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1.
Ecotoxicol Environ Saf ; 203: 111001, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32888585

RESUMO

Environmental nanomaterials contamination is a great concern for organisms including human. Copper oxide nanoparticles (CuO NPs) are widely used in a huge range of applications which might pose potential risk to organisms. This study investigated the in vivo transgenerational toxicity on development and reproduction with parental CuO NPs exposure in the nematode Caenorhabditis elegans. The results showed that CuO NPs (150 mg/L) significantly reduced the body length of parental C. elegans (P0). Only about 1 mg/L Cu2+ (~0.73%) were detected from 150 mg/L CuO NPs in 0.5X K-medium after 48 h. In transgenerational assays, CuO NPs (150 mg/L) parental exposure significantly induced developmental and reproductive toxicity in non-exposed C. elegans progeny (CuO NPs free) on body length (F1) and brood size (F1 and F2), respectively. In contrast, parental exposure to Cu2+ (1 mg/L) did not cause transgenerational toxicity on growth and reproduction. This suggests that the transgenerational toxicity was mostly attributed to the particulate form of CuO NPs. Moreover, qRT-PCR results showed that the mRNA levels of met-2 and spr-5 genes were significantly decreased at P0 and F1 upon only maternal exposure to CuO NPs (150 mg/L), suggesting the observed transgenerational toxicity was associated with possible epigenetic regulation in C. elegans.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Cobre/toxicidade , Epigênese Genética/efeitos dos fármacos , Nanopartículas/toxicidade , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Caenorhabditis elegans/fisiologia , Feminino , Humanos , Exposição Materna/efeitos adversos , Reprodução/efeitos dos fármacos , Reprodução/genética
2.
Environ Pollut ; 265(Pt B): 114973, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32806448

RESUMO

Maternal exposure to air pollution is associated with poor reproductive outcomes in in vitro fertilization (IVF). However, the susceptible time windows are still not been known clearly. In the present study, we linked the air pollution data with the information of 9001 women receiving 10,467 transfer cycles from August 2014 to August 2019 in The Second Hospital of Hebei Medical University, Shijiazhuang City, China. Maternal exposure was presented as individual average daily concentrations of PM2.5, PM10, NO2, SO2, CO, and O3, which were predicted by spatiotemporal kriging model based on residential addresses. Exposure windows were divided to five periods according to the process of follicular and embryonic development in IVF. Generalized estimating equation model was used to evaluate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for association between clinical pregnancy and interquartile range increased average daily concentrations of pollutants during each exposure period. The increased PM2.5 (adjusted OR = 0.95, 95% CI: 0.90, 0.99), PM10 (adjusted OR = 0.93, 95% CI: 0.89, 0.98), NO2 (adjusted OR = 0.89, 95% CI: 0.85, 0.94), SO2 (OR = 0.94, 95% CI: 0.90, 0.98), CO (adjusted OR = 0.93, 95% CI: 0.89, 0.97) whereas decreased O3 (OR = 1.08, 95% CI: 1.02, 1.14) during the duration from preantral follicles to antral follicles were the strongest association with decreased probability of clinical pregnancy among the five periods. Especially, women aged 20-29 years old were more susceptible in preantral-antral follicle transition stage. Women aged 36-47 years old were more vulnerable during post-oocyte retrieve period. Our results suggested air pollution exposure during preantral-antral follicle transition stage was a note-worthy challenge to conceive among females receiving IVF.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar , Adulto , China , Feminino , Fertilização In Vitro , Humanos , Exposição Materna , Pessoa de Meia-Idade , Gravidez , Adulto Jovem
3.
Environ Sci Pollut Res Int ; 27(30): 37527-37539, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32740838

RESUMO

There is increasing and inconsistent evidence of a linkage between maternal exposure to particulate matter 2.5 (PM2.5) and preeclampsia. Therefore, this study was conducted to investigate this relationship. Electronic databases including PubMed, Embase, Web of Science, and Cochrane Library were searched to identify articles published from inception to March 23, 2020, which showed a correlation between PM2.5 and preeclampsia. Finally, 9 of 523 initial studies were deemed eligible for inclusion. A random effect model was adopted to calculate the standardized odds ratio (OR) and 95% confidence interval (CI). Based on potential effect modification, subgroup analyses were further performed. Meta-analysis showed that maternal exposure to PM2.5 (per 10 µg/m3 increment) elevated the risk of preeclampsia (OR = 1.32, 95% CI 1.10 to 1.58%). Compared with other pregnancy trimesters, the third trimester of pregnancy seems to be the period in which women are more susceptible to PM2.5. Significant effect modification of the correlation between PM2.5 exposure and preeclampsia according to multiple pregnancies, pregnancy stage, maternal-related disease history, and sample size was not observed. The results demonstrated that maternal exposure to PM2.5 may predispose pregnant women to develop preeclampsia, especially in the third trimester of pregnancy. Therefore, more efforts should be made to improve air quality to maintain the health of pregnant women.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/análise , Pré-Eclâmpsia , Feminino , Humanos , Exposição Materna , Razão de Chances , Material Particulado/análise , Gravidez
4.
Environ Health Prev Med ; 25(1): 38, 2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770943

