophages in placental tissues from PE patients were detected by immunofluorescent staining. The mRNA expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin (IL-1ß), MCP-1, and proteins involved in extrinsic or intrinsic apoptosis signaling in the PE-like model was determined by qRT-PCR; immunofluorescent staining was used to detect the expression of TNF-α receptor (TNFR1), MCP-1 and apoptosis-related proteins. KEY FINDINGS: Placental apoptosis was increased in both PE patients and the PE-like model, more macrophages infiltrated into placenta in PE patients. A significant upregulation in mRNA expression of TNF-α, IL-1ß, MCP-1, and caspase 3, caspase 8, caspase 9 was found in the PE-like rats compared to the control animals, the immunoreactivity of placental MCP-1, TNFR1, and apoptosis-related proteins (caspase 3, caspase 8, caspase 9, Bax) was also enhanced; nicotine treatment significantly reversed those changes. SIGNIFICANCE: Our data suggests that the protective effects of nicotine are associated with inhibiting placenta inflammation and apoptosis, and nicotine might be a potentially therapeutic candidate for preventing preeclampsia.


Assuntos
Inflamação/tratamento farmacológico , Nicotina/farmacologia , Placenta/efeitos dos fármacos , Pré-Eclâmpsia/prevenção & controle , Adulto , Animais , Apoptose/efeitos dos fármacos , Estudos de Casos e Controles , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Marcação In Situ das Extremidades Cortadas , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Macrófagos/metabolismo , Placenta/patologia , Pré-Eclâmpsia/patologia , Gravidez , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Adulto Jovem
3.
Environ Toxicol ; 35(12): 1395-1405, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32790152

RESUMO

Per- and polyfluoroalkyl substances (PFAS), a class of environmental contaminants, have been detected in human placenta and cord blood. The mechanisms driving PFAS-induced effects on the placenta and adverse pregnancy outcomes are not well understood. This study investigated the impact of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and a replacement PFAS known as hexafluoropropylene oxide dimer acid (HFPO-DA, tradename GenX) on placental trophoblasts in vitro. Several key factors were addressed. First, PFAS levels in cell culture reagents at baseline were quantified. Second, the role of supplemental media serum in intracellular accumulation of PFAS in a human trophoblast (JEG3) cell line was established. Finally, the impact of PFAS on the expression of 96 genes involved in proper placental function in JEG3 cells was evaluated. The results revealed that serum-free media (SFM) contained no detectable PFAS. In contrast, fetal bovine serum-supplemented media (SSM) contained PFNA, PFUdA, PFTrDA, and 6:2 FTS, but these PFAS were not detected internally in cells. Intracellular accumulation following 24 hr treatments was significantly higher when cultured in SFM compared to SSM for PFOS and PFOA, but not HFPO-DA. Treatment with PFAS was associated with gene expression changes (n = 32) in pathways vital to placental function, including viability, syncytialization, inflammation, transport, and invasion/mesenchymal transition. Among the most robust PFAS-associated changes were those observed in the known apoptosis-related genes, BAD and BAX. These results suggest a complex relationship between PFAS, in vitro culture conditions, and altered expression of key genes necessary for proper placentation.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Caprilatos/toxicidade , Fluorcarbonetos/toxicidade , Expressão Gênica/efeitos dos fármacos , Placenta/efeitos dos fármacos , Soro/química , Trofoblastos/efeitos dos fármacos , Ácidos Alcanossulfônicos/sangue , Ácidos Alcanossulfônicos/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Bioacumulação/efeitos dos fármacos , Bioacumulação/genética , Caprilatos/sangue , Caprilatos/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Meios de Cultura Livres de Soro , Feminino , Fluorcarbonetos/sangue , Fluorcarbonetos/metabolismo , Humanos , Placenta/metabolismo , Gravidez , RNA Mensageiro/genética , Trofoblastos/metabolismo
4.
Artigo em Chinês | MEDLINE | ID: mdl-32746565

