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1.
Nat Commun ; 11(1): 5236, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067431

RESUMO

The etiology of major neurodevelopmental disorders such as schizophrenia and autism is unclear, with evidence supporting a combination of genetic factors and environmental insults, including viral infection during pregnancy. Here we utilized a mouse model of maternal immune activation (MIA) with the viral mimic PolyI:C infection during early gestation. We investigated the transcriptional changes in the brains of mouse fetuses following MIA during the prenatal period, and evaluated the behavioral and biochemical changes in the adult brain. The results reveal an increase in RNA editing levels and dysregulation in brain development-related gene pathways in the fetal brains of MIA mice. These MIA-induced brain editing changes are not observed in adulthood, although MIA-induced behavioral deficits are observed. Taken together, our findings suggest that MIA induces transient dysregulation of RNA editing at a critical time in brain development.


Assuntos
Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/genética , Complicações na Gravidez/imunologia , Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/genética , Edição de RNA , Animais , Comportamento Animal , Encéfalo/crescimento & desenvolvimento , Encéfalo/imunologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Imunidade Materno-Adquirida , Camundongos , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/psicologia , Poli I-C/efeitos adversos , Poli I-C/imunologia , Complicações na Gravidez/etiologia , Complicações na Gravidez/genética , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/psicologia
2.
PLoS One ; 15(9): e0239738, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976529

RESUMO

The levels and activity of the enzyme paraoxonase 1 affect the vulnerability to the teratogenic effects of organophosphate pesticides. Mutant mice lacking the gene for paraoxonase1 (PON1-/-) are more susceptible to the toxic effects of chlorpyrifos, and were hypothesized to be more vulnerable to social behavior deficits induced by exposure to chlorpyrifos during gestation. Three experiments were performed comparing PON1-/- mice to PON1+/+ mice born to dams treated with 0.5 mg/kg chlorpyrifos or cornoil vehicle on gestational days 12-15. Chlofpyrifos-exposed male PON1-/- mouse pups had delayed development of reflexes in in the first experiment. In the second experiment, adult male and female PON1-/- mice and the female PON1+/+ mice all displayed lower social preference than the male vehicle-treated PON1+/+ mice. The PON1-/- mice and the female PON1+/+ mice displayed lower social preference compared to the PON1+/+ male mice. Male adult mice that had been exposed in utero to chlorpyrifos showed less conditioned social preference regardless of genotype. In the third study, the delayed reflex development was replicated in male and female PON1-/- mice, but chlorpyrifos did not augment this effect. Nest Odor Preference, a test of early social attachment to dam and siblings, was lower in PON1-/- mouse pups compared to PON1+/+ pups. This study shows for the first time that PON1-/- mice have a behavioral phenotype that indicates impaired reflex development and social behavior. Chlorpyrifos exposure during gestation tended to augment some of these effects.


Assuntos
Arildialquilfosfatase/genética , Clorpirifos/toxicidade , Inibidores da Colinesterase/toxicidade , Deficiências do Desenvolvimento/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Comportamento Social , Teratogênios/toxicidade , Animais , Arildialquilfosfatase/deficiência , Feminino , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Reflexo
3.
Sci Rep ; 10(1): 9487, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32528016

RESUMO

Our recent study revealed that prenatal exposure to bisphenol A (BPA) disrupted the transcriptome profiles of genes in the offspring hippocampus. In addition to genes linked to autism, several genes associated with Alzheimer's disease (AD) were found to be differentially expressed, although the association between BPA-responsive genes and AD-related genes has not been thoroughly investigated. Here, we demonstrated that in utero BPA exposure also disrupted the transcriptome profiles of genes associated with neuroinflammation and AD in the hippocampus. The level of NF-κB protein and its AD-related target gene Bace1 were significantly increased in the offspring hippocampus in a sex-dependent manner. Quantitative RT-PCR analysis also showed an increase in the expression of Tnf gene. Moreover, the reanalysis of transcriptome profiling data from several previously published BPA studies consistently showed that BPA-responsive genes were significantly associated with top AD candidate genes. The findings from this study suggest that maternal BPA exposure may increase AD risk in offspring by dysregulating genes associated with AD neuropathology and inflammation and reveal a possible relationship between AD and autism, which are linked to the same environmental factor. Sex-specific effects of prenatal BPA exposure on the susceptibility of AD deserve further investigation.


