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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.
Ecotoxicol Environ Saf ; 205: 111154, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810643

RESUMO

The study focused on the toxicological effect of Di-n-butyl phthalate (DBP) on the expression of Phosphorylated signal transducer and activator of transcription 1 (pSTAT1) -regulated Forkhead box protein M1 (FoxM1), which might provide a new understanding of gestational diabetes mellitus (GDM) development and a potential target for treatment. Streptozotocin (STZ) (40 mg/kg) was introduced in maternal rats by intraperitoneal injection on gestation day 0 (GD 0) in the STZ and STZ + DBP groups. DBP was introduced in maternal rats by oral feeding in the STZ + DBP group over the following 3 days (750 mg/kg/day). The changes in fasting blood glucose level in rats were detected on GD 1 and GD 5. The insulin levels in maternal rats and PIBCs were measured on GD 18. The Oral Glucose Tolerance Test (OGTT) test was performed on GD 18 to check the stability of the GDM model. The primary islet ß cells (PIBCs) were established for in vitro experiments. We examined the FoxM1 and pSTAT1 expression in pancreas by immunohistochemistry. Real-time PCR and Western blot were used to detect the pSTAR1 and FoxM1 protein and mRNA gene expression levels in PIBCs. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis was used to test the viability and apoptosis of cells. The results showed that the STZ + DBP group had higher glucose and lower insulin secretion levels than the other groups by both fasting test and OGTT. FoxM1 was significantly suppressed while pSTAT1 was highly expressed after DBP exposure. FoxM1 could be regulated by pSTAT1. DBP can influence the progression of GDM through its toxicological effect, which significantly increases the expression of pSTAT1 and suppresses FoxM1, causing a decline in ß cell viability.


Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Gestacional/induzido quimicamente , Dibutilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Proteína Forkhead Box M1/metabolismo , Exposição Materna/efeitos adversos , Fator de Transcrição STAT1/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Gestacional/metabolismo , Feminino , Proteína Forkhead Box M1/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Fosforilação , Gravidez , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT1/genética , Transdução de Sinais
3.
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
4.
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
5.
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
6.
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
7.
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
8.
Am J Physiol Heart Circ Physiol ; 319(2): H282-H305, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32559138

RESUMO

Ambient air, occupational settings, and the use and distribution of consumer products all serve as conduits for toxicant exposure through inhalation. While the pulmonary system remains a primary target following inhalation exposure, cardiovascular implications are exceptionally culpable for increased morbidity and mortality. The epidemiological evidence for cardiovascular dysfunction resulting from acute or chronic inhalation exposure to particulate matter has been well documented, but the mechanisms driving the resulting disturbances remain elusive. In the current review, we aim to summarize the cellular and molecular mechanisms that are directly linked to cardiovascular health following exposure to a variety of inhaled toxicants. The purpose of this review is to provide a comprehensive overview of the biochemical changes in the cardiovascular system following particle inhalation exposure and to highlight potential biomarkers that exist across multiple exposure paradigms. We attempt to integrate these molecular signatures in an effort to provide direction for future investigations. This review also characterizes how molecular responses are modified in at-risk populations, specifically the impact of environmental exposure during critical windows of development. Maternal exposure to particulate matter during gestation can lead to fetal epigenetic reprogramming, resulting in long-term deficits to the cardiovascular system. In both direct and indirect (gestational) exposures, connecting the biochemical mechanisms with functional deficits outlines pathways that can be targeted for future therapeutic intervention. Ultimately, future investigations integrating "omics"-based approaches will better elucidate the mechanisms that are altered by xenobiotic inhalation exposure, identify biomarkers, and guide in clinical decision making.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Sistema Cardiovascular/efeitos dos fármacos , Exposição por Inalação/efeitos adversos , Material Particulado/efeitos adversos , Adaptação Fisiológica , Adolescente , Adulto , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatologia , Reprogramação Celular , Epigênese Genética , Feminino , Humanos , Masculino , Exposição Materna/efeitos adversos , Camundongos , Pessoa de Meia-Idade , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Medição de Risco , Fatores de Risco , Adulto Jovem
9.
PLoS One ; 15(6): e0234357, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32516339

