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1.
Klin Padiatr ; 231(5): 262-268, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31505693

RESUMO

OBJECTIVE: The consumption of illegal substances during pregnancy is an increasing social and medical issue. Main substances of prenatal drug exposure are beside tehtrahydrocannabinol (THC), opioids and methamphetamine. The effect of these substances on the long-term development of children remains uncertain. METHODS: Since 2012 newborn infants born at the university hospital of children at Leipzig which were prenatal exposed to drugs were followed long-term at the out-patient clinic for child protection. For 42 children with prenatal opioid or methamphetamine exposure the developmentent was analysed using the Bayley Scales (BSID III) at the age of 2-3 years. The children were compared with 84 unexposed control children. One case matched to 2 controls, adapted by age, gender, gestational age and birth weight. RESULTS: Motoric development between prenatal methylamphetamine, opioid exposed children and the control group showed no significant difference. Methylamphetamine exposed children (n=23) At 2 exposure show significantly lower scores in cognition and language (79,1 compared 95,9 of the control group), opioid exposed children have a slight cognitive deficits with a medium score of 91,7 (n=19). 56% of the methamphetamine group were developmentally retarded at the measurement date. Additionally, children had significant lower Bayley Scores which had single parent and/ or low educational and professional qualifications of their caregiver. Both substances increased the risk of postnatal complications to 46-53% despite of similar gestational ages in all groups. CONCLUSION: Children with prenatal methamphetamine or opioid exposure seem to have cognition and language deficits at 2 and 3 years of age. Methamphetamine might have a higher negative effect than opioids. The psychosocial risk factors associated with parental drug abuse are important for achieving age-appropriate development.


Assuntos
Analgésicos Opioides/toxicidade , Desenvolvimento Infantil/efeitos dos fármacos , Cognição/efeitos dos fármacos , Metanfetamina/toxicidade , Atividade Motora/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Comportamento do Lactente/efeitos dos fármacos , Comportamento do Lactente/psicologia , Recém-Nascido , Linguagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia
2.
Toxicol Lett ; 315: 64-76, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419470

RESUMO

To test the hypothesis that 3-7 ring polycyclic aromatic hydrocarbons (PAHs) are responsible for the prenatal developmental toxicity (PDT) as observed with some petroleum substances (PS), the present study evaluates the PDT potency of DMSO-extracts of 7 heavy fuel oils (HFO), varying in their PAH content, and 1 highly refined base oil (HRBO), containing no aromatics, in the embryonic stem cell test (EST). All DMSO-extracts of HFO inhibit ES-D3 cell differentiation in a concentration-dependent manner and their potency is proportional to the amount of 3-7 ring PAHs they contain. All DMSO-extracts of HFOs also show aryl hydrocarbon receptor (AhR)-mediated activities, as tested in the AhR-CALUX assay. Contrarily, the HRBO-extract tested negative in both assays. Co-exposure of ES-D3 cells with selected DMSO-extracts of PS and the AhR-antagonist trimethoxyflavone, successfully counteracted the PS-induced inhibition of ES-D3 cell differentiation, confirming the role of the AhR in mediating the observed PDT of PS extracts in the EST. A good correlation exists when comparing the in-vitro with the in-vivo PDT potencies of the PS under study. Altogether, our findings corroborate the hypothesis that PS-induced PDT is caused by 3-7 ring PAHs present in these substances and that the observed PDT is partially AhR-mediated.


Assuntos
Células-Tronco Embrionárias/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Petróleo/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Receptores de Hidrocarboneto Arílico/metabolismo , Bioensaio , Poluentes Ambientais/metabolismo , Feminino , Humanos , Petróleo/metabolismo , Gravidez
3.
Toxicol Lett ; 315: 87-95, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425726

RESUMO

Prenatal alcohol exposure (PAE) is often associated with congenital heart defects, most commonly septal, valvular, and great vessel defects. However, there have been no known studies on whether PAE affects the resulting fibroblast population after development, and whether this has any consequences in the postnatal period. Our previous study focused on the effects of PAE on the postnatal fibroblast population, which translated into changes in cardiac extracellular matrix (ECM) composition and cardiac function in the neonatal heart. Moreover, our lab has previously demonstrated that alcohol-induced fibrosis is mediated by oxidative stress mechanisms in adult rat hearts following chronic alcohol exposure. Thus, we hypothesize that PAE alters cardiac ECM composition that persists into the postnatal period, leading to cardiac dysfunction, and these effects are prevented by antioxidant treatment. To investigate these effects, pregnant mice were intraperitoneally injected with 2.9 g EtOH/kg body weight on gestation days 6.75 and 7.25. Controls were injected with vehicle saline. Randomly selected dams in both groups were then treated with 100 mg/kg body weight of the antioxidant N-acetylcysteine (NAC) immediately after EtOH or vehicle administration. Left ventricular (LV) chamber dimension and function were assessed in sedated animals on neonatal day 5 using echocardiography. Ejection fraction decreased in the PAE group. NAC treatment prevented this depression of systolic function in PAE neonates. Hearts were analyzed for expression of fibroblast activation markers. Alpha smooth muscle actin (α-SMA) increased in PAE neonatal hearts, and this increase was prevented by NAC treatment. In PAE pups, collagen I decreased, but collagen III expression increased compared to saline animals; the overall collagen I/III ratio significantly decreased. When PAE mice were treated with NAC, collagen I/III ratio did not change. Overall, our data demonstrate that prenatal alcohol exposure produces changes in collagen subtype in neonatal cardiac ECM and a decline in systolic function, and these adverse effects were prevented by NAC treatment.