RESUMO

BACKGROUND: Many studies have investigated heavy metal exposure could increase the occurrence of congenital heart defects (CHDs). However, there are limited data regarding the relationship between cobalt exposure and CHD occurrence in offspring. The aim of this study was to analyze the association between cobalt exposure in mothers and the risk of CHDs in offspring. MATERIALS AND METHODS: In order to explore the association between cobalt exposure and occurrence of congenital heart defect (CHD), a case-control study with 490 controls and 399 cases with CHDs in China were developed. The concentrations of cobalt in hair of pregnant woman and fetal placental tissue were measured and processed by a logistic regression analysis to explore the relationship between cobalt exposure and risk of CHDs. RESULTS: The median concentration of hair cobalt in the control and case group was 0.023 ng/mg and 0.033 ng/mg (aOR, 1.837; 95% CI, 1.468-2.299; P < 0.001), respectively. And the median (5-95% range) fetal placental cobalt concentrations were 19.350 ng/g and 42.500 ng/g (aOR, 2.924; 95% CI, 2.211-3.868; P < 0.001) in the control and case groups, respectively. Significant differences in the middle level of cobalt in hair were found in the different CHD subtypes, including septal defects, conotruncal defects, right ventricular outflow tract obstruction, and left ventricular outflow tract obstruction (P < 0.001). Dramatically, different cobalt concentrations in fetal placental tissue were found in all subtypes of cases with CHDs (P < 0.01). CONCLUSIONS: The finding suggested that the occurrence of CHDs may be associated with cobalt exposure.


Assuntos
Cobalto/efeitos adversos , Cabelo/química , Cardiopatias Congênitas/induzido quimicamente , Exposição Materna/efeitos adversos , Placenta/química , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adolescente , Adulto , Estudos de Casos e Controles , China , Feminino , Humanos , Gravidez , Fatores de Risco , Adulto Jovem
5.
PLoS One ; 15(8): e0236708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790684

RESUMO

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are a kind of endocrine disruptors, which can enter human body by the inhalation of PAH-containing matter and the ingestion of PAH-containing foodstuffs. Studies showed that PAHs can cross the placental barrier and might cause adverse effects on the fetus. OBJECTIVES: This meta-analysis aimed to estimate the associations between prenatal exposure to PAHs and birth weight. METHODS: Articles published in English until May 8, 2020 and reported the effects of prenatal exposure to PAHs on birth weight were searched in multiple electronic databases including PubMed, the Web of Science, EMBASE and the Cochrane Library. The included studies were divided into three groups in accordance with the measurement of PAHs exposure. Then coefficient was extracted, conversed and synthesized by random-effects meta-analysis. And risk of bias was assessed for each study. RESULTS: A total of 3488 citations were searched and only 11 studies were included finally after double assessment. We found that there were no association between PAH-DNA adducts in cord blood (low/high) (OR: 1.0, 95%CI: 0.97, 1.03), 1-hydroxy pyrene (1-HP) concentration in maternal urine (OR: 1.0, 95%CI: 0.97, 1.03) and prenatal maternal airborne PAHs exposure (OR: 0.97, 95%CI: 0.93, 1.01) and birth weight. However, we observed ethnicity may change the effects of PAHs exposure on birth weight. CONCLUSIONS: There is no significant relationship between prenatal exposure to PAHs and birth weight in our meta-analysis. Further studies are still needed for determining the effects of prenatal PAHs exposure on birth weight.


Assuntos
Peso ao Nascer/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Exposição Materna , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Poluentes Atmosféricos/química , Poluentes Atmosféricos/toxicidade , Adutos de DNA/química , Bases de Dados Factuais , Disruptores Endócrinos/química , Feminino , Sangue Fetal/química , Humanos , Razão de Chances , Hidrocarbonetos Policíclicos Aromáticos/química , Gravidez , Pirenos/urina
6.
Life Sci ; 258: 118197, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781059

RESUMO

AIMS: Patients with neurodevelopmental disorders, usually suffer from bone diseases. Many studies have revealed a higher risk of fracture after atypical antipsychotic drug Risperidone (RIS) treatment, which is usually used to treat such disorders. It remains debatable whether neurodevelopmental disorders by itself are the cause of bone diseases or pharmacotherapy may be the reason. MATERIALS AND METHODS: This study attempts to evaluate the biomechanical, histological, stereological, and molecular properties of bones in the offspring of Lipopolysaccharide (LPS) and saline-treated mothers that received saline, drug vehicle or the atypical antipsychotic drug risperidone (RIS) at different days of postnatal development. After postnatal drug treatment, animals were assessed for autistic-like behaviors. Then their bones were taken for evaluations. RESULTS: Maternal LPS exposure resulted in deficits in all behavioral tests and RIS ameliorated these behaviors (p < 0.01& p < 0.05). The administration of LPS and RIS individually led to a significant decrease in the biomechanical parameters such as bone stiffness, strength and the energy used to fracture of bone. The numerical density of osteocalcin-positive cells were significantly decreased in these groups. These rats also had decreased RUNX2 and osteocalcin gene expression. When LPS rats were treated with RIS, these conditions were accelerated (p < 0.001). DISCUSSIONS: The results of our preclinical study, consistent with previous studies in animals, explore that autistic-like deficits induced by prenatal exposure to LPS, can reduce bone stability and bone mass similar to those observed in neurodevelopmental disorders, and, for the first time, reveal that this condition worsened when these animals were treated with RIS.