RESUMO

Objective: To investigate the effect of perfluorooctane sulfonate (PFOS) on inflammatory factors in human placental trophoblast (HTR-8/Svneo) cells. Methods: HTR-8/Svneo cells were exposed to different concentrations of PFOS (0, 0.01, 0.1, 1.0 mg/L) for 24 h, and the cell survival rates were measured by CCK8. Secretion levels of interleukin-6 (IL-6) , tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) were detected by ELISA. The mRNA expressions of IL-6, TNF-α and IL-10 were detected by fluorescence quantitative PCR. One-way ANOVA was used to analyse the expressions of inflammatory factors. Results: Compared with the control group, the survival rates of 0.1 and 1.0 mg/L PFOS groups were significantly decreased (P<0.05) . Compared with the control group, the secretion levels of IL-6 were decreased in the 0.01, 0.1 and 1.0 mg/L PFOS groups (P<0.05) , the concentrations of TNF-α were increased in the 0.01 and 1.0 mg/L PFOS groups (P<0.05) , and the concentrations of IL-10 were increased in the 0.1 and 1.0 mg/L PFOS groups (P<0.05) . Compared with the control group, the expressions of IL-6 mRNA were increased in the 0.1 and 1.0 mg/L PFOS groups (P<0.05) , and the expressions of IL-10 mRNA were decreased in the 0.01 mg/L, 0.1 mg/L and 1.0 mg/L PFOS groups (P<0.05) . Conclusion: PFOS can induce changes in the secretion levels of inflammatory cytokines in HTR-8/Svneo cells, resulting in decreased activity of placental trophoblast cells and abnomal placental function.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Fluorcarbonetos/toxicidade , Placenta/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos , Feminino , Humanos , Gravidez , Testes de Toxicidade , Fator de Necrose Tumoral alfa/genética
5.
Environ Toxicol ; 35(11): 1161-1169, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32515542

RESUMO

The adverse outcomes of silver nanoparticles (AgNPs) on pregnancy have been studied in murine animals. However, the potential toxicity of AgNPs to immune balance, which is essential for maintaining a normal pregnancy, still requires further exploration. Therefore, this study assessed the effect of AgNPs on the immune balance during gestation time. Pregnant mice were given a dose of 1 mg/kg of AgNPs and silver ion on gestation days 3.5 to 9.5 by tail vein injection. Results showed that the AgNPs and silver ion decreased the number of CD4+ CD25+ Treg cells which were the important cells in the immune system, thereby disrupting the balance of normal immune tolerance function, activated the inflammatory responses, together with the reductive production of placental immunoregulatory genes, and the expression of inflammatory factors in the placenta in the Ag-treated groups increased. These effects increased the absorption rate. Furthermore, the inflammatory signaling pathway p38MAPK/AP-1/MMP-9 in the placenta was activated, indicating that Ag induced inflammation through this signaling pathway. All results indicated that undesirable pregnancy outcome caused by AgNPs could be happened by stimulating immunological dysfunction. Therefore, the potential risks to embryogenesis exposure to AgNPs that caused immune imbalance should be given sufficient attention.


Assuntos
Sistema Imunitário/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Animais , Desenvolvimento Embrionário , Feminino , Camundongos , Placenta/efeitos dos fármacos , Gravidez
6.
PLoS One ; 15(6): e0235217, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32574225

RESUMO

In sheep, polyunsaturated fatty acid (PUFA) supplementations in late gestation increases the growth of offspring; however, there is a lack of evidence on the effect of PUFA supplementation during early gestation. Thus, the objective of this study was to evaluate the effect of dietary supplementation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in early gestation pregnant ewes on fatty acid concentration of fetal liver (FL) and fetal central nervous system (FCNS), and relative abundance of the mRNA for genes associated with transport and metabolism of fatty acids in FL and placenta. A total of 12 ewes, block for stage of gestation were fed a diet containing 1.6% (dry matter basis) monounsaturated fatty acids (MUFA) or EPA+DHA during the first 45 days of gestation. A cesarean section was conducted on day 45 of gestation to collect placenta (caruncle and cotyledon), FL, and FCNS. Relative abundance of mRNA in FL and FCNS and fatty acid concentration were analyzed using a 2x2 factorial arrangement of treatments considering fatty acid supplementation and tissue as the main factors. Concentrations of C18:1 isomers increase (P < 0.05) in FL and FCNS with MUFA supplementation; the FL and FCNS had a greater concentration of C20:3(n-6), C20:3(n-3), C22:1, C22:5 and C22:6 (P < 0.05) with EPA+DHA supplementation. In FL, the relative abundance of LPL mRNA was greater (P = 0.02) as a result of MUFA supplementation. In placenta, there was a FA x tissue interaction for relative abundance of DNMT3b and FFAR-4 mRNA (P < 0.05). Fetus from MUFA-supplemented dams had a greater relative abundance of FABP-4 mRNA (P < 0.05). Results indicate supplementation with EPA+DHA during early gestation increases the total EPA and DHA in FL. For the placenta, EPA+DHA supplementation led to an increase in the relative abundance of lipid mRNA for transport genes.