Assuntos
Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Compostos Benzidrílicos/agonistas , Fenóis/agonistas , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Transcriptoma/efeitos dos fármacos , Animais , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/genética , Feminino , Perfilação da Expressão Gênica/métodos , Hipocampo/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/genética , Masculino , Exposição Materna , NF-kappa B/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos , Ratos Wistar
4.
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
5.
Diabetes Res Clin Pract ; 165: 108269, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32535117

RESUMO

AIMS: Researches on the relationship between maternal pregestational or gestational diabetes and attention deficit/hyperactivity disorder (ADHD) in offspring provided inconsistent findings; therefore, we performed an updated and comprehensive literature review and meta-analysis to evaluate the available evidence. METHOLDS: Relevant articles in Pubmed, Web of Science, Cochrane, Embase, and Wanfang database published until January 2019 were searched without language restriction. We performed a meta-analysis about maternal pregestational and gestational diabetes and risk of ADHD in offspring using odds ratio (OR), relative risk (RR), hazard ratio (HR) and 95% confidence interval (95% CI) extracted from each study. RESULTS: Seven articles were included in this study and a total of 3,169,529 participants were accumulated. We found maternal pregestational diabetes increased the risk of ADHD in offspring by 44% (95% CI was 1.32-1.57). CONCLUSIONS: Maternal pregestational diabetes is a potential adverse risk of ADHD in offspring. Considering the limited amount of reliable information availabe. In the future, more in-depth and detailed researches, especially population-based prospective cohort studies, are needed to explore this topic more comprehensively.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Diabetes Gestacional/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Estudos Prospectivos , Adulto Jovem
6.
Chemosphere ; 255: 127000, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32417515

RESUMO

BACKGROUND: Bisphenol-A (BPA) exposure is widespread and early life exposure is associated with metabolic syndrome. While visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are implicated in the development of metabolic syndrome, the adipose depot-specific effects of prenatal BPA treatment are poorly understood. OBJECTIVE: To determine the impact of prenatal BPA exposure on genome-wide gene expression of VAT and SAT depots. METHODS: RNA sequencing was performed on SAT and VAT from 21-month old control and prenatal BPA-treated female sheep. Gene expression and pathway differences between SAT and VAT depots with or without prenatal BPA-treatment and the effect of prenatal BPA treatment on each depot were tested. RESULTS: There were 179 differentially expressed genes (padjusted < 0.05, log2-fold change >2.5) between SAT and VAT. Development and immune response pathways were upregulated in SAT, while metabolic pathways were upregulated in VAT. These adipose depot-specific genes and pathways were consistent with prenatal BPA-treatment. In SAT, BPA-treatment resulted in differential expression of 108 genes (78% upregulated with BPA) and altered pathways (immune response downregulated, RNA processing upregulated). In contrast in VAT, BPA-treatment differentially expressed 4 genes and upregulated chromatin and RNA processing pathways. CONCLUSION: Prenatal BPA-treatment induces adult depot-specific alterations in RNA expression in inflammation, RNA processing, and chromatin pathways, reflecting the diverse roles of SAT and VAT in regulating lipid storage and insulin sensitivity. These adipose tissue transcriptional dysregulations may contribute to the metabolic disorders observed in prenatal BPA-treated female sheep.