Assuntos
Acetilcisteína/farmacologia , Alcoolismo/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Vasos Coronários/química , Etanol/toxicidade , Fibroblastos/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Camundongos , Gravidez
4.
Toxicol Lett ; 315: 39-46, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31442585

RESUMO

The recession of regulatory T cells (Tregs) is pivotal for type 1 diabetes (T1D) progressing. Our previous study observed the decreased Tregs in prenatal nicotine exposure (PNE) offspring, but whether this led to the onset of T1D remains uncertain. Thus, this study aimed to investigate the effects of PNE on T1D susceptibility and the role of PNE-suppressed Tregs in T1D of female offspring. The decreased body weights and elevated blood glucose levels from postnatal day (PND) 21 to PND 42 indicated that PNE caused persistent impaired glucose homeostasis in offspring. The elevated serum glutamic acid decarboxylase autoantibody, the "Gold Standard" for the detection of T1D, was observed on PND 42, suggesting the early stage of T1D in PNE offspring during adolescence. The reduced pancreatic islet areas and beta cells number in PNE offspring were observed at neonatal period and became more severe during adolescence. In addition, PNE caused immune dysfunction in offspring, manifested as suppressed thymic Tregs percentage from PND 4 to PND 42 and splenic Tregs/Th17 ratio on PND 42. In conclusion, PNE resulted in metabolic changes of offspring that were consistent with T1D characteristics, which could be the consequence of Tregs recession from early life to adolescence.


Assuntos
Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/fisiopatologia , Nicotina/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Feminino , Humanos , Camundongos , Gravidez
5.
BJOG ; 126(11): 1338-1345, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31188522

RESUMO

OBJECTIVE: Dolutegravir is recommended worldwide as a first-line antiretroviral therapy (ART) for individuals living with HIV. A recent study reported increased rates of neural tube defects in infants of dolutegravir-treated women. This study examined rates of congenital anomalies in infants born to women living with HIV (WLWH) in Canada. DESIGN: The Canadian Perinatal HIV Surveillance Programme captures surveillance data on pregnant WLWH and their babies and was analysed to examine the incidence of congenital anomalies. SETTING: Paediatric HIV clinics. POPULATION: Live-born infants born in Canada to WLWH between 2007 and 2017. METHODS: Data on mother-infant pairs, including maternal ART use at conception and during pregnancy, are collected by participating sites. MAIN OUTCOME MEASURES: Congenital anomalies. RESULTS: Of the 2423 WLWH, 85 (3.5%, 95% CI 2.85-4.36%) had non-chromosomal congenital anomalies. There was no evidence of a significant difference in rates of congenital anomalies between women who were on ART in their first trimester (3.9%, CI 1.7-7.6%) or later in the pregnancy (3.9%, 95% CI 2.6-5.6%). Four of the 80 (5.0%, 95% CI 1.4-12.3%) neonates born to WLWH on dolutegravir during the first trimester had congenital anomalies, none were neural tube defects (95% CI 0.00-3.10%). CONCLUSION: Despite recent evidence raising a safety concern, this analysis found no signal for increased congenital anomalies. TWEETABLE ABSTRACT: Five percent of the infants of Canadian women living with HIV on dolutegravir at conception had congenital anomalies; none had neural tube defects.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Anormalidades Congênitas/patologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Fármacos Anti-HIV/uso terapêutico , Canadá/epidemiologia , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/etiologia , Feminino , Infecções por HIV/transmissão , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Recém-Nascido , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Vigilância de Evento Sentinela
6.
Chemosphere ; 230: 432-439, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31121507