Assuntos
Sistema Nervoso Central/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/análogos & derivados , Ácidos Graxos/análise , Feto/efeitos dos fármacos , Placenta/efeitos dos fármacos , RNA Mensageiro/metabolismo , Animais , DNA (Citosina-5-)-Metiltransferases/genética , Suplementos Nutricionais , Ácido Eicosapentaenoico/farmacologia , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos/química , Feminino , Feto/metabolismo , Idade Gestacional , Lipase Lipoproteica/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Placenta/metabolismo , Gravidez , Ovinos
7.
PLoS One ; 15(4): e0232140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353010

RESUMO

BACKGROUND: Congenital cytomegalovirus infection can lead to severe sequelae. When fetal infection is confirmed, we hypothesize that fetal treatment could improve the outcome. Maternal oral administration of an effective drug crossing the placenta could allow fetal treatment. Letermovir (LMV) and Maribavir (MBV) are new CMV antivirals, and potential candidates for fetal treatment. METHODS: The objective was to investigate the placental transfer of LMV and MBV in the ex vivo method of the human perfused cotyledon. Term placentas were perfused, in an open-circuit model, with LMV or MBV at concentrations in the range of clinical peak plasma concentrations. Concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. Mean fetal transfer rate (FTR) (fetal (FC) /maternal concentration), clearance index (CLI), accumulation index (AI) (retention of each drug in the cotyledon tissue) were measured. Mean FC were compared with half maximal effective concentrations of the drugs (EC50(LMV) and EC50(MBV)). RESULTS: For LMV, the mean FC was (± standard deviation) 1.1 ± 0.2 mg/L, 1,000-fold above the EC50(LMV). Mean FTR, CLI and AI were 9 ± 1%, 35 ± 6% and 4 ± 2% respectively. For MBV, the mean FC was 1.4 ± 0.2 mg/L, 28-fold above the EC50(MBV). Mean FTR, CLI and AI were 10 ± 1%, 50 ± 7% and 2 ± 1% respectively. CONCLUSIONS: Drugs' concentrations in the fetal side should be in the range for in utero treatment of fetuses infected with CMV as the mean FC was superior to the EC50 for both molecules.


Assuntos
Infecções por Citomegalovirus/tratamento farmacológico , Troca Materno-Fetal/efeitos dos fármacos , Placenta/efeitos dos fármacos , Acetatos/farmacologia , Adulto , Antivirais/farmacologia , Benzimidazóis/farmacologia , Cromatografia Líquida/métodos , Feminino , Humanos , Cinética , Modelos Biológicos , Perfusão , Gravidez , Quinazolinas/farmacologia , Ribonucleosídeos/farmacologia , Espectrometria de Massas em Tandem/métodos
8.
Vasc Med ; 25(4): 295-301, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32469270

RESUMO

Preeclampsia is a life-threatening multiorgan systemic disease with manifestations including gestational hypertension, oxidative stress, and vascular dysfunction. We aimed to evaluate the therapeutic effects of melatonin on an L-NAME (NLG-nitro-l-arginine methyl ester)-induced rat preeclampsia model. During gestation, L-NAME was added to drinking water at 50 mg/kg/day from gestation day (GD) 8. Rats received the combination of L-NAME with melatonin (10 mg/kg/day), or aspirin (1.5 mg/kg/day), and rats that received only L-NAME or no treatments were used as controls. Aspirin was mixed with rodent chow and melatonin was administered intraperitoneally. Blood pressure and urine protein content were monitored every 3 days. On GD19, blood samples were collected for biochemical analysis. Compared to untreated L-NAME rats, melatonin led to markedly lowered blood pressure and urine protein content, and recovery in the fetus alive ratio, fetal weight, and the fetal weight/placental weight ratio. Compared to untreated L-NAME rats, plasma antioxidant capacity and plasma malondialdehyde were increased and decreased by melatonin, respectively, in L-NAME rats. Melatonin treatment also reduced sFlt-1, increased PlGF, and decreased the sFlt-1/PlGF ratio. In the placenta, melatonin also reduced sFlt-1 levels and increased Nrf2, PlGF, and HO-1 levels. We have demonstrated in a rat model of preeclampsia that melatonin exerts significant protective effects through lowering blood pressure and reducing oxidative stress.


Assuntos
Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão Induzida pela Gravidez/prevenção & controle , Melatonina/farmacologia , NG-Nitroarginina Metil Éster , Estresse Oxidativo/efeitos dos fármacos , Placenta/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Heme Oxigenase (Desciclizante)/metabolismo , Hipertensão Induzida pela Gravidez/induzido quimicamente , Hipertensão Induzida pela Gravidez/metabolismo , Hipertensão Induzida pela Gravidez/fisiopatologia , Fator 2 Relacionado a NF-E2/metabolismo , Placenta/metabolismo , Placenta/fisiopatologia , Fator de Crescimento Placentário/metabolismo , Gravidez , Proteinúria/induzido quimicamente , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Proteinúria/prevenção & controle , Ratos Sprague-Dawley , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo
9.
Artigo em Inglês | MEDLINE | ID: mdl-32260232