RESUMO

Congenital heart defects (CHDs) affect approximately 1% of newborns. Epidemiological studies have identified several genetically-mediated maternal phenotypes (e.g., pregestational diabetes, chronic hypertension) that are associated with the risk of CHDs in offspring. However, the role of the maternal genome in determining CHD risk has not been defined. We present findings from gene-level, genome-wide studies that link CHDs to maternal effect genes as well as to maternal genes related to hypertension and proteostasis. Maternal effect genes, which provide the mRNAs and proteins in the oocyte that guide early embryonic development before zygotic gene activation, have not previously been implicated in CHD risk. Our findings support a role for and suggest new pathways by which the maternal genome may contribute to the development of CHDs in offspring.


Assuntos
Cardiopatias Congênitas/genética , Herança Materna/genética , Adulto , Estudos de Casos e Controles , Pré-Escolar , Família , Feminino , Testes Genéticos/métodos , Cardiopatias Congênitas/etiologia , Humanos , Hipertensão/genética , Lactente , Recém-Nascido , Masculino , Exposição Materna/efeitos adversos , Pessoa de Meia-Idade , Oócitos/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Proteostase/genética , Fatores de Risco
10.
Ecotoxicol Environ Saf ; 201: 110726, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32480160

RESUMO

BACKGROUND: Impaired in utero fetal growth trajectory may have long term health consequences of the newborns and increase risk of adulthood metabolic diseases. Prenatal exposure to air pollution has been linked to fetal development restriction; however, the impact of exposure to ambient air pollutants on the entire course of intrauterine fetal development has not been comprehensively investigated. METHODS: During 2015-2018, two cohorts of mother-infant dyads (N = 678 and 227) were recruited in Shanghai China, from which three categories of data were systematically collected: (1) daily exposure to six air pollutants during pregnancy, (2) fetal biometry in the 2nd (gestational week 24, [GW24]) and 3rd trimester (GW36), and (3) neonatal outcomes at birth. We investigated the impact of prenatal exposure to air pollutant mixture on the trajectory of fetal development during the course of gestation, adjusting for a broad set of potential confounds. RESULTS: Prenatal exposure to PM2.5, PM10, SO2 and O3 significantly reduced fetal biometry at GW24, where SO2 had the most potent effect. For every 10 µg/m3 increment increase of daily SO2 exposure during the 1st trimester shortened femur length by 2.20 mm (p = 6.7E-21) translating to 5.3% reduction from the average of the study cohort. Prenatal air pollution exposure also decreased fetal biometry at GW36 with attenuated effect size. Comparing to the lowest exposed quartile, fetus in the highest exposed quartile had 6.3% (p = 3.5E-5) and 2.1% (p = 2.4E-3) lower estimated intrauterine weight in GW24 and GW36, respectively; however, no difference in birth weight was observed, indicating a rapid catch-up growth in the 3rd trimester. CONCLUSIONS: To our knowledge, for the first time, we demonstrated the impact of prenatal exposure to ambient air pollutants on the course of intrauterine fetal development. The altered growth trajectory and rapid catch-up growth in associated with high prenatal exposure may lead to long-term predisposition for adulthood metabolic disorders.


Assuntos
Poluentes Atmosféricos/toxicidade , Desenvolvimento Fetal/efeitos dos fármacos , Exposição Materna/efeitos adversos , Material Particulado/toxicidade , Adulto , Poluentes Atmosféricos/química , China/epidemiologia , Estudos de Coortes , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Material Particulado/química , Gravidez
11.
Chemosphere ; 256: 127169, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32464364