Assuntos
Transtorno Autístico/induzido quimicamente , Reabsorção Óssea/induzido quimicamente , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal/patologia , Risperidona/efeitos adversos , Animais , Animais Recém-Nascidos , Transtorno Autístico/sangue , Transtorno Autístico/complicações , Comportamento Animal , Fenômenos Biomecânicos , Reabsorção Óssea/sangue , Reabsorção Óssea/fisiopatologia , Citocinas/sangue , Citocinas/genética , Feminino , Lipopolissacarídeos/administração & dosagem , Masculino , Atividade Motora , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Risperidona/administração & dosagem , Comportamento Estereotipado
7.
PLoS One ; 15(8): e0237182, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764797

RESUMO

Necrotizing enterocolitis is the most common gastrointestinal disorder in premature neonates. This disease is characterized by massive epithelial necrosis, gut barrier dysfunction and improper mucosal defense development. Studies have shown that probiotic administration can decrease NEC incidence and mortality. The proposed mechanisms of probiotics for the prevention of NEC are: promotion of intestinal development; improved barrier function through decreased apoptosis and improved mucin production; decreased expression of proinflammatory cytokines IL6, IL8, and TNFα, and modulation of microbiota dysbiosis in preterm infants. However, reported sepsis in the immunocompromised preterm host has deterred routine prophylactic administration of probiotics in the neonatal intensive care unit. We hypothesize that maternal administration of probiotics to pregnant mouse dams can recapitulate the beneficial effects observed in neonates fed with probiotics directly. We exposed pregnant mice to the probiotics and monitored the changes in the developing intestines of the offspring. Pregnant mice were fed daily with the probiotics Lactobacillus acidophilus and Bifidobacterium infantis (LB) from embryonic day15 to 2-week-old postnatally. Intraperitoneal administration of IL-1ß in the pups was used to model proinflammatory insults. Sera were collected at 2 weeks of age and evaluated for inflammatory cytokines by enzyme-linked-immunosorbent-assay and gut permeability by Fluorescein isothiocyanate-dextran tracer assay. Ileal tissues were collected for the evaluation of apoptosis and proliferation of the intestinal epithelium; as well as mucin and tight junction integrity at mucosal surface by immunofluorescent staining. We find that maternal LB exposure facilitated intestinal epithelial cell differentiation, prevented loss of mucin and preserved the intestinal integrity and barrier function and decreased serum levels of IL-1ß, TNF-α and IL-6 in the preweaned offsprings. in LB exposed pups. We demonstrate that maternal probiotic supplementation promotes gut maturation in developing offspring. This is potentially a safe alternative therapy to induce intestinal maturation and prevent prematurity-associated neonatal disorders.


Assuntos
Enterocolite Necrosante/prevenção & controle , Microbioma Gastrointestinal/fisiologia , Mucosa Intestinal/crescimento & desenvolvimento , Exposição Materna , Probióticos/administração & dosagem , Animais , Animais Recém-Nascidos/crescimento & desenvolvimento , Animais Recém-Nascidos/microbiologia , Bifidobacterium longum subspecies infantis , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/microbiologia , Enterocolite Necrosante/patologia , Fezes/microbiologia , Feminino , Interações entre Hospedeiro e Microrganismos/fisiologia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Interleucina-1beta/administração & dosagem , Interleucina-1beta/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Lactobacillus acidophilus , Camundongos
8.
Environ Health ; 19(1): 90, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847589

RESUMO

BACKGROUND: Lower respiratory tract infections (LRTI) in early life, including pneumonia, bronchitis and bronchiolitis, can lead to decreased lung function, persistent lung damage and increased susceptibility to various respiratory diseases such as asthma. In-utero exposure to particulate matter (PM) during pregnancy may disrupt biological mechanisms that regulate fetal growth, maturation and development. We aimed to estimate the association between intrauterine exposure to PM of size < 2.5 µm in diameter (PM2.5) and incidence of LRTIs during the first year of life. METHODS: A retrospective population-based cohort study in a population of mothers and infants born in Soroka University Medical Center (SUMC) in the years 2004-2012. All infants < 1 year old that were hospitalized due to LRTIs were included. The main exposure assessment was based on a hybrid model incorporating daily satellite-based predictions at 1 km2 spatial resolution. Data from monitoring stations was used for imputation of main exposure and other pollutants. Levels of environmental exposures were assigned to subjects based on their residential addresses and averaged for each trimester. Analysis was conducted by a multivariable generalized estimating equation (GEE) Poisson regression. Data was analyzed separately for the two main ethnic groups in the region, Jewish and Arab-Bedouin. RESULTS: The study cohort included 57,331 deliveries that met the inclusion criteria. Overall, 1871 hospitalizations of infants < 1 year old due to pneumonia or bronchiolitis were documented. In a multivariable analysis, intrauterine exposure to high levels of PM2.5 (> 24 µg/m3) in the first and second trimesters was found to be adversely associated with LRTIs in the Arab-Bedouin population (1st trimester, RR = 1.31, CI 95% 1.08-1.60; 2nd trimester: RR = 1.34, CI 95% 1.09-1.66). CONCLUSION: Intrauterine exposure to high levels of PM2.5 is associated with a higher risk of hospitalizations due to lower respiratory tract infections in Arab-Bedouin infants.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Exposição Materna/efeitos adversos , Material Particulado/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Infecções Respiratórias/epidemiologia , Feminino , Hospitalização , Humanos , Incidência , Lactente , Recém-Nascido , Israel/epidemiologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Infecções Respiratórias/induzido quimicamente
9.
Ecotoxicol Environ Saf ; 204: 111052, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32739675