RESUMO

A relatively large branched-chain amino acid (BCAA) supplement, consumed for more than 10 days, appears to be especially effective at alleviating muscle damage and soreness during intense human training. However, perturbations in amino acid and protein consumption could have unwanted transgenerational effects on male and female reproduction. This paper hypothesizes that isoleucine consumption by female mice from days 2 to 10 of pregnancy will alter fetal and placental growth later in gestation. Mice that had received 118 mM isoleucine in their drinking water delivered pups on day 19 of pregnancy that were 9% larger than normal, whereas the reverse was true for pups born on day 20. Moreover, the inverse correlation between birth weight and litter size was lost in mice that previously consumed excess isoleucine. Similarly, the normal correlations between fetal and placental weights were lost by day 18 of pregnancy in mice that had consumed excess isoleucine. Mice that consumed excess isoleucine had placentas smaller than, and fetuses larger than normal on day 18 of pregnancy, but the reverse was true on day 15. Other unintended and unexpected effects of BCAA consumption should be studied more thoroughly due to the increasing use of BCAAs to alleviate muscle damage and soreness in athletes.


Assuntos
Aminoácidos de Cadeia Ramificada , Suplementos Nutricionais , Desenvolvimento Fetal , Músculo Esquelético , Placentação , Aminoácidos de Cadeia Ramificada/efeitos adversos , Animais , Atletas , Suplementos Nutricionais/efeitos adversos , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Humanos , Camundongos , Placenta/efeitos dos fármacos , Placentação/efeitos dos fármacos , Gravidez
10.
Toxicol Appl Pharmacol ; 394: 114960, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32201330

RESUMO

During pregnancy, fetal thyroid hormones (THs) are dependent on maternal placental transport and their physiological level is crucial for normal fetal neurodevelopment. Earlier research has shown that Di-(2-ethylhexyl) phthalate (DEHP) disrupts thyroid function and THs homeostasis in pregnant women and fetuses, and affects placental THs transport. However, the underlying mechanisms are poorly understood. The present study, therefore, aimed to systematically investigate the potential mechanisms of DEHP-induced disruption in the placental THs transport using two human placental trophoblastic cells, HTR-8/SVneo cells and JEG-3 cells. While the exposure of DEHP at the doses of 0-400 µM for 24 h did not affect cell viability, we found reduced consumption of T3 and T4 in the culture medium of HTR-8/Svneo cells treated with DEHP at 400 µM. DEHP treatment did not affect T3 uptake and the expression of monocarboxylate transporters 8 (MCT8) and organic anion transporters 1C1 (OATP1C1). However, DEHP significantly inhibited transthyretin (TTR) internalization, down-regulated TTR, deiodinase 2 (DIO2), and thyroid hormone receptors mRNA expression and protein levels, and up-regulated deiodinase 3 (DIO3) protein levels in a dose-dependent manner. These results indicate that DEHP acts on placental trophoblast cells, inhibits its TTR internalization, down-regulates TTR expression and affects the expression of DIO2, DIO3, and thyroid hormone receptor. These may be the mechanisms by which PAEs affects THs transport through placental.


Assuntos
Dietilexilftalato/toxicidade , Placenta/metabolismo , Pré-Albumina/metabolismo , Trofoblastos/metabolismo , Adulto , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Humanos , Iodeto Peroxidase/antagonistas & inibidores , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Placenta/citologia , Placenta/efeitos dos fármacos , Pré-Albumina/biossíntese , Gravidez , Receptores dos Hormônios Tireóideos/biossíntese , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Simportadores/antagonistas & inibidores , Hormônios Tireóideos/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/biossíntese , Trofoblastos/efeitos dos fármacos
11.
Nitric Oxide ; 99: 7-16, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32165314

RESUMO

Insulin regulates the l-arginine/nitric oxide (NO) pathway in human umbilical vein endothelial cells (HUVECs), increasing the plasma membrane expression of the l-arginine transporter hCAT-1 and inducing vasodilation in umbilical and placental veins. Placental vascular relaxation induced by insulin is dependent of large conductance calcium-activated potassium channels (BKCa), but the role of KCa channels on l-arginine transport and NO synthesis is still unknown. The aim of this study was to determine the contribution of KCa channels in both insulin-induced l-arginine transport and NO synthesis, and its relationship with placental vascular relaxation. HUVECs, human placental vein endothelial cells (HPVECs) and placental veins were freshly isolated from umbilical cords and placenta from normal pregnancies. Cells or tissue were incubated in absence or presence of insulin and/or tetraethylammonium, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole, iberiotoxin or NG-nitro-l-arginine methyl ester. l-Arginine uptake, plasma membrane polarity, NO levels, hCAT-1 expression and placenta vascular reactivity were analyzed. The inhibition of intermediate-conductance KCa (IKCa) and BKCa increases l-arginine uptake, which was related with protein abundance of hCAT-1 in HUVECs. IKCa and BKCa activities contribute to NO-synthesis induced by insulin but are not directly involved in insulin-stimulated l-arginine uptake. Long term incubation (8 h) with insulin increases the plasma membrane hyperpolarization and hCAT-1 expression in HUVECs and HPVECs. Insulin-induced relaxation in placental vasculature was reversed by KCa inhibition. The results show that the activity of IKCa and BKCa channels are relevant for both physiological regulations of NO synthesis and vascular tone regulation in the human placenta, acting as a part of negative feedback mechanism for autoregulation of l-arginine transport in HUVECs.