RESUMO

Parental exposure to perfluorobutane sulfonate (PFBS), an aquatic pollutant of emerging concern, is previously found to impair the embryonic development of offspring. However, the impairing mechanisms remain to clarify. In the present study, adult zebrafish were exposed to 0, 10 and 100 µg/L PFBS for 28 d, after which disturbances in maternal transcript transfer and offspring embryogenesis were investigated. Prior to zygotic genome activation, high-throughput transcriptomic sequencing revealed that parental PFBS exposure significantly altered the transcript profile of maternal origin in offspring eggs, while toxic actions varied as a function of PFBS concentrations. In offspring eggs derived from 10 µg/L exposure group, differential transcripts were mainly associated with the histone-DNA interaction of nucleosome, which would modify the compacted chromatin configuration and accessibility of transcriptional factors to DNA sequences. In this regard, the timing of zygotic genome activation was presumably disrupted. Parental exposure to 100 µg/L PFBS primarily interrupted the maternal transfer of adherens junction transcripts, which was supposed to dysregulate the cell-cell adhesion during early embryo formation. Development and growth of offspring embryos were significantly compromised by parental PFBS exposure, as exemplified by higher mortality, delayed hatching, slower heart rate, reduced body weight and neurobehavioral disorders. Overall, the present study presented the first toxicological evidence about the disturbances of PFBS in maternal transcript transfer, although the inherent linkage between maternal transcript modifications and offspring development defects still needs future works to construct.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Fluorcarbonetos/toxicidade , Exposição Materna/efeitos adversos , Ácidos Sulfônicos/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Animais , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Histonas/metabolismo , Reprodução , Zigoto/efeitos dos fármacos
12.
Chemosphere ; 255: 126920, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32387734

RESUMO

The pathological traits or diseases susceptibility caused by maternal exposure to environmental adverse insults (infection, malnutrition, environmental toxicants) could be transmitted across generations. It remains uncertain, however, whether the neurodevelopmental disturbances of offspring induced by maternal exposure to PM2.5 during early life can be inherited by subsequent generations without further exposure. In the current study, using transgenerational animal models, we found that F1 female showed poorer performance in Morris Water Maze (MWM), and the deficits in spatial learning and memory similarly presented in F2-F3 female. The transgenerationally-transmitted neurobehavioral disorders were mediated both via maternal and paternal lineage. Since the epigenetic modifications have been reported to be involved in the disturbed neurodevelopment induced by maternal exposure to detrimental environmental factors during early life, we further explored the possible epigenetic mechanism of the transgenerational effects. Intriguingly, the results displayed the significant increase in expression of Dnmt3a in F1 female offspring. And the hypermethylation of Bdnf promoter Ⅳ and downregulated expression of Bdnf in hippocampus were stably transmitted across the generations until the third generation. There was another interesting finding that the transgenerational effects were sex-specific and only emerged in female offspring. Together, our study indicated for the first time that maternal exposure to PM2.5 during early life could detrimentally affect neurobehaviors in multiple generations, and the declined expression of Bdnf induced by hypermethylation of Bdnf promoter Ⅳ mediated by Dnmts might be the potential molecular mechanism.


Assuntos
Exposição Materna/estatística & dados numéricos , Material Particulado/toxicidade , Animais , Metilação de DNA , Epigênese Genética , Feminino , Humanos , Masculino , Exposição Materna/efeitos adversos , Transtornos do Neurodesenvolvimento/epidemiologia , Fenótipo , Gravidez
13.
Ecotoxicol Environ Saf ; 199: 110697, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32416368

RESUMO

OBJECTIVES: Based on a prospective birth cohort, we aimed to investigate the associations between maternal circulating metals exposure and gestational weight gain (GWG) across pregnancy, and explore whether maternal inflammatory cytokines could contribute to the GWG changes associated with metals exposure. METHODS: A total of 234 pregnant women from the Shanghai Maternal-Child Pairs cohort were enrolled in this panel study. 547 blood and serum samples were collected from pregnant women during three follow-up visits, and the circulating concentrations of 27 metals were determined by using the ICP-MS method. Five inflammatory cytokines in serum samples were measured through multiplexed immunoassays. The linear mixed models were used to estimate the association between each ln-transformed metal concentration and GWG across pregnancy. Robust generalized linear regression models were used to estimate the associations among circulating metals, GWG, and inflammatory cytokines. RESULTS: The GWG during pregnancy was 13.76 ± 1.40 kg. The concentrations Co, Zn, Mo, B, Ag and Te in second or third trimesters were significantly higher than those in early second trimester. The concentration of Mg decreased with the increase of pregnant weeks and no significant statistical differences were found in the concentrations of other metals in different trimesters. Among the detected 26 metals, Li and Sr concentrations were positively associated with GWG in the third trimester. The GWG increased by 0.100 kg (95% CI 0.005, 0.195) and 0.120 kg (95% CI 0.009, 0.232) with each one ln-concentration increase in circulating Li and Sr concentrations, respectively. Concentrations of Li and Sr in the third trimester were positively associated with tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, but negatively associated with growth differentiation factor-15 (GDF-15) significantly. Besides, IL-6 and GDF-15 levels were associated with the increase or decrease of overall pregnancy GWG, respectively. CONCLUSIONS: Results showed that maternal exposure to Li and Sr were associated with increased GWG, in which maternal IL-6 and GDF-15 could contribute to the associations between metal exposures and GWG in pregnant women.