Assuntos
Adiposidade/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Gordura Intra-Abdominal/efeitos dos fármacos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Gordura Subcutânea/efeitos dos fármacos , Adiposidade/genética , Animais , Compostos Benzidrílicos/sangue , Regulação para Baixo , Disruptores Endócrinos/sangue , Feminino , Perfilação da Expressão Gênica , Inflamação , Gordura Intra-Abdominal/crescimento & desenvolvimento , Gordura Intra-Abdominal/metabolismo , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Fenóis/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , RNA/genética , RNA/metabolismo , Ovinos , Gordura Subcutânea/crescimento & desenvolvimento , Gordura Subcutânea/metabolismo
7.
J Clin Psychiatry ; 81(3)2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32459403

RESUMO

In observational studies, significant associations have often been identified between antidepressant drug prescription during pregnancy, on the one hand, and autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), on the other. Interpreting these associations is problematic because they are based on analyses that could not adjust for inadequately measured, unmeasured, and unknown confounds. Recent clinical data suggest that a genetic relationship exists between depression and neurodevelopmental disorders. A very recent study identified many genetic loci that were common to depression, ASD, and ADHD. These findings suggest the possibility that depression in a pregnant woman may predispose to neurodevelopmental disorders in offspring through shared genes and not through antidepressant use during pregnancy. Previous studies that significantly associated gestational exposure to antidepressants with adverse pregnancy outcomes could not adjust for genetic factors because they were unknown confounds at the time. Now that common risk loci have been identified, at least some of the unknown (genetic) confounds are no longer unknown; however, unless specifically examined in prospective studies, they will remain as unmeasured confounds that will continue to compromise the interpretation of study results. The possibility of confounding by inadequately measured, unmeasured, and unknown risk factors must therefore be considered before indicting antidepressant use during pregnancy in neurodevelopmental risks. In this context, the importance of genetic factors as unmeasured and unknown confounds must be acknowledged.


Assuntos
Antidepressivos/efeitos adversos , Transtorno Depressivo/complicações , Transtornos do Neurodesenvolvimento/genética , Complicações na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/genética , Antidepressivos/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/genética , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , Feminino , Loci Gênicos , Predisposição Genética para Doença/genética , Humanos , Transtornos do Neurodesenvolvimento/induzido quimicamente , Gravidez , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
8.
Sci Rep ; 10(1): 5705, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32235866

RESUMO

In males, defective reproductive traits induced by an exposure to an endocrine disruptor are transmitted to future generations via epigenetic modification of the germ cells. Interestingly, the impacted future generations display a wide range of heterogeneity in their reproductive traits. In this study, the role that the Y chromosome plays in creating such heterogeneity is explored by testing the hypothesis that the Y chromosome serves as a carrier of the exposure impact to future generations. This hypothesis implies that a male who has a Y chromosome that is from a male that was exposed to an endocrine disruptor will display a more severe reproductive phenotype than a male whose Y chromosome is from an unexposed male. To test this hypothesis, we used a mouse model in which F1 generation animals were exposed prenatally to an endocrine disruptor, di-2-ethylhexyl phthalate (DEHP), and the severity of impacted reproductive traits was compared between the F3 generation males that were descendants of F1 males (paternal lineage) and those from F1 females (maternal lineage). Pregnant dams (F0 generation) were exposed to the vehicle or 20 or 200 µg/kg/day of DEHP from gestation day 11 until birth. Paternal lineage F3 DEHP males exhibited decreased fertility, testicular steroidogenic capacity, and spermatogenesis that were more severely impaired than those of maternal lineage males. Indeed, testicular transcriptome analysis found that a number of Y chromosomal genes had altered expression patterns in the paternal lineage males. This transgenerational difference in the DEHP impact can be attributed specifically to the Y chromosome.