Assuntos
Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Alta/metabolismo , Óxido Nítrico/metabolismo , Veias Umbilicais/metabolismo , Adulto , Arginina/metabolismo , Transportador 1 de Aminoácidos Catiônicos/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Insulina/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/antagonistas & inibidores , Canais de Potássio Ativados por Cálcio de Condutância Alta/antagonistas & inibidores , Peptídeos/farmacologia , Placenta/efeitos dos fármacos , Placenta/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Gravidez , Pirazóis/farmacologia , Veias Umbilicais/efeitos dos fármacos , Adulto Jovem
12.
Clin Sci (Lond) ; 134(6): 571-592, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32129440

RESUMO

Gestational diabetes mellitus (GDM) is a global health issue, whereby pregnant women are afflicted with carbohydrate intolerance with first onset during pregnancy. GDM is characterized by maternal peripheral insulin resistance, thought to be driven by low-grade maternal inflammation. Nobiletin, a polymethoxylated flavonoid, possesses potent glucose-sensitizing and anti-inflammatory properties; however, its effects in GDM have not been assessed. The present study aimed to determine the effects of nobiletin on glucose metabolism and inflammation associated with GDM in both in vitro human tissues and an in vivo animal model of GDM. In vitro, treatment with nobiletin significantly improved TNF-impaired glucose uptake in human skeletal muscle, and suppressed mRNA expression and protein secretion of pro-inflammatory cytokines and chemokines in human placenta and visceral adipose tissue (VAT). Mechanistically, nobiletin significantly inhibited Akt and Erk activation in placenta, and NF-κB activation in VAT. In vivo, GDM mice treated with 50 mg/kg nobiletin daily via oral gavage from gestational day (gd) 1-17 or via i.p. injections from gd 10-17 significantly improved glucose tolerance. Pregnant GDM mice treated with nobiletin from either gd 1-17 or gd 10-17 exhibited significantly suppressed mRNA expression of pro-inflammatory cytokines and chemokines in placenta, VAT and subcutaneous adipose tissue (SAT). Using a quantitative mass spectrometry approach, we identified differentially abundant proteins associated with the effect of nobiletin in vivo. Together, these studies demonstrate that nobiletin improves glucose metabolism and reduces inflammation associated with GDM and may be a novel therapeutic for the prevention of GDM.


Assuntos
Anti-Inflamatórios/administração & dosagem , Diabetes Gestacional/tratamento farmacológico , Flavonas/administração & dosagem , Hipoglicemiantes/administração & dosagem , Animais , Citocinas/imunologia , Diabetes Gestacional/genética , Diabetes Gestacional/imunologia , Diabetes Gestacional/metabolismo , Modelos Animais de Doenças , Feminino , Glucose/metabolismo , Humanos , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Placenta/efeitos dos fármacos , Placenta/imunologia , Placenta/metabolismo , Gravidez , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismo
13.
Clin Sci (Lond) ; 134(5): 459-472, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32068238

RESUMO

Antiphospholipid autoantibodies (aPLs), a major maternal risk factor for preeclampsia, are taken into the syncytiotrophoblast where they bind intracellular vesicles and mitochondria. Subsequently, large quantities of extracellular vesicles (EVs) extruded from syncytiotrophoblast into the maternal circulation are altered such that they cause maternal endothelial cell activation. However, the mechanism driving this change is unknown. First trimester placental explants were treated with aPL for 18 h. The EVs were then collected by different centrifugation. The levels of HSP 70, misfolded proteins, caspase 8 activity, and Mixed Lineage Kinase domain-Like (MLKL) were measured in placental explants and EVs. In addition, the levels of TNF-α and CD95 in conditioned medium were also measured. Treating placental explants with aPL caused an increase in levels of HSP 70, misfolded proteins and MLKL in placental explants and EVs. Increased activity of caspase 8 was also seen in placental explants. Higher levels of TNF-α were seen conditioned medium from aPL-treated placental explant cultures. aPLs appear to induce endoplasmic reticulum stress in the syncytiotrophoblast in a manner that involved caspase 8 and TNF-α. To avoid accumulation of the associated misfolded proteins and MLKL, the syncytiotrophoblast exports these potentially dangerous proteins in EVs. It is likely that the dangerous proteins that are loaded into placental EVs in preeclampsia contribute to dysfunction of the maternal cells.