Assuntos
Poluentes Ambientais/sangue , Ganho de Peso na Gestação/efeitos dos fármacos , Fator 15 de Diferenciação de Crescimento/sangue , Interleucina-6/sangue , Lítio/sangue , Exposição Materna/efeitos adversos , Estrôncio/sangue , Adulto , China , Estudos de Coortes , Feminino , Humanos , Gravidez , Trimestres da Gravidez , Estudos Prospectivos
14.
Chemosphere ; 256: 127133, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32454355

RESUMO

Atmospheric fine particulate matter exposure (PM2.5) can increase the incidence and mortality of heart disease, and raise the risk of fetal congenital heart defect, which have recently drawn much attention. In this study, C57BL/6 mice were exposed to PM2.5 (approximately equivalent to 174 µg/m3) by intratracheal instillation during the gestation. After birth, 10 weeks old offspring mice were divided into four groups: male exposed group (ME), female exposed group (FE), male control group (MC), female control group (FC). The pathological injury, pro-inflammatory cytokines, histone acetylation levels, and expressions of GATA-binding protein 4 (GATA4) and downstream genes were investigated. The results showed that exposure to PM2.5 in utero increased pathological damage and TNF-α and IL-6 levels in hearts of offspring mice, and effects in ME were more serious than FE. Notably, GATA4 protein levels in hearts in ME were significantly lower than that of MC, accompanied by down-regulation of histone acetyltransferase (HAT)-p300 and up-regulation of histone deacetylase-SIRT3. As GATA4 downstream genes, ratios of ß-MHC gene expression to α-MHC significantly raised in ME relative to the MC. Results of chromatin immunoprecipitation (ChIP)-qPCR assay found that binding levels of acetylated histone 3 lysine 9 (H3K9ac) in GATA4 promoter region in the hearts of ME or FE were markedly decreased compared with their corresponding control groups. It suggested that maternal exposure to PM2.5 may cause cardiac injury in the offspring, heart damage of male mice was worse than female mice, in which process HAT-p300, H3K9ac, transcription factor GATA4 may play an important regulation role.


Assuntos
Poluentes Atmosféricos/toxicidade , Fator de Transcrição GATA4/genética , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/efeitos dos fármacos , Histonas/metabolismo , Material Particulado/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Acetilação , Animais , Animais Recém-Nascidos , Regulação para Baixo , Proteína p300 Associada a E1A/metabolismo , Feminino , Coração/embriologia , Coração/crescimento & desenvolvimento , Histonas/genética , Humanos , Masculino , Exposição Materna/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Caracteres Sexuais , Regulação para Cima
15.
PLoS One ; 15(4): e0232454, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353037

RESUMO

OBJECTIVE: This study attempts to investigate the association between maternal exposure to intimate partner violence (IPV) and morbidity and mortality of children. STUDY DESIGN: A cross-sectional study was carried out using the most recent nationally representative data of the National Family Health Survey (NFHS-4) in India. RESULTS: The prevalence of morbidity and mortality was higher among the children whose mothers faced physical, emotional, or sexual violence perpetrated by the partner than those who did not encounter any violence. Multivariate analysis revealed that maternal exposure to physical and sexual violence significantly increased the risks of childhood diarrhea and fever; and emotional violence was associated with an increased likelihood of diarrhea, fever, and acute respiratory infection (ARI) in the past 2 weeks among under-five children. Moreover, women's experience of physical and emotional violence were associated with increased odds of infant mortality (<1 year) and under-five mortality (<5 years) in crude analysis. However, these associations were insignificant in the adjusted analysis. Similarly, we did not find any significant association between maternal exposure to IPV and child mortality (1 to < 5 years). CONCLUSION: Maternal experience of domestic violence was associated with an increased risk of childhood morbidity (diarrhea, fever and ARI). However, no significant association was found between violence against women and mortality of children. Prevention of domestic violence may help to reduce childhood illnesses. Additional efforts are needed for maternal and child healthcare programs to improve health status of women and children.