Assuntos
Dietilexilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Reprodução/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Animais , Feminino , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Testículo/efeitos dos fármacos
9.
Mol Cell Biochem ; 468(1-2): 83-96, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32189172

RESUMO

Vitamin B12 deficiency is a critical problem worldwide and peri-conceptional deficiency of this vitamin is associated with the risk of complex cardio-metabolic diseases. Nutritional perturbations during these stages of development may lead to changes in the fetal epigenome. Using Wistar rat model system, we have earlier shown that low maternal B12 levels are associated with low birth weight, adiposity, insulin resistance, and increased triglyceride levels in the offspring, which might predispose them to the risk of cardio-metabolic diseases in adulthood. In this study, we have investigated the effects of maternal B12 deficiency on genome-wide DNA methylation profile of the offspring and the effect of rehabilitation of mothers with B12 at conception. We have performed methylated DNA immunoprecipitation sequencing of liver from pups in four groups of Wistar rats: Control (C), B12-restricted (B12R), B12-rehabilitated at conception (B12RC), and B12-rehabilitated at parturition (B12RP). We have analyzed differentially methylated signatures between the three groups as compared to controls. We have identified a total of 214 hypermethylated and 142 hypomethylated regions in the 10 kb upstream region of transcription start site in pups of B12-deficient mothers, which are enriched in genes involved in fatty acid metabolism and mitochondrial transport/metabolism. B12 rehabilitation at conception and parturition is responsible for reversal of methylation status of many of these regions to control levels suggesting a causal association with metabolic phenotypes. Thus, maternal B12 restriction alters DNA methylation of genes involved in important metabolic processes and influences the offspring phenotype, which is reversed by B12 rehabilitation of mothers at conception.


Assuntos
Metilação de DNA , Fígado/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Deficiência de Vitamina B 12 , Vitamina B 12/metabolismo , Animais , Animais Recém-Nascidos , Ilhas de CpG/genética , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Imunoprecipitação , Resistência à Insulina/genética , Masculino , Mitocôndrias/genética , Mitocôndrias/metabolismo , Obesidade/metabolismo , Fenótipo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos , Ratos Wistar , Transdução de Sinais/genética
10.
Environ Int ; 138: 105659, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32203807

RESUMO

BACKGROUND: Early-life exposure to nitrogen dioxide (NO2) is associated with an increased risk of developing a neurodevelopmental disorder during childhood or later in life. OBJECTIVES: We investigated whether prenatal NO2 inhalation causes neurodevelopmental abnormalities and cognitive deficits in weanling offspring without subsequent postnatal NO2 exposure and how this prenatal exposure contributes to postnatal consequences. METHODS: Pregnant C57BL/6 mice were exposed to air or NO2 (2.5 ppm, 5 h/day) throughout gestation, and the offspring were sacrificed on postnatal days (PNDs) 1, 7, 14 and 21. We determined the mRNA profiles of different postnatal developmental windows, detected the long noncoding RNA (lncRNA) profiles and cognitive function in weanling offspring, and analyzed the effects of hub lncRNAs on differentially expressed genes (DEGs). RESULTS: Prenatal NO2 inhalation significantly impaired cognitive function in the weanling male, but not female, offspring. The male-specific response was coupled with abnormal neuropathologies and transcriptional profiles in the cortex during different postnatal developmental windows. Consistently, Gene Ontology (GO) analysis of the DEGs revealed persistent disruptions in neurodevelopment-associated biological processes and cellular components in the male offspring, and Apolipoprotein E (ApoE) was one of key factors contributing to prenatal exposure-induced male-specific neurological dysfunction. In addition, distinct sex-dependent lncRNA expression was identified in the weanling offspring, and metastasis-associated lung adenocarcinoma transcript 1 (Malat1) acted as a hub lncRNA and was coexpressed with most coding genes in the lncRNA-mRNA coexpressed pairs in the male offspring. Importantly, lncRNA Malat1 expression was elevated, and Malat1 modulated ApoE expression through NF-κB activation during this process. CONCLUSIONS: Prenatal NO2 exposure is related to sex-dependent neurocognitive deficits and transcriptomic profile changes in the cortices of the prenatally exposed offspring. Male-specific neurological dysfunction is associated with the constant alteration of genes during postnatal neurodevelopment and their transcriptional modulation by hub lncRNAs.