Assuntos
Anticorpos Antifosfolipídeos/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Placenta/efeitos dos fármacos , Trofoblastos/efeitos dos fármacos , Caspase 8/metabolismo , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Humanos , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Gravidez , Primeiro Trimestre da Gravidez , Proteínas Quinases/metabolismo , Técnicas de Cultura de Tecidos , Trofoblastos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
14.
Environ Sci Process Impacts ; 22(3): 472-486, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32022077

RESUMO

Trichloroethylene (TCE) is an industrial solvent and a common environmental contaminant detected in thousands of hazardous waste sites. Risk of exposure is a concern for workers in occupations that use TCE as well as for residents who live near industries that use TCE or who live near TCE-contaminated sites. Although renal, hepatic and carcinogenic effects of TCE have been documented, less is known about TCE impacts on reproductive functions despite epidemiology reports associating maternal TCE exposure with adverse pregnancy outcomes. Toxicological evidence suggests that the placenta mediates at least some of the adverse pregnancy outcomes associated with TCE exposure. Toxicology studies show that the TCE metabolite, S-(1,2-dichlorovinyl)-l-cysteine (DCVC) generates toxic effects such as mitochondrial dysfunction, apoptosis, oxidative stress, and release of prostaglandins and pro-inflammatory cytokines in placental cell lines. Each of these mechanisms of toxicity have significant implications for placental functions and, thus, ultimately the health of mother and developing child. Despite these findings there remain significant gaps in our knowledge about effects of TCE on the placenta, including effects on specific placental cell types and functions as well as sex differences in response to TCE exposure. Due to the critical role that the placenta plays in pregnancy, future research addressing some of these knowledge gaps could lead to significant gains in public health.


Assuntos
Placenta/efeitos dos fármacos , Tricloroetileno/toxicidade , Criança , Cisteína , Feminino , Humanos , Masculino , Estresse Oxidativo , Gravidez , Solventes
15.
Pharm Res ; 37(3): 58, 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32086630

RESUMO

PURPOSE: S-(4-Nitrobenzyl)-6-thioinosine (NBMPR) is routinely used at concentrations of 0.10 µM and 0.10 mM to specifically inhibit transport of nucleosides mediated by equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2), respectively. We recently showed that NBMPR (0.10 mM) might also inhibit placental active efflux of [3H]zidovudine and [3H]tenofovir disoproxil fumarate. Here we test the hypothesis that NBMPR abolishes the activity of P-glycoprotein (ABCB1) and/or breast cancer resistance protein (ABCG2). METHODS: We performed accumulation assays with Hoechst 33342 (a model dual substrate of ABCB1 and ABCG2) and bi-directional transport studies with the ABCG2 substrate [3H]glyburide in transduced MDCKII cells, accumulation studies in choriocarcinoma-derived BeWo cells, and in situ dual perfusions of rat term placenta with glyburide. RESULTS: NBMPR inhibited Hoechst 33342 accumulation in MDCKII-ABCG2 cells (IC50 = 53 µM) but not in MDCKII-ABCB1 and MDCKII-parental cells. NBMPR (0.10 mM) also inhibited bi-directional [3H]glyburide transport across monolayers of MDCKII-ABCG2 cells and blocked ABCG2-mediated [3H]glyburide efflux by rat term placenta in situ. CONCLUSION: NBMPR at a concentration of 0.10 mM abolishes ABCG2 activity. Researchers using NBMPR to evaluate the effect of ENTs on pharmacokinetics must therefore interpret their results carefully if studying compounds that are substrates of both ENTs and ABCG2.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transporte Biológico/efeitos dos fármacos , Proteínas de Neoplasias/antagonistas & inibidores , Tioinosina/análogos & derivados , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Antivirais/metabolismo , Antivirais/farmacocinética , Linhagem Celular , Cães , Feminino , Humanos , Células Madin Darby de Rim Canino , Proteínas de Neoplasias/metabolismo , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Ratos , Ratos Wistar , Tioinosina/farmacologia
16.
Environ Health Perspect ; 128(2): 27006, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32074459