RESUMO

This study was conducted to investigate the effects of maternal exposure to BPA on testicular development in offspring males. Pregnant Kunming mice were randomly divided into 7 groups with 20 mice in each group. Group A was the control group and the mice were given distilled water orally. Mice in groups B, C, D, E, F, G received BPA orally at a dose of 0.05 mg/kg/d, 0.5 mg/kg/d, 5 mg/kg/d, 10 mg/kg/d, 20 mg/kg/d, 50 mg/kg/d, respectively. F0 mice were exposed to BPA for 40 days from gestation day 0 to lactation day 21. F1 male mice were sacrificed at weaning (postnatal day 21). Histological observations revealed architectural damages in testis in BPA exposed groups. The testicular organ index increased significantly when the BPA oral exposure dose was above 20 mg/kg/d (P < 0.05). BPA contents in serum of F1 male mice increased significantly when BPA was above 5 mg/kg/d (P < 0.05), while the contents significant increased in maternal serum when BPA was higher than 0.5 mg/kg/d. The damage of cell nuclear DNA of testis was significantly aggravated when BPA was above 5 mg/kg/d. The expression of AR in the testis was significantly increased when BPA was above 20 mg/kg/d (P < 0.05). Transcriptome sequencing showed that the Snrnp 40 which encoding U5 snRNA subunit was significantly up-regulated in spliceosome pathway, and the Hnrnpu which encoding splicing universal protein component was significantly down-regulated. The blockage of spliceosome might be one of the reasons why BPA affects testicular development.


Assuntos
Compostos Benzidrílicos/toxicidade , Poluentes Ambientais/toxicidade , Exposição Materna/efeitos adversos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Processamento de RNA/efeitos dos fármacos , Testículo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Perfilação da Expressão Gênica , Lactação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Testículo/embriologia , Testículo/crescimento & desenvolvimento , Testículo/metabolismo , Transcriptoma/efeitos dos fármacos
7.
Chemosphere ; 231: 25-31, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31128349

RESUMO

Atopic dermatitis (AD) is the most common childhood skin disease and the first step of atopic march. Perfluoroalkyl substance (PFAS) exposure is associated with atopic diseases, including AD. However, whether PFAS exposure is related to earlier AD onset remains unclear. We aimed to investigate the association between prenatal PFAS exposure and earlier onset of AD in children in a 5-year follow-up study. From 2001 to 2005, 1264 mother-infant pairs were recruited from eight Taiwanese maternity hospitals. PFAS levels were analyzed from cord blood. Information on children's health status, including AD occurrence, was obtained via phone interviews at multiple time points. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) concentrations were measured by ultra-high performance liquid chromatography/tandem mass spectrometry. Cox proportional hazards models assessed associations between prenatal PFAS exposure and early onset AD. Overall, 863 mother-infant pairs with complete measurements were recruited. The prevalence of physician-diagnosed AD before 5 years of age was 7.1%. PFOA and PFOS concentrations were grouped based on whether they were above the 75th percentile. PFOA exposure was positively associated with earlier onset of AD (Kaplan-Meier estimate, p = 0.014). In the Cox model, after adjusting for sex, family income, parental atopy, breast feeding, and maternal age at childbirth, significance was observed in children above the upper quartile (≥75th) of the PFOA group (hazard ratio: 1.89; 95% confidence interval, 1.10-3.16). Our findings suggested that children with higher prenatal PFOA exposure have a higher risk of earlier AD development. Minimizing early life PFAS exposure may help inhibit AD development.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Caprilatos/toxicidade , Dermatite Atópica/induzido quimicamente , Eczema/induzido quimicamente , Fluorcarbonetos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Aleitamento Materno , Criança , Saúde da Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Dermatite Atópica/epidemiologia , Eczema/epidemiologia , Feminino , Sangue Fetal/química , Seguimentos , Humanos , Lactente , Masculino , Idade Materna , Mães , Gravidez , Taiwan/epidemiologia
8.
Environ Sci Pollut Res Int ; 26(18): 18866-18875, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31062244

RESUMO

The study was conducted to investigate the liver toxicity in female offspring mice induced by maternal exposure to perfluorooctanoic acid (PFOA). Fifty pregnant Kunming mice were randomly divided into 5 groups with 10 of each, which were treated with 0.2 mL PFOA solution dissolved with deionized water at 0, 1, 2.5, 5, and 10 mg/kg BW, respectively, from the pregnancy day (PND) 0 to day 17. Female offspring mice were sacrificed to collect serum and liver at postpartum day 21. The results showed that PFOA significantly reduced the body weight at weaning and the survival rate of the female offspring mice (P < 0.01) increased the liver index of the pups (P < 0.01). Meanwhile, PFOA also caused hepatic bleeding, local necrosis, and enlargement of hepatocytes and vacuolization. The levels of serum AST, ALT, SOD, and CAT in PFOA treatment group were upregulated significantly (P < 0.01). The expressions of Acot1, Acox1, and Acsl1 genes were increased significantly (P < 0.01). The expression of PPAR-α gene was decreased significantly (P < 0.01). There was no significant difference in the expression of Cpt1a gene among the 5 groups. HAT activity was reduced significantly and HDAC activity was increased significantly. The expression of anti-acetyl-histone H3 and acetyl-histone H4 was reduced significantly. Thus, our findings indicate that exposure to PFOA during pregnancy affects the growth and development of the pups and causes liver damage, disrupting the secretion of enzymes involved in fatty acid oxidation induced by PPAR-α, leading to liver oxidative stress and a decrease in the degree of histone acetylation. Elevated HDAC may aggravate downstream fatty acid metabolism disorders through PPAR-α.


