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1.
Int J Mol Sci ; 22(4)2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33562259

RESUMO

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase in dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure.


Assuntos
Comportamento Animal/efeitos dos fármacos , Dopamina/metabolismo , Dronabinol/toxicidade , Sistema Límbico/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/patologia , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Feminino , Alucinógenos/toxicidade , Sistema Límbico/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Área Tegmentar Ventral/patologia
2.
Chemosphere ; 262: 127792, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32805656

RESUMO

Tebuconazole is a triazole fungicide, used in agriculture to treat phytopathogenic fungi, and as a biocide, has been reported to be related to reproductive and developmental toxicity. The purpose of this study was to investigate the effect of tebuconazole exposure on rat fetal Leydig cells and fetal testis during pregnancy. Pregnant Sprague-Dawley rats were randomly divided into 4 groups, daily gavaged with corn oil (as a control), 25, 50, and 100 mg/kg body weight tebuconazole for 10 days (from the 12th day of pregnancy). Tebuconazole increased fetal serum testosterone and progesterone levels at a dose of 100 mg/kg. Exposure to 100 mg/kg tebuconazole significantly caused an increase in the number of fetal Leydig cells per testis without inducing cell aggregation. Tebuconazole up-regulated the expression of Star, Cyp11a1, Hsd17b3, and Fshr and their proteins. Further investigation found that tebuconazole caused increased phosphorylation of AKT1, ERK1/2, and mTOR, the level of BCL2, as well as the decrease of Beclin1, LC3B, and BAX, which may contribute to the fetal Leydig cell autophagy and proliferation. In conclusion, in utero exposure of tebuconazole causes the proliferation of fetal Leydig cells.


Assuntos
Fungicidas Industriais/toxicidade , Células Intersticiais do Testículo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Reprodução/efeitos dos fármacos , Triazóis/toxicidade , Animais , Feminino , Células Intersticiais do Testículo/metabolismo , Masculino , Fosfoproteínas/genética , Fosforilação , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Testículo/efeitos dos fármacos , Testículo/embriologia , Testículo/patologia , Testosterona/sangue , Regulação para Cima
3.
PLoS One ; 15(10): e0235877, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33091010

RESUMO

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.


Assuntos
Transtornos da Audição/patologia , Malformações do Sistema Nervoso/patologia , Complicações Infecciosas na Gravidez/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Transtornos da Visão/patologia , Infecção por Zika virus/complicações , Zika virus/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Transtornos da Audição/etiologia , Macaca mulatta , Malformações do Sistema Nervoso/etiologia , Gravidez , Complicações Infecciosas na Gravidez/etiologia , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Transtornos da Visão/etiologia , Infecção por Zika virus/virologia
4.
Life Sci ; 261: 118367, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32882266

RESUMO

AIMS: Evaluate the effects of maternal high fat and high cholesterol (HFHC) diet consumption on blood pressure (BP), renal function and oxidative stress along the gut-kidney axis in male and female rat offspring. MATERIALS AND METHODS: Pregnant rats were fed with a control (CTL) or HFHC diet during pregnancy and lactation. At 90 days, BP was assessed by tail-cuff plethysmography, and urinary and biochemical variables were measured. Biomarkers for oxidative stress, enzymatic antioxidant defense (activity of superoxide dismutase-SOD, catalase, and glutathione-S-transferase-GST) and nonenzymatic antioxidant defense (thiols content) were evaluated in the colon and renal cortex. KEY FINDINGS: Male and female offspring from dams fed with a HFHC diet presented increased BP when compared to their respective CTL group. Male offspring from dams fed with HFHC diet showed reduced GST activity and thiols content in the colon, reduced SOD activity in the renal cortex and decreased urinary creatinine excretion when compared to the CTL group. Regarding female offspring, catalase activity and thiols content were reduced in the colon when compared to CTL group. Although lipid peroxidation had been increased in the renal cortex of HFHC female offspring, the CAT and SOD enzymatic antioxidant acitivities (CAT and SOD) were increased in the renal cortex of female offspring when compared with male offspring; and the renal function was not impaired by maternal HFHC diet consumption. SIGNIFICANCE: HFHC diet during pregnancy and lactation induces sex-specific oxidative stress along the gut-kidney axis in offspring, which might induce renal dysfunction and arterial hypertension in later life.