RESUMO

BACKGROUND: Perfluorooctanoic acid (PFOA) is a poly- and perfluoroalkyl substance (PFAS) associated with adverse pregnancy outcomes in mice and humans, but little is known regarding one of its replacements, hexafluoropropylene oxide dimer acid (HFPO-DA, referred to here as GenX), both of which have been reported as contaminants in drinking water. OBJECTIVES: We compared the toxicity of PFOA and GenX in pregnant mice and their developing embryo-placenta units, with a specific focus on the placenta as a hypothesized target. METHODS: Pregnant CD-1 mice were exposed daily to PFOA (0, 1, or 5mg/kg) or GenX (0, 2, or 10mg/kg) via oral gavage from embryonic day (E) 1.5 to 11.5 or 17.5 to evaluate exposure effects on the dam and embryo-placenta unit. Gestational weight gain (GWG), maternal clinical chemistry, maternal liver histopathology, placental histopathology, embryo weight, placental weight, internal chemical dosimetry, and placental thyroid hormone levels were determined. RESULTS: Exposure to GenX or PFOA resulted in increased GWG, with increase in weight most prominent and of shortest latency with 10mg/kg/d GenX exposure. Embryo weight was significantly lower after exposure to 5mg/kg/d PFOA (9.4% decrease relative to controls). Effect sizes were similar for higher doses (5mg/kg/d PFOA and 10mg/kg/d GenX) and lower doses (1mg/kg/d PFOA and 2mg/kg/d GenX), including higher maternal liver weights, changes in liver histopathology, higher placental weights and embryo-placenta weight ratios, and greater incidence of placental abnormalities relative to controls. Histopathological features in placentas suggested that PFOA and GenX may exhibit divergent mechanisms of toxicity in the embryo-placenta unit, whereas PFOA- and GenX-exposed livers shared a similar constellation of adverse pathological features. CONCLUSIONS: Gestational exposure to GenX recapitulated many documented effects of PFOA in CD-1 mice, regardless of its much shorter reported half-life; however, adverse effects toward the placenta appear to have compound-specific signatures. https://doi.org/10.1289/EHP6233.


Assuntos
Caprilatos/toxicidade , Fluorcarbonetos/toxicidade , Hidrocarbonetos Fluorados/toxicidade , Placenta/efeitos dos fármacos , Testes de Toxicidade , Animais , Feminino , Camundongos , Neprilisina , Gravidez/efeitos dos fármacos
17.
Sci Rep ; 10(1): 544, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953475

RESUMO

1 in 5 women report cannabis use during pregnancy, with nausea cited as their primary motivation. Studies show that (-)-△9-tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis, causes fetal growth restriction, though the mechanisms are not well understood. Given the critical role of the placenta to transfer oxygen and nutrients from mother, to the fetus, any compromise in the development of fetal-placental circulation significantly affects maternal-fetal exchange and thereby, fetal growth. The goal of this study was to examine, in rats, the impact of maternal Δ9-THC exposure on fetal development, neonatal outcomes, and placental development. Dams received a daily intraperitoneal injection (i.p.) of vehicle control or Δ9-THC (3 mg/kg) from embryonic (E)6.5 through 22. Dams were allowed to deliver normally to measure pregnancy and neonatal outcomes, with a subset sacrificed at E19.5 for placenta assessment via immunohistochemistry and qPCR. Gestational Δ9-THC exposure resulted in pups born with symmetrical fetal growth restriction, with catch up growth by post-natal day (PND)21. During pregnancy there were no changes to maternal food intake, maternal weight gain, litter size, or gestational length. E19.5 placentas from Δ9-THC-exposed pregnancies exhibited a phenotype characterized by increased labyrinth area, reduced Epcam expression (marker of labyrinth trophoblast progenitors), altered maternal blood space, decreased fetal capillary area and an increased recruitment of pericytes with greater collagen deposition, when compared to vehicle controls. Further, at E19.5 labyrinth trophoblast had reduced glucose transporter 1 (GLUT1) and glucocorticoid receptor (GR) expression in response to Δ9-THC exposure. In conclusion, maternal exposure to Δ9-THC effectively compromised fetal growth, which may be a result of the adversely affected labyrinth zone development. These findings implicate GLUT1 as a Δ9-THC target and provide a potential mechanism for the fetal growth restriction observed in women who use cannabis during pregnancy.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Dronabinol/efeitos adversos , Orelha Interna/embriologia , Retardo do Crescimento Fetal/induzido quimicamente , Placenta/irrigação sanguínea , Animais , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Retardo do Crescimento Fetal/fisiopatologia , Transportador de Glucose Tipo 1/metabolismo , Placenta/efeitos dos fármacos , Gravidez , Ratos , Receptores de Glucocorticoides/metabolismo , Trofoblastos/efeitos dos fármacos , Trofoblastos/patologia
18.
Toxicol Lett ; 322: 39-49, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31927052