Assuntos
Saúde da Criança/estatística & dados numéricos , Mortalidade da Criança , Exposição Materna/efeitos adversos , Maus-Tratos Conjugais/estatística & dados numéricos , Adolescente , Adulto , Pré-Escolar , Estudos Transversais , Diarreia/epidemiologia , Feminino , Febre/epidemiologia , Inquéritos Epidemiológicos/estatística & dados numéricos , Humanos , Índia/epidemiologia , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prevalência , Infecções Respiratórias/epidemiologia , Fatores de Risco , Adulto Jovem
17.
Nanotoxicology ; 14(5): 711-724, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32374645

RESUMO

Prenatal particle exposure has been shown to increase allergic responses in offspring. Carbon nanotubes (CNTs) possess immunomodulatory properties, but it is unknown whether maternal exposure to CNTs interferes with offspring immune development. Here, C57Bl/6J female mice were intratracheally instilled with 67 of µg multiwalled CNTs on the day prior to mating. After weaning, tolerance and allergy responses were assessed in the offspring. Offspring of CNT-exposed (CNT offspring) and of sham-exposed dams (CTRL offspring) were intranasally exposed to ovalbumin (OVA) once weekly for 5 weeks to induce airway mucosal tolerance. Subsequent OVA sensitization and aerosol inhalation caused low or no OVA-specific IgE production and no inflammation. However, the CNT offspring presented with significantly lower OVA-specific IgG1 levels than CTRL offspring. In other groups of 5-week-old offspring, low-dose sensitization with OVA and subsequent OVA aerosol inhalation led to significantly lower OVA-specific IgG1 production in CNT compared to CTRL offspring. OVA-specific IgE and airway inflammation were non-significantly reduced in CNT offspring. The immunomodulatory effects of pre-gestational exposure to multiwalled CNTs were unexpected, but very consistent. The observations of suppressed antigen-specific IgG1 production may be of importance for infection or vaccination responses and warrant further investigation.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Antígenos/toxicidade , Hipersensibilidade/etiologia , Nanotubos de Carbono/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Antígenos/química , Feminino , Humanos , Hipersensibilidade/imunologia , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Inflamação , Exposição Materna/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Nanotubos de Carbono/química , Ovalbumina/imunologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia
18.
Nat Commun ; 11(1): 2555, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444624

RESUMO

Fetal alcohol exposure (FAE) is the leading preventable developmental cause of cognitive dysfunction. Even in the absence of binge drinking, alcohol consumption during pregnancy can leave offspring deficient. However, the mechanisms underlying these deficiencies are unknown. Using a mouse model of gestational ethanol exposure (GEE), we show increased instrumental lever-pressing and disruption of efficient habitual actions in adults, indicative of disrupted cognitive function. In vivo electrophysiology reveals disrupted action encoding in dorsolateral striatum (DLS) associated with altered habit learning. GEE mice exhibit decreased GABAergic transmission onto DLS projection neurons, including inputs from parvalbumin interneurons, and increased endocannabinoid tone. Chemogenetic activation of DLS parvalbumin interneurons reduces the elevated lever pressing of GEE mice. Pharmacologically increasing endocannabinoid tone mimics GEE effects on cognition and synaptic transmission. These findings show GEE induces long-lasting deficits in cognitive function that may contribute to human FAE, and identify potential mechanisms for future therapeutic targeting.