Assuntos
Caprilatos/toxicidade , Fluorcarbonetos/toxicidade , Histonas/metabolismo , Fígado/efeitos dos fármacos , Exposição Materna/efeitos adversos , PPAR alfa/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Acetilação , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Fígado/patologia , Camundongos , Necrose , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Distribuição Aleatória
9.
Ecotoxicol Environ Saf ; 180: 123-129, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31082575

RESUMO

1-Nitropyrene (1-NP), a typical nitrated polycyclic aromatic hydrocarbon, is widely distributed in the environment and is well known for its mutagenic effects. Recently, we found that gestational 1-NP exposure induced fetal growth restriction. In this study, we further evaluated the effect of in utero 1-NP exposure on postnatal growth and neurobehavioral development in the offspring. Pregnant mice were administered with 1-NP (10 µg/kg) by gavage daily in late pregnancy (GD13-GD17). The body weight of each offspring was measured from PND1 to 12 weeks postpartum. Exploration and anxiety related activities were detected by open-field test at 6 weeks postpartum. Learning and memory were assessed by Morris Water Maze at 7 weeks postpartum. And depressive-like behaviors were estimated by sucrose preference test at 10 weeks postpartum. Significant body weight reduction was observed in 1-NP-exposed female offspring at PND1, PND14 and PND21 while the lower body weight was only found at PND1 for 1-NP-exposed male offspring. Exploration and anxiety activities at puberty, and depressive-like behavior in adulthood were not disturbed in offspring prenatally exposed to 1-NP. Interestingly, spatial learning and memory ability at puberty was impaired in females but not in males prenatally exposed to 1-NP. These findings suggest that gestational 1-NP exposure delays postnatal growth and impaired neurobehavioral development in a gender-dependent manner.


Assuntos
Poluentes Ambientais/toxicidade , Exposição Materna/efeitos adversos , Mutagênicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Pirenos/toxicidade , Animais , Feminino , Masculino , Memória/efeitos dos fármacos , Camundongos Endogâmicos ICR , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Fatores Sexuais , Aprendizagem Espacial/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos
10.
Environ Pollut ; 251: 538-546, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108286

RESUMO

Chlorpyrifos (CPF), an organophosphate insecticide, has been linked to adverse neurodevelopmental effects in animal studies. However, little is known about long-term neurotoxicity of early-life CPF exposure in humans. We aimed to evaluate the associations of both prenatal and early childhood CPF exposure with neurodevelopment of children. In this observational study based on Sheyang Mini Birth Cohort, pregnant women were recruited from an agricultural region between June 2009 and January 2010, and their children were followed up from birth to age three. Urinary 3,5,6-Trichloro-2-pyridinol (TCPy), a specific metabolite of CPF, was quantified using large-volume-injection gas chromatography-tandem mass spectrometry. Developmental quotients (DQs) of children in motor, adaptive, language, and social areas were assessed by trained pediatricians. Data from 377 mother-child pairs were used in the current study. Associations between CPF exposure and neurodevelopmental indicators were estimated using generalized linear models with adjustment for potential confounders. The median concentrations of TCPy in maternal and children's urine were 5.39 µg/L and 5.34 µg/L, respectively. No statistically significant association was found between maternal urinary TCPy concentrations and children neurodevelopment. While for postnatal exposure, we found lower motor area DQ score 0.61 [95% confidence interval (CI): -1.13, -0.09; p = 0.02] and social area DQ score 0.55 (95% CI: -1.07, -0.03; p = 0.04) per one-unit increase in the ln-transformed childhood urinary TCPy concentrations. Further stratification by sex indicated that the inverse associations were only observed in boys, but not in girls. Our findings suggest that adverse neurodevelopmental effects were associated with early childhood CPF exposure, but not prenatal exposure. Additional longitudinal studies are needed to replicate these results and to further understand the toxicological mechanisms of CPF.