RESUMO

Transgenerational effects on sensitivity to pesticides are poorly studied. This study investigated the transgenerational influences of maternal body mass in the major pest moth Spodoptera littoralis, with a focus on sensitivity to chlorpyrifos pesticide. In 147 clutches of a laboratory strain of S. littoralis, we compared larval mortality between control larvae and larvae treated with chlorpyrifos. Because of the classic positive relationships between offspring size and maternal size and between offspring size and offspring quality, sensitivity to chlorpyrifos was predicted to be lower in larvae of larger mothers. Surprisingly, we found the opposite result, with higher pesticide toxicity in larvae of larger mothers. This result is partly explained by the lack of a relationship between larval mass and larval sensitivity to chlorpyrifos. This means that another offspring characteristic linked to maternal size should have affected larval sensitivity to chlorpyrifos. More generally, knowledge of the effects of the traits and ecological environments of mothers on offspring sensitivity to pesticides remains limited. Ecotoxicologists should pay more attention to such maternal effects on sensitivity to pesticides, both in pests and non-target species.


Assuntos
Clorpirifos/toxicidade , Epigênese Genética , Resistência a Inseticidas/genética , Inseticidas/toxicidade , Spodoptera/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Larva/efeitos dos fármacos , Larva/genética , Larva/crescimento & desenvolvimento , Longevidade/efeitos dos fármacos , Exposição Materna , Spodoptera/genética , Spodoptera/crescimento & desenvolvimento
10.
Chemosphere ; 257: 127035, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32702804

RESUMO

Human exposure to environmental chemicals might play a role in the pathogenesis of unexplained recurrent spontaneous abortion (URSA). Bisphenol A (BPA) and bisphenol S (BPS) have been suggested to affect reproductive health. However, the mechanism remains unclear. To explore the association between BPA and BPS exposure and oxidative stress and immune homeostasis, we conducted a cross-sectional study and revealed BPA and BPS levels in relation to these two factors which were supposed to be implicated in miscarriage. 111 URSA patients were recruited and we analyzed urinary BPA and BPS concentrations, oxidative stress biomarkers (8-hydroxydeoxyguanosine and 8-isoprostane) and serum immune balance biomarkers (IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, TNF-α, TGF-ß and IFN-γ). Multivariable linear regression models were used to evaluate the correlation between bisphenols exposure and outcome biomarkers. After adjustment for age, BMI, menstrual cycle, and parity history, creatinine-adjusted BPA was significantly associated with increases in 8-isoprostane (ß = 0.74, 95% CI = 0.07, 1.41; p = 0.031) and IFN-γ (ß = 0.18, 95% CI = 0.00, 0.36; p = 0.046). No statistical correlation between BPS and biomarkers of oxidative stress or immune balance was observed when all participants were analyzed. Further analysis revealed that in the subgroup of BPS > limit of detection (0.01 ng/ml), creatinine-adjusted BPS was significantly associated with increases in IL-10 (ß = 0.22, 95% CI = 0.00, 0.45; p = 0.048). Our findings suggested that BPA and BPS exposure might be related to oxidative stress and immune imbalance in URSA patients. Overall, our work might suggest potential pathogenic and aetiological associations among the bisphenols, biomarkers and URSA, which offers hypotheses for further studies.


Assuntos
Aborto Espontâneo/epidemiologia , Compostos Benzidrílicos/toxicidade , Poluentes Ambientais/toxicidade , Exposição Materna/estatística & dados numéricos , Fenóis/toxicidade , Sulfonas/toxicidade , Adulto , Biomarcadores/sangue , Estudos Transversais , Dinoprosta/análogos & derivados , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Estresse Oxidativo/fisiologia , Gravidez
11.
Chemosphere ; 255: 127003, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32679629

RESUMO

In this study, we assessed the presence of 14 phthalate metabolites in the urine of 104 lactating mothers from Valencia (Spain) who took part in the human biomonitoring project BETTERMILK. Nine of the metabolites studied showed detection frequencies >80%, whereas the rest of the metabolites presented low detection frequencies (<5%). The concentrations ranged from

Assuntos
Monitoramento Biológico , Aleitamento Materno/estatística & dados numéricos , Exposição Materna/estatística & dados numéricos , Ácidos Ftálicos , Adulto , Coleta de Dados , Dietilexilftalato , Exposição Ambiental/análise , Poluentes Ambientais/metabolismo , Feminino , Humanos , Lactação , Mães , Embalagem de Produtos , Medição de Risco , Espanha
12.
Hum Reprod ; 35(8): 1781-1796, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32712670