RESUMO

Exposure to the environmental pollutants organotins is of toxicological concern for the marine ecosystem and sensitive human populations, including pregnant women and their unborn children. Using a placenta cell model, we investigated whether organotins at nanomolar concentrations affect the expression and activity of 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 11ß-HSD2 represents a placental barrier controlling access of maternal glucocorticoids to the fetus. The organotins tributyltin (TBT) and triphenyltin (TPT) induced 11ß-HSD2 expression and activity in JEG-3 placenta cells, an effect confirmed at the mRNA level in primary human trophoblast cells. Inhibition/knock-down of retinoid X receptor alpha (RXRα) in JEG-3 cells reduced the effect of organotins on 11ß-HSD2 activity, mRNA and protein levels, revealing involvement of RXRα. Experiments using RNA and protein synthesis inhibitors indicated that the effect of organotins on 11ß-HSD2 expression was direct and caused by increased transcription. Induction of placental 11ß-HSD2 activity by TBT, TPT and other endocrine disrupting chemicals acting as RXRα agonists may affect placental barrier function by altering the expression of glucocorticoid-dependent genes and resulting in decreased availability of active glucocorticoids for the fetus, disturbing development and increasing the risk for metabolic and cardiovascular complications in later life.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Disruptores Endócrinos/toxicidade , Expressão Gênica/efeitos dos fármacos , Compostos Orgânicos de Estanho/toxicidade , Receptor X Retinoide alfa/metabolismo , Compostos de Trialquitina/toxicidade , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Receptor X Retinoide alfa/genética , Transfecção , Regulação para Cima
19.
Mol Med Rep ; 21(2): 623-630, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31974593

RESUMO

Placental structural abnormalities and dysfunction in those with gestational diabetes mellitus (GDM) can lead to increased placental permeability, which is in turn related to a poorer maternal and fetal prognosis. The present study sought to assess whether increased placental permeability in rats with GDM was accompanied by alterations in tight junction (TJ) factors and to evaluate the impact of low molecular weight heparin (LMWH) on these factors. The present study was conducted using pregnant female rats that were randomized into control, GDM and GDM + LMWH groups. Diabetes was induced via intraperitoneal administration of streptozotocin to rats in the GDM and GDM + LMWH groups, whereas rats in the GDM + LMWH group received daily subcutaneous LMWH starting on day 5 of pregnancy. On gestational day 16, all rats were sacrificed and Evans Blue (EB) assay was used to gauge vascular permeability based on EB dye leakage. Transmission electron microscopy was further used to assess TJ structures, and the TJ proteins zonular occludens­1 (ZO­1) and occludin (OCLN) were assessed using immunohistochemistry and western blotting. Blood samples were obtained from the abdominal aorta for ELISA measurements of advanced glycation end products (AGEs) concentrations, and placental receptor for AGEs (RAGE) and vascular endothelial growth factor (VEGF) expression was assessed using reverse transcription­quantitative PCR. In addition, western blotting was used to measure placental NF­κB. Compared with in the control group, EB leakage was markedly increased in GDM group rats; this was associated with reduced ZO­1 and OCLN expression. Conversely, LMWH attenuated this increase in placental permeability in rats with GDM and also mediated a partial recovery of ZO­1 and OCLN expression. Blood glucose and serum AGEs concentrations did not differ between the GDM and GDM + LMWH groups. Furthermore, LMWH treatment resulted in decreases in RAGE and VEGF mRNA expression levels, which were upregulated in the GDM group, whereas it had the opposite effect on the expression of NF­κB. In conclusion, GDM was associated with increased placental permeability and this may be linked with changes in TJs. LMWH intervention mediated protection against this GDM­associated shift in placental permeability via the RAGE/NF­κB pathway.


Assuntos
Diabetes Gestacional/tratamento farmacológico , Nadroparina/uso terapêutico , Placenta/metabolismo , Junções Íntimas/metabolismo , Animais , Diabetes Gestacional/sangue , Modelos Animais de Doenças , Feminino , Produtos Finais de Glicação Avançada/sangue , NF-kappa B/metabolismo , Nadroparina/farmacologia , Permeabilidade , Placenta/efeitos dos fármacos , Placenta/ultraestrutura , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/ultraestrutura , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
20.
Environ Toxicol ; 35(1): 97-107, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31566301

RESUMO

Tri-ortho-cresyl phosphate (TOCP) has been widely used as plasticizers, and reported causing reproductive toxicity in mammals. However, little is known about the toxic effect on the placenta. In this study, dams were orally administered different doses of TOCP to explore the effect of TOCP on placental development. Results showed that TOCP exposure significantly reduced numbers of implanted embryo, caused atrophy and collapse of ectoplacental cone, and decreased total areas of placenta and numbers of PCNA-positive cells. Expression levels of placental development genes were prominently downregulated in the TOCP-treated groups. Moreover, TOCP administration induced placental apoptosis and autophagy by upregulating P53, Bax, Beclin-1, ratio of LC3 II/LC3 I and Atg5 and downregulating Bcl-2 protein. In addition, TOCP exposure markedly inhibited activities of catalase and superoxide dismutase and increased the production of H2 O2 and malondialdehyde. Collectively, these findings suggest that apoptosis, autophagy and oxidative stress may be involved in the TOCP-induced reproductive toxicity.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Placenta/efeitos dos fármacos , Plastificantes/toxicidade , Tritolil Fosfatos/toxicidade , Animais , Feminino , Masculino , Camundongos , Placenta/metabolismo , Placenta/patologia , Gravidez , Reprodução/efeitos dos fármacos
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