Assuntos
Comportamento Infantil/efeitos dos fármacos , Clorpirifos/toxicidade , Exposição Ambiental/efeitos adversos , Inseticidas/toxicidade , Sistema Nervoso/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Criança , Pré-Escolar , China , Clorpirifos/urina , Feminino , Humanos , Inseticidas/urina , Estudos Longitudinais , Masculino , Sistema Nervoso/embriologia , Sistema Nervoso/crescimento & desenvolvimento , Gravidez , Efeitos Tardios da Exposição Pré-Natal/urina , Estudos Prospectivos , Piridonas/urina , Fatores Sexuais , Inquéritos e Questionários
11.
Artigo em Inglês | MEDLINE | ID: mdl-31013727

RESUMO

Background: Exposure to endocrine disruptors is on the rise, with new compounds regularly incriminated. In animals and humans, this exposure during critical developmental windows has been associated with various developmental abnormalities, including the emergence of psychiatric disorders. We aimed to review the association between perinatal endocrine disruptor exposure and neurodevelopmental disorders in humans, focusing on cognitive and psychiatric disorders. Methods: We performed a systematic review with key words referring to the fields of neurodevelopment and endocrine disruptors. We reviewed 896 titles, choosing studies on the basis of titles and abstracts. We searched through the methodology sections to find perinatal exposure and neurodevelopmental disorders, following the categories indicated in the Diagnostic and Statistic Manual of Mental Disorders (5th edition). References in some studies brought us to a total of 47 studies included here. Results: Convergent studies report an association between exposure to endocrine disruptors and autism spectrum disorder, attention-deficit hyperactivity disorder, global developmental delay, intellectual disability, communication disorders and unspecified neurodevelopmental disorders. Conclusion: Sufficient data exist to report that exposure to some endocrine disruptors is a risk factor for the emergence of neurodevelopmental disorders. Studying endocrine disruptor exposure in humans is still associated with some limits that are difficult to overcome.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/induzido quimicamente , Disruptores Endócrinos/toxicidade , Exposição Ambiental , Exposição Materna/efeitos adversos , Criança , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
12.
J Environ Radioact ; 204: 125-131, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029986

RESUMO

Uranium and thorium are common radioactive elements that exist in the environment. However, few environmental epidemiological studies have focused on their possible effects on congenital malformations. Here, we explored the association between uranium and thorium concentrations in maternal scalp hair grown from 3 months before to 3 months after conception, namely during the periconceptional period and the risk of orofacial clefts (OFCs) in offspring. Our study included 153 women whose pregnancies were affected by OFCs (cases) and 601 women who delivered infants without birth defects (controls) from four provinces in China. Face-to-face interviews were used to collect sociodemographic characteristics with a structured questionnaire. Concentrations of uranium and thorium in maternal scalp hair grown during the periconceptional period were detected using inductively coupled plasma-mass spectrometry. The risk of OFCs in association with higher concentrations of the two radioactive elements was estimated using odds ratios (ORs) and 95% confidence intervals (CIs) while adjusting for potential confounding factors. The levels of uranium and thorium in maternal hair were in agreement with the published literature. After adjusting for several confounders, the ORs of thorium in the highest, upper, and lower quartile versus the lowest quartile were 2.63 (95% CI, 1.41-4.92), 1.98 (95% CI, 1.03-3.79), and 2.73 (95% CI, 1.46-5.12), respectively. No association was found between levels of uranium and the risk of OFCs. Maternal periconceptional exposure to thorium may be a risk factor for OFCs in offspring.


Assuntos
Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , Cabelo/química , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Tório/análise , Urânio/análise , Adulto , China/epidemiologia , Fenda Labial/induzido quimicamente , Fissura Palatina/induzido quimicamente , Feminino , Humanos , Recém-Nascido , Masculino , Razão de Chances , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Fatores de Risco , Couro Cabeludo/química , Adulto Jovem
13.
Med Sci (Paris) ; 35(3): 236-243, 2019 Mar.
Artigo em Francês | MEDLINE | ID: mdl-30931908

RESUMO

Autism is a neuro-developmental pathology affecting 1 out of 100 children worldwide. The trauma and social consequences induced by autism are a real public health issue. Clinically, autism is characterized primarily by communications and social interactions deficits associated with repetitive behaviors and restricted interests. The term of autism spectrum disorders (ASD) is used to account for the diversity of symptoms that characterize this pathology. Based on observations made in humans, a rodent (rats and mice) model of autism was obtained and validated by prenatal exposure to sodium valproate. Using this model, mechanisms that concern both the functioning of neural networks and the properties of neurons have been proposed to account for some disorders that characterize autism. This model is also widely used in pre-clinical studies to evaluate new therapies against ASD.