RESUMO

STUDY QUESTION: Does HIV protease inhibitor (PI)-based combination antiretroviral therapy (cART) initiated at periconception affect key events in early pregnancy, i.e. decidualization and spiral artery remodeling? SUMMARY ANSWER: Two PIs, lopinavir and darunavir, currently offered as cART options in HIV-positive pregnancies were evaluated, and we found that lopinavir-based cART, but not darunavir-based cART, impaired uterine decidualization and spiral artery remodeling in both human ex vivo and mouse in vivo experimental models. WHAT IS KNOWN ALREADY: Early initiation of cART is recommended for pregnant women living with HIV. However, poor birth outcomes are frequently observed in HIV-positive pregnancies exposed to PI-based cART, especially when it is initiated prior to conception. The correlation between early initiation of PI-cART and adverse birth outcomes is poorly understood, due to lack of data on the specific effects of PI-cART on the early stages of pregnancy involving uterine decidualization and spiral artery remodeling. STUDY DESIGN, SIZE, DURATION: Lopinavir and darunavir were evaluated in clinically relevant combinations using an ex vivo human first-trimester placenta-decidua explant model, an in vitro human primary decidual cell culture system, and an in vivo mouse pregnancy model. The first-trimester (gestational age, 6-8 weeks) human placenta-decidua tissue was obtained from 11 to 15 healthy women undergoing elective termination of pregnancy. C57Bl/6 female mice (four/treatment group) were administered either lopinavir-cART, darunavir-cART or water by oral gavage once daily starting on the day of plug detection until sacrifice. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human: Spiral artery remodeling was assessed by immunohistochemical analysis of first-trimester placenta-decidua explant co-culture system. Trophoblast migration was measured using a placental explant culture. A primary decidual cell culture was used to evaluate the viability of immune cell populations by flow cytometry. Soluble factors, including biomarkers of decidualization and angiogenesis, were quantified by ELISA and Luminex assay using decidua-conditioned media. Mouse: In the mouse pregnancy model, gestational day 6.5 or 9.5 implantation sites were used to assess decidualization, spiral artery remodeling and uterine natural killer (uNK) cell numbers by immunohistochemistry. Transcription factor STAT3 was assayed by immunohistochemistry in both human decidua and mouse implantation sites. MAIN RESULTS AND THE ROLE OF CHANCE: Lopinavir-cART, but not darunavir-cART, impaired uterine decidualization and spiral artery remodeling in both experimental models. Lopinavir-cART treatment was also associated with selective depletion of uNK cells, reduced trophoblast migration and defective placentation. The lopinavir-associated decidualization defects were attributed to a decrease in expression of transcription factor STAT3, known to regulate decidualization. Our results suggest that periconceptional initiation of lopinavir-cART, but not darunavir-cART, causes defective maturation of the uterine endometrium, leading to impairments in spiral artery remodeling and placentation, thus contributing to the poor birth outcomes. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The human first-trimester placenta/decidua samples could only be obtained from healthy females undergoing elective termination of pregnancy. As biopsy is the only way to obtain first-trimester decidua from pregnant women living with HIV on PI-cART, ethics approval and participant consent are difficult to obtain. Furthermore, our animal model is limited to the study of cART and does not include HIV. HIV infection is also associated with immune dysregulation, inflammation, alterations in angiogenic factors and complement activation, all of which could influence decidual and placental vascular remodeling and modify any cART effects. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide mechanistic insight with direct clinical implications, rationalizing why the highest adverse birth outcomes are reported in HIV-positive pregnancies exposed to lopinavir-cART from conception. We demonstrate that dysregulation of decidualization is the mechanism through which lopinavir-cART, but not darunavir-cART, use in early pregnancy leads to poor birth outcomes. Although lopinavir is no longer a first-line regimen in pregnancy, it remains an alternate regimen and is often the only PI available in low resource settings. Our results highlight the need for reconsidering current guidelines recommending lopinavir use in pregnancy and indicate that lopinavir should be avoided especially in the first trimester, whereas darunavir is safe to use and should be the preferred PI in pregnancy.Further, in current times of the COVID-19 pandemic, lopinavir is among the top drug candidates which are being repurposed for inclusion in clinical trials world-over, to assess their therapeutic potential against the dangerous respiratory disease. Current trials are also testing the efficacy of lopinavir given prophylactically to protect health care workers and people with potential exposures. Given the current extraordinary numbers, these might include women with early pregnancies, who may or may not be cognizant of their gestational status. This is a matter of concern as it could mean that women with early pregnancies might be exposed to this drug, which can cause decidualization defects. Our findings provide evidence of safety concerns surrounding lopinavir use in pregnancy, that women of reproductive age considering participation in such trials should be made aware of, so they can make a fully informed decision. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by funding from the Canadian Institutes of Health Research (CIHR) (PJT-148684 and MOP-130398 to L.S.). C.D. received support from CIHR Foundation (FDN143262 to Stephen Lye). S.K. received a TGHRI postdoctoral fellowship. The authors declare that there are no conflicts of interest. L.S. reports personal fees from ViiV Healthcare for participation in a Women and Transgender Think Tank.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Lopinavir/efeitos adversos , Placentação/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Animais , Betacoronavirus/efeitos dos fármacos , Células Cultivadas , Ensaios Clínicos como Assunto , Técnicas de Cocultura , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Darunavir/efeitos adversos , Decídua/irrigação sanguínea , Decídua/citologia , Decídua/efeitos dos fármacos , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Implantação do Embrião/efeitos dos fármacos , Endométrio/irrigação sanguínea , Endométrio/efeitos dos fármacos , Feminino , Humanos , Exposição Materna/efeitos adversos , Camundongos , Pandemias , Pneumonia Viral/virologia , Gravidez , Primeiro Trimestre da Gravidez/efeitos dos fármacos , Cultura Primária de Células , Trofoblastos , Remodelação Vascular/efeitos dos fármacos
13.
Sci Total Environ ; 742: 140613, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-32640390