Assuntos
Artérias/patologia , Trato Gastrointestinal/patologia , Hipertensão/patologia , Rim/patologia , Exposição Materna , Estresse Oxidativo , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Artérias/fisiopatologia , Biomarcadores/sangue , Pressão Sanguínea , Colesterol , Colo/patologia , Colo/fisiopatologia , Diástole , Dieta Hiperlipídica , Feminino , Trato Gastrointestinal/fisiopatologia , Frequência Cardíaca , Hipertensão/sangue , Hipertensão/fisiopatologia , Rim/fisiopatologia , Masculino , Gravidez , Ratos Wistar , Sístole
5.
Toxicol Lett ; 333: 222-231, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32798538

RESUMO

Despite many hypothesized benefits of dietary isoflavone genistein (GEN) deriving from soy-based products, questions surrounding GEN's developmental effects are increasing. To understand if in utero GEN exposure modulated postnatal respiratory allergies in the middle age, we conducted a time course study in the B6C3F1 offspring (PND 240-330) using a common household allergen (house dust mites: HDM; 10 µg/mouse for PND 240 and 290, and 50 µg/mouse for PND 330, a middle age in mice) following intranasal instillation, a physiological route of allergen exposure. GEN was administered to dams by gavage from gestational day 14 to parturition at a physiologically relevant dose (20 mg/kg body weight). Female and male offspring were sensitized with HDM allergens beginning about one month prior to sacrifice followed by challenges with three weekly dosings of HDM extracts, and they were euthanized at day 3 following the final HDM exposure. In utero exposure to GEN decreased HDM allergen-induced respiratory allergy in male B6C3F1 offspring at PND 330 as reflected by decreases in airway hyperresponsiveness (e.g., Penh value), HDM-specific IgG1 (a Th2 type Ab) and the activity of eosinophil peroxidase in the lung (an indication of eosinophil recruitment to the lungs). However, in utero exposure to GEN had minimal effects on HDM allergen-induced respiratory allergy in the middle-aged female offspring. Changes in serum total IgE, HDM-specific IgE, and lung histopathology scores in both male and female offspring were not biologically significant. Overall, in utero GEN exposure exerted a protective effect on respiratory allergy in the middle-aged male, but not female, B6C3F1 offspring following later-life HDM exposures.


Assuntos
Envelhecimento/imunologia , Genisteína/farmacologia , Pulmão/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Hipersensibilidade Respiratória/prevenção & controle , Envelhecimento/sangue , Alérgenos/imunologia , Animais , Peroxidase de Eosinófilo/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/enzimologia , Feminino , Genisteína/administração & dosagem , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Pulmão/embriologia , Pulmão/imunologia , Pulmão/patologia , Masculino , Exposição Materna , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Pyroglyphidae/imunologia , Hipersensibilidade Respiratória/sangue , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia
6.
Toxicol Lett ; 333: 279-289, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32822773