Assuntos
Transtorno Autístico/induzido quimicamente , Transtorno Autístico/patologia , Modelos Animais de Doenças , Ácido Valproico , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/patologia , Feminino , Humanos , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ratos
14.
BMC Med ; 17(1): 77, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30971237

RESUMO

BACKGROUND: The uterine environment may influence telomere length at birth, which is essential for cellular function, aging, and disease susceptibility over the lifespan. However, little is known about the impact of toxic chemicals on early-life telomeres. Therefore, we assessed the potential impact of multiple toxic metals on relative telomere length (rTL) in the maternal blood, cord blood, and placenta, as well as the potential modifying effects of pro-oxidants. METHOD: In a mother-child cohort in northern Argentina (n = 169), we measured multiple toxic metals in the maternal blood or urine collected during late pregnancy, as well as the placenta and cord blood collected at delivery, using inductively coupled plasma mass spectrometry (ICP-MS). We assessed associations of log2-transformed metal concentrations with rTL, measured in maternal and cord blood leukocytes and the placenta by real-time PCR, using multivariable-adjusted linear regression. Additionally, we tested for modifications by antioxidants (zinc, selenium, folate, and vitamin D3). RESULTS: Exposure to boron and antimony during pregnancy was associated with shorter maternal rTL, and lithium with longer maternal rTL; a doubling of exposure was associated with changes corresponding to 0.2-0.4 standard deviations (SD) of the rTL. Arsenic concentrations in the placenta (n = 98), blood, and urine were positively associated with placental rTL, about 0.2 SD by doubled arsenic. In the cord blood (n = 88), only lead was associated with rTL (inversely), particularly in boys (p for interaction 0.09). Stratifying by newborn sex showed ten times stronger association in boys (about 0.6 SD) than in girls. The studied antioxidants did not modify the associations, except that with antimony. CONCLUSIONS: Elevated exposure to boron, lithium, arsenic, and antimony was associated with maternal or newborn rTL in a tissue-specific, for lead also sex-specific, manner. Nutritional antioxidants did not generally influence the associations.


Assuntos
Antioxidantes/administração & dosagem , Exposição Ambiental/análise , Exposição Materna , Fenômenos Fisiológicos da Nutrição Materna , Metais Pesados/toxicidade , Homeostase do Telômero/fisiologia , Telômero/fisiologia , Adolescente , Adulto , Argentina/epidemiologia , Criança , Estudos de Coortes , Dieta , Exposição Ambiental/prevenção & controle , Feminino , Sangue Fetal/efeitos dos fármacos , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Masculino , Exposição Materna/estatística & dados numéricos , Fenômenos Fisiológicos da Nutrição Materna/efeitos dos fármacos , Troca Materno-Fetal/efeitos dos fármacos , Troca Materno-Fetal/genética , Metais Pesados/análise , Metais Pesados/sangue , Metais Pesados/urina , Mães , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Telômero/efeitos dos fármacos , Homeostase do Telômero/efeitos dos fármacos , Adulto Jovem
15.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(4): 332-336, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31014424

RESUMO

OBJECTIVE: To study the association of exposure to polycyclic aromatic hydrocarbons (PAH) during pregnancy and autism spectrum disorder (ASD)-related behaviors in toddlers. METHODS: A total of 348 toddlers who had accepted the measurement of PAH-DNA adduct in umbilical cord blood and evaluation of behavior problems at the age of 36 months were enrolled in this birth cohort study. Child Behavior Checklist (CBCL) and Autism Behavior Checklist (ABC) were used to evaluate behavior problems at the age of 36 months. The correlation of the concentration of PAH-DNA adduct in umbilical cord blood with CBCL and ABC scores at the age of 36 months were analyzed. RESULTS: The detection rate of PAH-DNA adduct in umbilical cord blood was 52.3%, and the median concentration was 0.68 ng/mL. The median total scores of CBCL and ABC scales were 23 and 8 respectively. In children aged 36 months, the concentration of PAH-DNA adduct was positively correlated with the score of social withdrawal in the CBCL scale (rs=0.205, P<0.05), the total score of the ABC scale (rs=0.412, P<0.05), and the self-care score of the ABC scale (rs=0.355, P<0.05). The concentration of PAH-DNA adduct was closely associated with the total score of the ABC scale in children aged 36 months (ß=0.122, P<0.05). CONCLUSIONS: PAH exposure during pregnancy may be a risk factor for ASD-related behaviors in toddlers. Effective reduction of PAH exposure during pregnancy and detection of PAH-DNA adduct in neonatal umbilical cord blood are of vital importance for early prevention, screening and intervention of ASD.