RESUMO

BACKGROUND: The human placenta is vulnerable to environmental pollutants, but the associations between exposure to multiple, correlated metals and placental characteristics have not been studied. METHODS: The current study population was derived from the Hangzhou Birth Cohort Study. Whole blood and urine samples were collected from mothers during 20-28 gestational week. The concentrations of 11 metals in blood and 11 metals in urine were evaluated by inductively coupled plasma mass spectrometry. The data on placental characteristics and birth weight were retrieved from medical records. The elastic net (ENET) model combined with unpenalized regression model was employed to estimate the relationship between levels of metals and placental characteristics (placental weight, chorionic disc area, chorionic disc eccentricity, placental thickness, placental-fetal birth weight ratio) and birth weight. Mediation analysis was performed to explore the mediated effect of placenta on the association of prenatal metals exposure with birth weight. RESULTS: Among 512 participants with urine metal levels, the ENET model retained Cadmium (Cd) and Selenium (Se) for placental weight. Further unpenalized regression model including Cd and Se simultaneously showed that one-unite increased natural-logarithm (ln)-transformed urine creatinine corrected (CC) Cd levels was associated with reductions in placental weight of -7.2 g (95% confidence interval (CI): -14.0, -0.4). Among 483 participants with blood metal levels, similarly, blood Cd levels were negatively associated with placental weight (ß = -7.5, 95% CI: -17.0, 1.9). Furthermore, mediation analysis demonstrated that urine CC-Cd level was associated with a 21.3 g decrease (95% CI: -42.0, -2.5, p = 0.024) in birth weight through a reduction in placental weight, while blood Cd levels presented a negative association at borderline significance. CONCLUSION: Our findings suggest a mediation effect of the placenta in the relationship between prenatal Cd exposure and lower birth weight. Additional studies with repeated assessment of exposure and more placental parameters are warranted to confirm this relationship.


Assuntos
Poluentes Ambientais/análise , Metais Pesados , Peso ao Nascer , Estudos de Coortes , Feminino , Humanos , Exposição Materna , Placenta/química , Gravidez
14.
Environ Pollut ; 266(Pt 1): 115128, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32650160

RESUMO

Maternal blood glucose level is associated with fetal growth, therefore, its role in the associations between air pollution and birth weight deserves investigation. We examined the mediation effect of maternal blood glucose on the associations between maternal air pollution exposure and birth weight. A total of 10,904 pregnant women in Foshan, China during 2015-2019 were recruited. Oral glucose tolerance test (OGTT) was administered to each participant after late trimester 2. Air pollution data at the monitoring stations in residential districts was used to estimate exposures of each participant during trimester 1 and trimester 2. Mixed-effects linear models were used to estimate the associations between air pollution and birth weight. After controlling for ten covariates, the direct effect of PM2.5 and SO2 (each 10 µg/m3 increment) on birth weight was -15.7 g (95% CI: -29.4, -4.8 g) and -83.6 g (95% CI: -134.8, -33.0 g) during trimester 1. The indirect effect of PM2.5 and SO2 (each 10 µg/m3 increment) on birth weight by increasing maternal fasting glucose level was 6.6 g (95% CI: 4.6, 9.1 g) and 22.0 g (95% CI: 4.1, 44.0 g) during trimester 1. Our findings suggest that air pollution might affect the birth weight through direct and indirect pathway, and the indirect effect might be mediated by maternal blood glucose.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/análise , Peso ao Nascer , China , Feminino , Glucose , Humanos , Exposição Materna , Material Particulado , Gravidez
15.
Sci Total Environ ; 743: 140678, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32653713