RESUMO

Simazine is a kind of persistent organic pollutant that is detected in both ground and water and has several routes of exposure. Here, we explored the mechanisms underlying simazine-related effects on dopaminergic neurons via development-related factors using mouse embryos and embryonic mesencephalic hybrid cell line (MN9D cells). We treated pregnant mice with 50 µg/kg bw, 200 µg/kg bw simazine from the 0.5 day to the 10.5 day of embryonic phase and MN9D cells with 600 µM simazine for 24 h to research the mechanism of dopaminergic neurons acute respond to simazine through preliminary experiments. Protein expressions of LIM homeobox transcription factor 1-alpha (Lmx1a) and LIM homeobox transcription factor 1-beta (Lmx1b) displayed a dose- and time-dependent increase after the exposure to simazine. In the 200 µg/kg bw of embryos and the 24h-600 µM of MN9D cells, protein levels of dopaminergic developmental factors were significantly upregulated, and dopaminergic function was significantly damaged for the abnormal expression of Dyt5b. We demonstrated simazine induced the injury to dopaminergic neurons via the Lmx1a/wingless-related integration site 1 (Wnt1) and Lmx1b pathways. In the transfection experiments, we knocked down Lmx1a and Lmx1b of cells to verify the potential target of simazine-induced injury to dopaminergic neurons, respectively. We detected the protein and mRNA levels of development-related genes of dopaminergic neurons and intracellular dopamine levels in different treatment groups. Based on our experiments' results, we demonstrated an acute response to 24 h-600 µM simazine treatment, the simazine-induced injury to dopaminergic neuronal which leads to abnormal dopamine levels and dopaminergic impairment is via the activation of the Lmx1a/Wnt1 autoregulatory loop. Lmx1a is a promising target in the search for the mechanisms underlying simazine-induced dopaminergic injury.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Proteínas com Homeodomínio LIM/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Simazina/toxicidade , Fatores de Transcrição/metabolismo , Proteína Wnt1/metabolismo , Animais , Linhagem Celular , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Relação Dose-Resposta a Droga , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Transdução de Sinais , Fatores de Tempo
7.
Life Sci ; 258: 118197, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32781059

RESUMO

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


Assuntos
Transtorno Autístico/induzido quimicamente , Reabsorção Óssea/induzido quimicamente , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal/patologia , Risperidona/efeitos adversos , Animais , Animais Recém-Nascidos , Transtorno Autístico/sangue , Transtorno Autístico/complicações , Comportamento Animal , Fenômenos Biomecânicos , Reabsorção Óssea/sangue , Reabsorção Óssea/fisiopatologia , Citocinas/sangue , Citocinas/genética , Feminino , Lipopolissacarídeos/administração & dosagem , Masculino , Atividade Motora , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Risperidona/administração & dosagem , Comportamento Estereotipado
8.
Toxicol Lett ; 333: 90-96, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32768652

RESUMO

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) effectively induces cleft palate at increased doses, but its mechanism of involvement is unclear, and arguments have examined palatal shelf contact and/or fusion failure. The role of different types of cells constituting palatal skulls remains elusive regarding TCDD dosage. No reports have simultaneously compared the biological behaviors of TCDD- induced mesenchymal and epithelial cells in vitro. This study employed primary epithelial and mesenchymal cells as models in vitro to explore proliferation, migration, apoptosis and epithelial-to-mesenchymal transition with two different doses of TCDD (10 nmol/L, 100 nmol/L), contrasted with a control group without TCDD. Interestingly, we found the EMT process of primary palatal epithelial cells occurred automatically in vitro without helping bilateral palatal contact. The results showed that, with the low dose of TCDD, transformation of epithelial cells to mesenchymal cells was inhibited, and mesenchymal cell proliferation and migration were promoted. At high doses, mesenchymal cells decreased, preventing palate development, uprising and contact, while the EMT of epithelial cells decreased. Regardless of dose of TCDD, no impact on migration and apoptosis of epithelial cells was noted, but there was increased apoptosis of mesenchymal cell in a dose-dependent manner.


Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Células Epiteliais/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Palato/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fissura Palatina/induzido quimicamente , Fissura Palatina/embriologia , Fissura Palatina/patologia , Relação Dose-Resposta a Droga , Células Epiteliais/patologia , Feminino , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Palato/embriologia , Palato/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia
9.
Life Sci ; 260: 118309, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841664