Assuntos
Transtorno do Espectro Autista , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Transtorno do Espectro Autista/induzido quimicamente , Comportamento Infantil , Pré-Escolar , Estudos de Coortes , Feminino , Sangue Fetal , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
16.
Chemosphere ; 226: 290-297, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30933738

RESUMO

This study determined whether maternal bisphenol A (BPA) exposure influences birth outcomes through oxidative stress and estimated the daily intake of BPA through breast milk for infants. One hundred and eighty-six pregnant women without pregnancy complications were enrolled and maternal urine was collected in the third trimester. Postnatal breast milk was collected in the first and third months after delivery. Concentrations of BPA were determined through ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Generalized additive model-penalized regression splines and a multivariable regression model were employed to determine the effects of BPA exposure and oxidative stress levels on birth outcomes. A causal mediation analysis was conducted to clarify the mediation effects of oxidative stress due to maternal BPA exposure on birth outcomes. The daily intake of BPA in breast milk was calculated using probabilistic risk assessment methods. The geometric means (geometric standard deviation) of BPA levels for maternal urine and first- and third-month breast milk were 2.19 (2.88) µg/g creatinine., 1.35 (3.53) ng/g, and 3.17 (2.97) ng/g, respectively. No significant mediation existed among maternal BPA exposure, oxidative stress level, and neonatal head circumference. Three percent of 1-monthold babies and 1% of 3-month-old babies exceeded the BPA tolerable daily intake of 4 µg/kg-bw/day proposed by the European Food Safety Authority. This study revealed the BPA exposure profile for pregnant women and infants in northern Taiwan. The marginally significant correlation between maternal BPA exposure and neonatal head circumference should be considered.


Assuntos
Compostos Benzidrílicos/análise , Exposição Materna/efeitos adversos , Leite Humano/química , Estresse Oxidativo/efeitos dos fármacos , Fenóis/análise , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Pesos e Medidas Corporais , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Feminino , Humanos , Lactente , Saúde do Lactente , Recém-Nascido , Espectrometria de Massas , Gravidez , Análise de Regressão , Medição de Risco , Taiwan
17.
Proc Natl Acad Sci U S A ; 116(14): 7083-7088, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30890645

RESUMO

Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or EPHX2) mRNA in induced pluripotent stem cell-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.


Assuntos
Epóxido Hidrolases/biossíntese , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Exposição Materna/efeitos adversos , Transtornos do Neurodesenvolvimento , Compostos de Fenilureia/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal , Efeitos Tardios da Exposição Pré-Natal , Esquizofrenia , Animais , Epóxido Hidrolases/genética , Feminino , Camundongos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/prevenção & controle , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Esquizofrenia/induzido quimicamente , Esquizofrenia/genética , Esquizofrenia/metabolismo , Esquizofrenia/prevenção & controle
18.
Eur J Epidemiol ; 34(7): 651-660, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30868347

RESUMO

Recent studies have shown that certain pharmacological agents used by fathers before conception may increase the risk of adverse neonatal outcomes in offspring. However, little is known about the effect of paternal use of antiepileptic drugs (AEDs) on congenital anomalies in children. Based on Danish national registers, we conducted a cohort study of 733, 282 singletons born from 1997 to 2008, with follow-up throughout 2013. The children whose fathers used AEDs during the 3 months before conception were categorized as the exposed. Logistic regression model was used to examine association between paternal AEDs use before conception and the risk of congenital anomalies in offspring. Compared with unexposed children, the exposed had a 23% increased risk of congenital anomalies (odds ratios (OR) 1.23, 95% confidence interval [CI] 1.10-1.37) after adjusting for potential confounders. When extending the exposure window to 1 year before conception to the end of pregnancy, except for those using AEDs during 3 months before conception (the susceptible period of exposure), the increased risks were also observed in children whose fathers were former users (i.e., those using AEDs only from 1 year to 3 months before conception) (OR 1.29, 95%CI 1.03-1.61) and later users (i.e., those using AEDs only during pregnancy) (OR 1.35, 95%CI 1.12-1.65). This study suggested that the mildly increased risk of congenital anomalies in the offspring associated with paternal AEDs use before conception may be attributable to the underlying indications related to AEDs use.


Assuntos
Anticonvulsivantes/efeitos adversos , Epilepsia/tratamento farmacológico , Pai/psicologia , Exposição Paterna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Dinamarca/epidemiologia , Epilepsia/epidemiologia , Pai/estatística & dados numéricos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Vigilância da População , Cuidado Pré-Concepcional , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia
19.
BMJ ; 364: l962, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30894343