Assuntos
Transtornos do Neurodesenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento/induzido quimicamente , Transtornos do Neurodesenvolvimento/genética , Dióxido de Nitrogênio , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Transcriptoma
11.
Cell ; 180(5): 847-861.e15, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32142678

RESUMO

Early life environmental exposure, particularly during perinatal period, can have a life-long impact on organismal development and physiology. The biological rationale for this phenomenon is to promote physiological adaptations to the anticipated environment based on early life experience. However, perinatal exposure to adverse environments can also be associated with adult-onset disorders. Multiple environmental stressors induce glucocorticoids, which prompted us to investigate their role in developmental programming. Here, we report that perinatal glucocorticoid exposure had long-term consequences and resulted in diminished CD8 T cell response in adulthood and impaired control of tumor growth and bacterial infection. We found that perinatal glucocorticoid exposure resulted in persistent alteration of the hypothalamic-pituitary-adrenal (HPA) axis. Consequently, the level of the hormone in adults was significantly reduced, resulting in decreased CD8 T cell function. Our study thus demonstrates that perinatal stress can have long-term consequences on CD8 T cell immunity by altering HPA axis activity.


Assuntos
Infecções Bacterianas/imunologia , Desenvolvimento Embrionário/imunologia , Glucocorticoides/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Infecções Bacterianas/genética , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Dexametasona/farmacologia , Desenvolvimento Embrionário/genética , Feminino , Glucocorticoides/imunologia , Glucocorticoides/metabolismo , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Interleucina-4/farmacologia , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Neoplasias/induzido quimicamente , Neoplasias/genética , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Receptores de Glucocorticoides/genética , Transdução de Sinais/genética
12.
Sci Rep ; 10(1): 2419, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32051445

RESUMO

Chronic nicotine exposure during pregnancy has been shown to induce physiological and anatomical alterations in offspring. Previously, we investigated the complexity of dopamine (DA) neuron firing in the sub-regions of the ventral tegmental area (VTA) following perinatal nicotine exposure. Using approximate entropy, we found that within the middle sub-region, the parainterfascicular nucleus (PIF), there was higher complexity indicating more random neural firing and a less homogeneous neuron population. Therefore, we sought to investigate the neuron populations within the sub-regions of the VTA following perinatal nicotine exposure. We used real time PCR in order to find the relative quantity of glutamate to γ-aminobutyric acid (GABA), DA, and glutamate neurons within three sub-regions: the parabrachial pigmented nucleus (PBP), parainterfascicular nucleus (PIF), and paranigral nucleus (PN). Our results showed that the PIF region of the VTA contained a more diverse population of neurons resulting in a more complex system. In addition, we found that DA neurons are more activated in PN sub-region of the VTA, which mediates the rewarding effects of drugs including nicotine. Lastly, using immunohistochemistry, we observed an overall decrease in DA neurons following perinatal nicotine exposure.


Assuntos
Expressão Gênica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Feminino , Perfil Genético , Masculino , Neurônios/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos Sprague-Dawley , Área Tegmentar Ventral/citologia
13.
Nat Commun ; 11(1): 561, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047148

RESUMO

Parabens are preservatives widely used in consumer products including cosmetics and food. Whether low-dose paraben exposure may cause adverse health effects has been discussed controversially in recent years. Here we investigate the effect of prenatal paraben exposure on childhood overweight by combining epidemiological data from a mother-child cohort with experimental approaches. Mothers reporting the use of paraben-containing cosmetic products have elevated urinary paraben concentrations. For butyl paraben (BuP) a positive association is observed to overweight within the first eight years of life with a stronger trend in girls. Consistently, maternal BuP exposure of mice induces a higher food intake and weight gain in female offspring. The effect is accompanied by an epigenetic modification in the neuronal Pro-opiomelanocortin (POMC) enhancer 1 leading to a reduced hypothalamic POMC expression. Here we report that maternal paraben exposure may contribute to childhood overweight development by altered POMC-mediated neuronal appetite regulation.