RESUMO

AIMS: Oral cavity pathogens play an important systemic role, modulating the development of several diseases. Periodontitis is a very common oral disease associated with dental biofilm. It is characterized by gum inflammation, periodontal ligament degeneration, dental cementum and alveolar bone loss. Studies point to the association between maternal periodontitis and adverse outcomes during pregnancy. However, they did not evaluate the impact of maternal periodontitis in the offspring. Thus, our objective was to investigate the effects of maternal periodontitis in the immune system of offspring. MATERIAL AND METHODS: For this evaluation we induced acute lung injury in rat pups. Pregnant rats were submitted or not to periodontitis by ligature technique. Thirty days after the birth, offspring was submitted to acute lung inflammation by administration of lipopolysaccharide (LPS, Salmonella abortus equi, 5 mg/kg, ip). KEY FINDINGS: Our results showed that maternal periodontitis increased myeloperoxidase activity, the levels of TNF-alpha and IL-17A in the bronchoalveolar fluid, the gene expression of TNF-alpha, IL-17A, and cyclooxygenases 1 and 2. In addition, maternal periodontitis did not alter the number of leukocytes migrated into the lung, tracheal responsiveness, expression of TLR4 and NF-KB translocation. SIGNIFICANCE: This study showed prenatal programming of the immune response induced by maternal periodontitis, and reinforces the importance of oral health care during pregnancy.


Assuntos
Lesão Pulmonar Aguda/imunologia , Reprogramação Celular , Periodontite/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/patologia , Animais , Animais Recém-Nascidos , Feminino , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , NF-kappa B/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Fator de Necrose Tumoral alfa/metabolismo
10.
Proc Natl Acad Sci U S A ; 117(32): 19578-19589, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32727894

RESUMO

The CreER/LoxP system is widely accepted to track neural lineages and study gene functions upon tamoxifen (TAM) administration. We have observed that prenatal TAM treatment caused high rates of delayed delivery and fetal mortality. This substance could produce undesired results, leading to data misinterpretation. Here, we report that administration of TAM during early stages of cortical neurogenesis promoted precocious neural differentiation, while it inhibited neural progenitor cell (NPC) proliferation. The TAM-induced inhibition of NPC proliferation led to deficits in cortical neurogenesis, dendritic morphogenesis, synaptic formation, and cortical patterning in neonatal and postnatal offspring. Mechanistically, by employing single-cell RNA-sequencing (scRNA-seq) analysis combined with in vivo and in vitro assays, we show TAM could exert these drastic effects mainly through dysregulating the Wnt-Dmrta2 signaling pathway. In adult mice, administration of TAM significantly attenuated NPC proliferation in both the subventricular zone and the dentate gyrus. This study revealed the cellular and molecular mechanisms for the adverse effects of TAM on corticogenesis, suggesting that care must be taken when using the TAM-induced CreER/LoxP system for neural lineage tracing and genetic manipulation studies in both embryonic and adult brains.


Assuntos
Encéfalo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/patologia , Tamoxifeno/efeitos adversos , Animais , Encéfalo/embriologia , Encéfalo/patologia , Diferenciação Celular , Proliferação de Células , Giro Denteado/efeitos dos fármacos , Giro Denteado/patologia , Feminino , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/patologia , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , RNA-Seq , Análise de Célula Única , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
11.
J Vis Exp ; (160)2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32658199

RESUMO

Chorioamnionitis is a common precipitant of preterm birth and is associated with many of the morbidities of prematurity, including necrotizing enterocolitis (NEC). However, a mechanistic link between these two conditions remains yet to be discovered. We have adopted a murine model of chorioamnionitis involving lipopolysaccharide (LPS)-induced fetal exposure to maternal inflammation (FEMI). This model of FEMI induces a sterile maternal, placental, and fetal inflammatory cascade, which is also present in many cases of clinical chorioamnionitis. Although models exist that utilize live bacteria and more accurately mimic the pathophysiology of an ascending infection resulting in chorioamnionitis, these methods may cause indirect effects on development of the immature intestinal tract and the associated developing microbiome. Using this protocol, we have demonstrated that LPS-induced FEMI results in a dose-dependent increase in pregnancy loss and preterm birth, as well as disruption of normal intestinal development in offspring. Further, we have demonstrated that FEMI significantly increases intestinal injury and serum cytokines in offspring, while simultaneously decreasing goblet and Paneth cells, both of which provide a first line of innate immunity against intestinal inflammation. Although a similar model of LPS-induced FEMI has been used to model the association between chorioamnionitis and subsequent abnormalities of the central nervous system, to our knowledge, this protocol is the first to attempt to elucidate a mechanistic link between chorioamnionitis and later perturbations in intestinal development as a potential link between chorioamnionitis and NEC.