RESUMO

OBJECTIVE: To examine associations between early developmental exposure to ambient pesticides and autism spectrum disorder. DESIGN: Population based case-control study. SETTING: California's main agricultural region, Central Valley, using 1998-2010 birth data from the Office of Vital Statistics. POPULATION: 2961 individuals with a diagnosis of autism spectrum disorder based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, revised (up to 31 December 2013), including 445 with intellectual disability comorbidity, were identified through records maintained at the California Department of Developmental Services and linked to their birth records. Controls derived from birth records were matched to cases 10:1 by sex and birth year. EXPOSURE: Data from California state mandated Pesticide Use Reporting were integrated into a geographic information system tool to estimate prenatal and infant exposures to pesticides (measured as pounds of pesticides applied per acre/month within 2000 m from the maternal residence). 11 high use pesticides were selected for examination a priori according to previous evidence of neurodevelopmental toxicity in vivo or in vitro (exposure defined as ever v never for each pesticide during specific developmental periods). MAIN OUTCOME MEASURE: Odds ratios and 95% confidence intervals using multivariable logistic regression were used to assess associations between pesticide exposure and autism spectrum disorder (with or without intellectual disabilities) in offspring, adjusting for confounders. RESULTS: Risk of autism spectrum disorder was associated with prenatal exposure to glyphosate (odds ratio 1.16, 95% confidence interval 1.06 to 1.27), chlorpyrifos (1.13, 1.05 to 1.23), diazinon (1.11, 1.01 to 1.21), malathion (1.11, 1.01 to 1.22), avermectin (1.12, 1.04 to 1.22), and permethrin (1.10, 1.01 to 1.20). For autism spectrum disorder with intellectual disability, estimated odds ratios were higher (by about 30%) for prenatal exposure to glyphosate (1.33, 1.05 to 1.69), chlorpyrifos (1.27, 1.04 to 1.56), diazinon (1.41, 1.15 to 1.73), permethrin (1.46, 1.20 to 1.78), methyl bromide (1.33, 1.07 to 1.64), and myclobutanil (1.32, 1.09 to 1.60); exposure in the first year of life increased the odds for the disorder with comorbid intellectual disability by up to 50% for some pesticide substances. CONCLUSION: Findings suggest that an offspring's risk of autism spectrum disorder increases following prenatal exposure to ambient pesticides within 2000 m of their mother's residence during pregnancy, compared with offspring of women from the same agricultural region without such exposure. Infant exposure could further increase risks for autism spectrum disorder with comorbid intellectual disability.


Assuntos
Transtorno do Espectro Autista/induzido quimicamente , Exposição Ambiental/efeitos adversos , Praguicidas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adolescente , Adulto , Agricultura/estatística & dados numéricos , Transtorno do Espectro Autista/epidemiologia , California/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/induzido quimicamente , Deficiência Intelectual/epidemiologia , Masculino , Exposição Materna/efeitos adversos , Exposição Materna/estatística & dados numéricos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Fatores de Risco , Distribuição por Sexo , Adulto Jovem
20.
Epilepsy Res ; 152: 31-34, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30875634

RESUMO

Epileptic spasms during infancy (infantile spasms) represent a serious treatment and social problem despite their rare occurrence. Current treatments include hormonal therapy (adrenocorticotropin-ACTH or corticosteroids) or vigabatrin (per se or in the combination). These treatments are partially effective and with potentially significant adverse effects. Thus, the search for new effective drugs is warranted. We tested efficacy of a novel fusion peptide AQB-565 developed by Aequus Biopharma in a model of infantile spasms consisting of prenatal exposure to betamethasone and repeated postnatal trigger of spasms with N-methyl-d-aspartic acid (NMDA). AQB-565 molecule includes the first 24 amino acids of ACTH, a ten amino acid linker and a modified melanocyte-stimulating hormone molecule. In contrast to ACTH with almost uniform activity over all peripheral and central melanocortin receptor isoforms, AQB is preferentially active on central melanocortin receptors MC3 and MC4. Here, we used equivalent doses of rat ACTH (full molecule) and AQB-565 and compared their efficacy in a prospective randomized test against of repeated bouts of spasms on postnatal days (P)12, P13 and P15 in the rat model. All doses of ACTH (range 0.02-1.0 mg/kg s.c.) and all doses but one of AQB-565 in the same range suppressed spasms in P15 rats (treatment stopped on P14). There was no dose-dependent effect and both compounds had all-or-none effect that is similar to clinical outcome of hormonal treatment of infantile spasms in children. Thus, AQB-565 may represent a novel treatment of infantile spasms similarly effective as ACTH but with potentially limited side effects.


Assuntos
Hormônio Adrenocorticotrópico/uso terapêutico , Hormônios Estimuladores de Melanócitos/uso terapêutico , Espasmos Infantis/tratamento farmacológico , Hormônio Adrenocorticotrópico/química , Hormônio Adrenocorticotrópico/metabolismo , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Eletroencefalografia , Agonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Humanos , Lactente , Masculino , Hormônios Estimuladores de Melanócitos/química , Hormônios Estimuladores de Melanócitos/metabolismo , N-Metilaspartato/toxicidade , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Espasmos Infantis/induzido quimicamente , Resultado do Tratamento
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