RESUMO

BACKGROUND: Environmental phenols, bisphenol A (BPA), triclosan (TCS), and benzophenone-3 (BP-3), are known as emerging endocrine-disrupting chemicals; however, their impacts on thyroid hormones and children's neurobehaviors are still unclear. OBJECTIVES: We aimed to examine the associations of prenatal and childhood exposure to phenols with neonatal thyroid function and childhood behavioral problems aged 10 years. METHODS: A total of 386 mother-singleton pairs were included from Sheyang Mini Birth Cohort Study (SMBCS), a longitudinal birth cohort in China. We quantified urinary BPA, TCS and BP-3 concentrations in maternal and 10-year-old children's urine samples using gas chromatography tandem mass spectrometry and thyroid function parameters in cord serum samples. Caregivers completed the Strength and Difficulties Questionnaire (SDQ) for their children at 10 years of age. Multivariable linear regression models and logistic regression models were applied to estimate associations of urinary phenol concentrations with thyroid hormones and risks of children's behavioral problems, respectively. RESULTS: The median values of urinary BPA, TCS and BP-3 concentrations for pregnant women were 1.75 µg/L, 0.54 µg/L and 0.37 µg/L, while 1.29 µg/L, 6.64 µg/L and 1.39 µg/L for children, respectively. Maternal urinary BPA concentrations were in associations with 1.00% [95% confidence interval (CI): 0.20%, 1.92%] increases in cord serum FT4 concentrations and significantly associated with increased risks of total difficulties [odds ratio (OR): 1.45, 95% CI: 1.07, 1.97], while maternal urinary levels of BP-3 were significantly related to poorer prosocial behaviors (OR: 1.58, 95% CI: 1.04, 2.39) of children at 10 years of age. In sex-stratified analyses, maternal urinary BPA concentrations were related to increased total difficulty subscales only in boys. CONCLUSIONS: The findings indicated that higher prenatal urinary BPA concentrations were associated with increased risks of total difficulties, especially in boys and maternal urinary BP-3 concentrations were related to poorer prosocial behaviors at 10 years.


Assuntos
Fenol , Comportamento Problema , Compostos Benzidrílicos , Criança , China , Estudos de Coortes , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Recém-Nascido , Masculino , Exposição Materna , Fenóis , Gravidez , Glândula Tireoide
16.
PLoS One ; 15(7): e0236394, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32702712

RESUMO

BACKGROUND: Maldescended testes or cryptorchidism is a genital birth defect that affects 2-9% of all male new-borns. Over the last 40 years there have been reports of increased prevalence in countries like the US, the UK and the Scandinavian countries. This possible increase has in some studies been linked to a foetal exposure to chemical pollutants. In this matched case-control study, we analysed maternal serum samples in early pregnancy for three different organochlorine compounds, to investigate whether the levels were associated with the risk of cryptorchidism. METHOD: Maternal serum samples taken during the first trimester of pregnancy from 165 cases (boys born with cryptorchidism) and 165 controls, matched for birth year and maternal age, parity and smoking habits during the pregnancy, were retrieved from the Southern Sweden Maternity Biobank. The samples were analysed for 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), dichlorodiphenyltrichloroethane (p,p'-DDE) and hexachlorobenzene (HCB), using gas chromatography mass spectrometry. Associations between exposure and cryptorchidism were evaluated by conditional logistic regression. RESULTS: We found no statistically significantly associations between exposure to these compounds and cryptorchidism, either when the exposure variables were used as a continuous variable, or when the exposure levels were divided in quartiles. CONCLUSION: We found no evidence of an association between maternal levels of PCB-153, p,p'-DDE or HCB during the pregnancy and the risk of having cryptorchidism in the sons.


Assuntos
Criptorquidismo/sangue , Poluentes Ambientais/sangue , Hidrocarbonetos Clorados/sangue , Exposição Materna/efeitos adversos , Adulto , Estudos de Casos e Controles , Criptorquidismo/induzido quimicamente , Criptorquidismo/epidemiologia , Criptorquidismo/patologia , Diclorodifenil Dicloroetileno/sangue , Diclorodifenil Dicloroetileno/toxicidade , Poluentes Ambientais/toxicidade , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Hexaclorobenzeno/sangue , Hexaclorobenzeno/toxicidade , Humanos , Hidrocarbonetos Clorados/toxicidade , Recém-Nascido , Masculino , Bifenilos Policlorados/sangue , Bifenilos Policlorados/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Suécia/epidemiologia
17.
Chem Biol Interact ; 328: 109189, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32622864

RESUMO

Di-n-butyl phthalate (DBP) is a pollutant that is widely present in the environment. We have previously demonstrated that maternal exposure to DBP resulted in renal fibrosis in offspring, but the underlying mechanism was not well elucidated. Therefore, the current study aims to understand the underlying molecular mechanisms in these sex-specific developmental alterations. Here, we used RNA-seq analysis to explore the underlying molecular mechanisms of DBP-associated renal fibrosis. Pregnant rats received DBP orally at a dose of 850 mg/kg BW/day during gestational days 14-18. Upregulated autophagy in renal tubules in offspring was confirmed in the DBP-treated group via accessing LC3Ⅱ/Ⅰ protein expression. Increased expression of the HhIP gene was found in the DBP-treated group via RNA-seq analysis. Immunohistochemistry (IHC) staining and Western blot analysis confirmed increased expression of HhIP protein and inhibited hedgehog signaling. Increased HhIP expression further leaded to impaired activation of hedgehog signaling, which is critical for normal embryonic development. Additional in vitro experiments on renal tubular cells suggest that inactivation of hedgehog signaling induced autophagy in renal tubular cells. Taken together, our findings show that maternal exposure to DBP induced autophagy through regulation of hedgehog signaling via overexpression of HhIP in foetal renal tubular cells, which may be essential for renal fibrosis development.