Assuntos
Exposição Materna/efeitos adversos , Sobrepeso/etiologia , Parabenos/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/etiologia , Conservantes Farmacêuticos/efeitos adversos , Animais , Criança , Pré-Escolar , Ingestão de Alimentos , Feminino , Humanos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sobrepeso/genética , Sobrepeso/metabolismo , Sobrepeso/fisiopatologia , Parabenos/análise , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Conservantes Farmacêuticos/análise , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Urina/química , Ganho de Peso
14.
J Med Microbiol ; 69(4): 591-599, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32043953

RESUMO

Introduction. Staphylococcal enterotoxin B (SEB) is an extensively studied super-antigen. A previous study by us suggested that SEB exposure during pregnancy could alter the percentage of CD4+ and CD8+ T cells in the peripheral blood of neonatal offspring rats.Aim. It is unknown whether SEB exposure during pregnancy can influence the development of regulatory T cells (Tregs) in the peripheral blood of neonatal offspring rats.Methodology. Pregnant rats at gestational day 16 were intravenously injected with 15 µg SEB. Peripheral blood was acquired from neonatal offspring rats on days 1, 3 and 5 after delivery and from adult offspring rats for determination of Treg number by cytometry, cytokines by ELISA, and FoxP3 expression by real-time PCR and western blot.Results. SEB given to pregnant rats significantly increased the absolute number of Tregs and the expression levels of FoxP3, IL-10 and TGF-ß (P<0.05, P<0.01) in the peripheral blood of not only neonatal but also adult offspring rats. Furthermore, repeated SEB exposure in adult offspring rats significantly decreased the absolute number of Tregs (P<0.01), and the expression levels of FoxP3, IL-10 and TGF-ß (P<0.05, P<0.01) in their peripheral blood.Conclusion. Prenatal SEB exposure attenuates the development and function of Tregs to repeated SEB exposure in the peripheral blood of adult offspring rats.


Assuntos
Enterotoxinas/imunologia , Complicações na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Infecções Estafilocócicas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Masculino , Exposição Materna/efeitos adversos , Gravidez , Complicações na Gravidez/microbiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/microbiologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/imunologia , Linfócitos T Reguladores/citologia
15.
Adv Neurobiol ; 24: 143-162, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32006359

RESUMO

Autism spectrum disorder (ASD) is a rapidly growing global pandemic that affects an estimated 1 in 59-68 children. It is a complex disease with both genetic and environmental etiologies. Due to the rapid increase in the incidence of ASD, environmental causes for ASD are gaining attention. Efforts to probe several environmental exposures that could contribute to causing ASD are underway. In this regard, this chapter is directed towards understanding prenatal exposure to key environmental factors i.e., drugs and dietary nutrients that may act via the same molecular pathway - epigenetics as a potential etiological factor for ASD. Epigenetic regulation is a molecular mechanism known to be a significant contributor to neurodevelopmental disorders. It also offers a means to explain how environmental exposures can impact genetics. We discuss the impact of maternal exposures to certain drugs, and dietary intake, on the developing fetus during pregnancy. Maternal Exposure to some drugs during gestation are associated with a higher risk of ASD, while exposure to other dietary compounds may offer promise to rescue epigenetic regulatory insults related to ASD. However, more work in this important area is still required, nevertheless preliminary research already has important implications in the understanding, prevention and treatment of ASD.