Assuntos
Corpo Estriado/fisiopatologia , Etanol/efeitos adversos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/psicologia , Animais , Cognição/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Etanol/metabolismo , Feminino , Desenvolvimento Fetal , Humanos , Masculino , Camundongos Endogâmicos C57BL , Linhagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
19.
Med J Aust ; 212(11): 519-524, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32452049

RESUMO

OBJECTIVES: To evaluate whether cannabis use during pregnancy is associated with adverse neonatal outcomes that are independent of cigarette smoking. DESIGN: Prospective cohort study. SETTING: Adelaide (Australia), Auckland (New Zealand), Cork (Ireland), and Leeds, London and Manchester (United Kingdom). PARTICIPANTS: 5610 pregnant nulliparous women with low risk pregnancies recruited for the Screening for Pregnancy Endpoints (SCOPE) study, November 2004 - February 2011. At 14-16 weeks of pregnancy, women were grouped by self-reported cannabis use. MAIN OUTCOME MEASURES: Infant birthweight, head circumference, birth length, gestational age, and severe neonatal morbidity or mortality. RESULTS: 314 women (5.6%) reported using cannabis in the 3 months before or during their pregnancy; 97 (31%) stopped using it before and 157 (50%) during the first 15 weeks of pregnancy, while 60 (19%) were still using cannabis at 15 weeks. Compared with babies of mother who had never used cannabis, infants of those who still used it at 15 weeks had lower mean values for birthweight (adjusted mean difference [aMD], -127 g; 95% CI, -238 to -17 g), head circumference (aMD, -0.5 cm; 95% CI, -0.8 to -0.1 cm), birth length (aMD, -0.8 cm; 95% CI, -1.4 to -0.2 cm), and gestational age at birth (aMD, -8.1 days; 95% CI, -12.1 to -4.0 days). The differences for all outcomes except gestational age were greater for women who used cannabis more than once a week than for those who used it less frequently. CONCLUSIONS: Continuing to use cannabis during pregnancy is an independent risk factor for poorer neonatal outcomes.


Assuntos
Fumar Maconha/efeitos adversos , Exposição Materna/efeitos adversos , Resultado da Gravidez , Adulto , Austrália , Peso ao Nascer , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Irlanda , Nova Zelândia , Gravidez , Estudos Prospectivos , Reino Unido , Adulto Jovem
20.
J Toxicol Sci ; 45(5): 281-291, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32404560

RESUMO

Despite the developmental toxicity reported in animals, few epidemiologic studies have investigated the potential effects of prenatal exposure to pyrethroid pesticides (PYRs) on fetal growth. A birth cohort study was conducted to examine the association between prenatal exposure to PYRs and birth outcomes, and a nested case-control study was conducted in this cohort to evaluate the effects of PYR on congenital defects. The assessment of PYR exposure was based on self-reported household pesticide use and urinary PYR metabolite levels. We found that pregnant women in this region were ubiquitously exposed to low-level PYRs, although few reported household pesticide use. Women who often ate bananas or cantaloupes had a higher level of urinary 3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA), and the number of fruit types consumed by pregnant women was positively related to the concentrations of 3-phenoxybenzoic acid (3PBA) and total PYR metabolites (P < 0.05). Increased urinary 4-fluoro-3-phenoxybenzoic acid (4F3PBA), DBCA, and total PYR metabolites were associated with increased birth weight, length, and gestational age, and with decreased risk of small for gestational age (SGA) and/or premature birth. However, maternal household pesticides use was related to congenital anomalies. Thus, although prenatal exposure to low-dose PYRs promoted the fetal growth, the beneficial effects of fruit intake may outweigh the adverse effects of pesticide exposure. This study provided us an insight into the biological mechanisms for the effect of prenatal PYR exposure on fetal development, and suggested that further investigations in a larger study population with low-dose PYR exposure is needed.


Assuntos
Desenvolvimento Fetal/efeitos dos fármacos , Exposição Materna/efeitos adversos , Praguicidas/efeitos adversos , Piretrinas/efeitos adversos , Anormalidades Induzidas por Medicamentos/etiologia , Adulto , Estudos de Coortes , Feminino , Humanos , Troca Materno-Fetal , Praguicidas/metabolismo , Gravidez , Resultado da Gravidez , Piretrinas/metabolismo , Piretrinas/urina , Adulto Jovem
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