Assuntos
Autofagia , Dibutilftalato/toxicidade , Proteínas Hedgehog/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Transdução de Sinais , Animais , Animais Recém-Nascidos , Autofagia/efeitos dos fármacos , Linhagem Celular , Feminino , Túbulos Renais/efeitos dos fármacos , Exposição Materna , Gravidez , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
18.
Nat Commun ; 11(1): 3593, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681096

RESUMO

During pregnancy, maternal endocrine signals drive fetal development and program the offspring's physiology. A disruption of maternal glucocorticoid (GC) homeostasis increases the child's risk of developing psychiatric disorders later in life. We here show in mice, that the time of day of antenatal GC exposure predicts the behavioral phenotype of the adult offspring. Offspring of mothers receiving GCs out-of-phase compared to their endogenous circadian GC rhythm show elevated anxiety, impaired stress coping, and dysfunctional stress-axis regulation. The fetal circadian clock determines the vulnerability of the stress axis to GC treatment by controlling GC receptor (GR) availability in the hypothalamus. Similarly, a retrospective observational study indicates poorer stress compensatory capacity in 5-year old preterm infants whose mothers received antenatal GCs towards the evening. Our findings offer insights into the circadian physiology of feto-maternal crosstalk and assign a role to the fetal clock as a temporal gatekeeper of GC sensitivity.


Assuntos
Relógios Circadianos/efeitos dos fármacos , Glucocorticoides/efeitos adversos , Exposição Materna/efeitos adversos , Transtornos Mentais/etiologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ansiedade , Comportamento/efeitos dos fármacos , Feminino , Glucocorticoides/administração & dosagem , Humanos , Recém-Nascido Prematuro/psicologia , Masculino , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Gravidez , Complicações na Gravidez/tratamento farmacológico , Cuidado Pré-Natal , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo
19.
Environ Health ; 19(1): 83, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32664952

RESUMO

BACKGROUND: Parabens are a group of esters of para-hydroxybenzoic acid utilized as antimicrobial preservatives in many personal care products. Epidemiological studies regarding the adverse effects of parabens on fetuses are limited. The aim of this study was to determine the association between placental paraben exposure and birth outcomes. We assessed paraben concentrations in placental tissue, which potentially gives a better understanding of fetal exposure than the maternal urinary concentrations which are the current golden standard. METHODS: Placental tissue was collected immediately after birth from 142 mother-child pairs from the ENVIRONAGE birth cohort. The placental concentrations of four parabens (methyl (MeP), ethyl (EtP), propyl (PrP), and butyl (BuP)) were determined by ultra-performance liquid chromatography coupled with tandem mass-spectrometry. Generalized linear regression models were used to determine the association between paraben exposure levels and birth outcomes. RESULTS: The geometric means of placental MeP, EtP, PrP, and BuP were 1.84, 2.16, 1.68 and 0.05 ng/g tissue, respectively. The sum of parabens (∑ parabens, including MeP, EtP and PrP) was negatively associated with birth weight in newborn girls (- 166 g, 95% CI: - 322, - 8.6, p = 0.04) after adjustment for a priori selected covariates. The sum of parabens was negatively associated with head circumference (- 0.6 cm, 95% CI: - 1.1, - 0.2, p = 0.008) and borderline associated with birth length (- 0.6 cm, 95% CI:-1.3, 0.1, p = 0.08). In newborn girls the placental concentration of EtP was negatively associated with head circumference (- 0.6 cm, 95% CI:-1.1, - 0.1, p = 0.01) and borderline significantly associated with birth weight and birth length. Lastly, placental EtP and ∑parabens were negatively associated with placental weight in newborn girls but not in newborn boys (- 45.3 g, 95% CI:-86.2, - 4.4, p = 0.03). CONCLUSION: The negative association between maternal paraben exposure and birth outcomes warrants further research and follow-up over time to determine long term effects of gestational exposure to parabens.


Assuntos
Peso ao Nascer , Poluentes Ambientais/metabolismo , Cabeça/anatomia & histologia , Exposição Materna , Parabenos/metabolismo , Placenta/química , Bélgica , Estudos de Coortes , Monitoramento Ambiental , Feminino , Humanos , Recém-Nascido , Gravidez
20.
Toxicol Lett ; 331: 124-129, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32534006

RESUMO

DNA damage quantified as the comet tail length was assessed using in vitro and in vivo comet assay on one- and two-cell mouse embryos obtained by natural mating. The use of a protocol with three layers of agarose reduces the embryo loss and makes it possible to study a small number of embryos. A significantly lower level of basal, but not induced DNA damage was found in embryos with cleaved zona pellucida compared to embryos with intact zona pellucida. There were no significant differences in the length of the comet's tail between embryos lysed in different lysis solutions, both in cases of basal and induced DNA damage. A significant increase in the comet tail length was detected in one-cell embryos of mice treated with methyl methanesulfonate and etoposide compared to the control. The data show that DNA damage induced in maternal germ cells persists, which can be detected in embryos using the comet assay.


Assuntos
Dano ao DNA , Embrião de Mamíferos/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Mutagênicos/toxicidade , Zona Pelúcida/efeitos dos fármacos , Animais , Ensaio Cometa , Embrião de Mamíferos/patologia , Desenvolvimento Embrionário/genética , Feminino , Masculino , Exposição Materna , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Gravidez , Zona Pelúcida/patologia
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