Assuntos
Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/genética , Dieta/efeitos adversos , Epigênese Genética/efeitos dos fármacos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética , Transtorno do Espectro Autista/prevenção & controle , Transtorno do Espectro Autista/terapia , Feminino , Humanos , Recém-Nascido , Gravidez
16.
Horm Behav ; 119: 104677, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31927019

RESUMO

It is our hope this mini-review will stimulate discussion and new research. Here we briefly examine the literature on transgenerational actions of endocrine disrupting chemicals (EDCs) on brain and behavior and their underlying epigenetic mechanisms including: DNA methylation, histone modifications, and non-coding RNAs. We stress that epigenetic modifications need to be examined in a synergistic manner, as they act together in situ on chromatin to change transcription. Next we highlight recent work from one of our laboratories (VGC). The data provide new evidence that the sperm genome is poised for transcription. In developing sperm, gene enhancers and promoters are accessible for transcription and these activating motifs are also found in preimplantation embryos. Thus, DNA modifications associated with transcription factors during fertilization, in primordial germ cells (PGCs), and/or during germ cell maturation may be passed to offspring. We discuss the implications of this model to EDC exposures and speculate on whether natural variation in hormone levels during fertilization and PGC migration may impart transgenerational effects on brain and behavior. Lastly we discuss how this mechanism could apply to neural sexual differentiation.


Assuntos
Comportamento/efeitos dos fármacos , Disruptores Endócrinos/farmacologia , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Pesquisa Comportamental/métodos , Pesquisa Comportamental/tendências , Efeito de Coortes , Metilação de DNA/efeitos dos fármacos , Exposição Ambiental/análise , Exposição Ambiental/estatística & dados numéricos , Feminino , Humanos , Masculino , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/embriologia , Sistema Nervoso/crescimento & desenvolvimento , Neuroendocrinologia/métodos , Neuroendocrinologia/tendências , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Reprodução/efeitos dos fármacos , Diferenciação Sexual/efeitos dos fármacos
17.
Toxicology ; 432: 152378, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-31972234

RESUMO

Prenatal nicotine exposure (PNE) could induce an increased susceptibility to multiple chronic diseases in adult offspring, that mainly caused by intrauterine maternal glucocorticoid (GC) over-exposure. We investigated the changes and inheritability of hepatic glucose and lipid metabolism caused by PNE, to decipher the possible intrauterine programming mechanism. Pregnant Wistar rats were administered subcutaneously with 2 mg/kg·d nicotine from gestational day (GD) 9∼20, and second-generation (F2) were set according to the mating between control females and PNE males. The results showed that serum phenotypes and hepatic enzymes of glucose and lipid metabolism were lower in F1 fetal rats of PNE but higher in the F1 adult rats. Meanwhile, the activated states of hepatic glucocorticoid-activation system, including type 1 and type 2 11ß-hydroxysteroid dehydrogenases (Hsd11b1/2), nuclear receptor subfamily 3, group C, member 1 (Nr3c1) and CCAAT enhancer binding protein α (Cebpa), were positively correlated with serum corticosterone levels but negatively correlated with the histone acetylation (H3K27ac) and expression levels of insulin-like growth factor 1 (Igf1) before and after birth. Furthermore, serum phenotypes and hepatic enzymes of glucose and lipid metabolism were lower in both F2 fetal and adult rats of PNE, which were consistent with the hepatic changes of GC-IGF1 axis and the glucocorticoid-activation system. In conclusion, PNE could lead to inheritable changes of hepatic glucose and lipid metabolism, which are related to the intrauterine programming of GC-IGF1 axis induced by the glucocorticoid-activation system.


Assuntos
Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Nicotina/toxicidade , Agonistas Nicotínicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/psicologia , Animais , Epigênese Genética/efeitos dos fármacos , Feminino , Desenvolvimento Fetal , Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/metabolismo , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Exposição Materna , Fenótipo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos , Ratos Wistar
18.
Arch Sex Behav ; 49(2): 447-454, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31975033

RESUMO

We assessed the associations of prenatal diethylstilbestrol (DES) exposure, a potent estrogen, with sexual orientation and gender identity in 3306 women and 1848 men who participated in a study of prenatal DES exposure. Odds ratios (OR) and 95% confidence intervals (CI) were derived from logistic regression models adjusted for birth year, study cohort, and education. Among women, the OR for DES in relation to reporting sexual orientation identity as nonheterosexual was 0.61 (95% CI 0.40-0.92) primarily due to a strong inverse association with a lesbian identity (OR 0.44, 95% CI 0.25-0.76). Among men, the OR for DES in relation to reporting a nonheterosexual sexual orientation identity was 1.4 (95% CI 0.82-2.4), and ORs were similar for having a gay identity (1.4, 95% CI 0.72-2.85) and bisexual identity (1.4, 95% CI 0.57-3.5). Only five individuals reported a gender identity not conforming to that assigned at birth, preventing meaningful analysis. Women who were prenatally exposed to DES were less likely to have a lesbian or bisexual orientation, while DES-exposed men were somewhat more likely to report being gay or bisexual, but estimates were imprecise.


Assuntos
Dietilestilbestrol/efeitos adversos , Identidade de Gênero , Efeitos Tardios da Exposição Pré-Natal/genética , Comportamento Sexual/efeitos dos fármacos , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Gravidez
19.
Gene ; 731: 144354, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31935513

RESUMO

BACKGROUND AND AIMS: Maternal obesity predispose offspring to metabolic disorders and obesity, but the mechanisms are not fully understood, especially during early life. Circular RNA (circRNA) can regulate the expression of target genes through the regulatory pathways of competing endogenous RNA (ceRNA). We hypothesized that the offspring of obese dams exhibit impaired metabolic health through the dysregulated expression of hepatic circRNA. METHODS AND RESULTS: A high-fat diet (HFD) or standard chow diet (CD) were randomized to dams for 12 weeks before mating. Specific diets continued for each dam throughout pregnancy and lactation. Then, lipid metabolic parameters were assessed in dams and female offspring. We performed liver RNA sequencing (RNA-seq) for the offspring of HFD- and CD-dams to comprehensively identify differentially expressed (DE) circRNA and messenger RNA (mRNA). Further, ceRNA networks combining DE circRNA, mRNA, and microRNA were predicted based on MiRanda and TargetScan databases combined with the lipid metabolism-related pathway. As a result, the circRNA_0000660-miR_693-Igfbp1 regulatory pathway was selected from liver and AML12 cell line. Quantitative real-time polymerase chain reaction, dual luciferase reporter gene system, and Small interfering RNA for circRNA_0000660 transfection experiment were applied to validate. CONCLUSIONS: Our work investigated new mechanisms of the effect of maternal obesity on offspring's lipid metabolism. Several novel targets were uncovered to reverse the effect.


Assuntos
Fígado/metabolismo , MicroRNAs/genética , Obesidade Materna/genética , Efeitos Tardios da Exposição Pré-Natal/genética , RNA Circular/genética , Animais , Animais Lactentes , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Obesidade Materna/complicações , Obesidade Materna/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , RNA Circular/metabolismo , Desmame
20.
Diabetes Care ; 43(1): 98-105, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31601636

RESUMO

OBJECTIVE: Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium. RESEARCH DESIGN AND METHODS: Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate. RESULTS: Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345-248100614) was located in the OR2L13 promoter, and the other (chr 10: 135341870-135342620) was located in the gene body of CYP2E1. Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate-adjusted P value threshold of 0.05. CONCLUSIONS: Maternal GDM was associated with lower cord blood methylation levels within two regions, including the promoter of OR2L13, a gene associated with autism spectrum disorder, and the gene body of CYP2E1, which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.


Assuntos
Metilação de DNA , Diabetes Gestacional , Epigênese Genética/fisiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Adulto , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Estudos de Casos e Controles , Criança , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Gestacional/epidemiologia , Epigenoma/fisiologia , Feminino , Sangue Fetal/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Gravidez , Adulto Jovem
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