Assuntos
Corioamnionite , Intestinos/crescimento & desenvolvimento , Mães , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Doença Aguda , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Feto/patologia , Humanos , Recém-Nascido , Camundongos , Celulas de Paneth/patologia , Placenta/patologia , Gravidez
12.
Chem Biol Interact ; 328: 109189, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32622864

RESUMO

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


Assuntos
Autofagia , Dibutilftalato/toxicidade , Proteínas Hedgehog/metabolismo , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Transdução de Sinais , Animais , Animais Recém-Nascidos , Autofagia/efeitos dos fármacos , Linhagem Celular , Feminino , Túbulos Renais/efeitos dos fármacos , Exposição Materna , Gravidez , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
13.
Toxicol Appl Pharmacol ; 401: 115077, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32479917

RESUMO

Triclocarban (TCC) is an antimicrobial compound, widely used in personal care products, such as soaps, toothpaste, and shampoo. This agent is incompletely removed by wastewater treatment and represents an environmental contaminant. Studies show that TCC has been associated with some endocrine disruptions. In vitro, TCC demonstrated potent androgen-augmenting activity and aromatase inhibition. In this sense, exposure during critical periods of development (gestation and lactation) could lead to some adverse health outcomes in offspring. Therefore, the present study evaluated if maternal exposure to three different doses of TCC could interfere in the reproductive parameters of male offspring. Pregnant female Wistar rats were separated into four groups: vehicle Control (CTR); TCC 0.3 mg/kg (TCC 0.3); TCC 1.5 mg/kg (TCC 1.5); TCC 3.0 mg/kg (TCC 3.0). Dams were treated daily by oral gavage from gestational day 0 to lactational day 21. The males were evaluated in different timepoint: infancy (PND 21), puberty (PND 50) and adult life (PND 90-120). The histomorphometric analysis of testis and testosterone level were assessed on PND 21, 50, 120; sexual behavior and sperm parameters at adulthood. In the TCC 3.0 group, a decrease in the testis interstitial volume and an increase in testosterone levels were observed on PND 21. Moreover, there was a decrease in the diameter of the seminiferous tubules on PND 50, and a decrease in sexual competency in adulthood. These results suggest that exposure to a human relevant dose of TCC may interfere with reproduction and could have implications for human health.


Assuntos
Anti-Infecciosos Locais/toxicidade , Carbanilidas/toxicidade , Lactação/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Reprodução/efeitos dos fármacos , Comportamento Sexual Animal/efeitos dos fármacos , Fatores Etários , Animais , Feminino , Lactação/fisiologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar , Reprodução/fisiologia , Comportamento Sexual Animal/fisiologia , Testículo/efeitos dos fármacos , Testículo/patologia , Testosterona/sangue
14.
Sci Rep ; 10(1): 8567, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444626

RESUMO

In 1973, the Velsicol Chemical Company, which manufactured FireMaster, a brominated flame retardant, and NutriMaster, a nutritional supplement, mistakenly shipped hundreds of pounds of FireMaster to grain mills around Michigan where it was incorporated into animal feed and then into the food chain across the state. An estimated 6.5 million Michigan residents consumed polybrominated biphenyl (PBB)-laced animal products leading to one of the largest agricultural accidents in U.S. history. To date, there have been no studies investigating the effects of PBB on epigenetic regulation in sperm, which could explain some of the endocrine-related health effects observed among children of PBB-exposed parents. Fusing epidemiological approaches with a novel in vitro model of human spermatogenesis, we demonstrate that exposure to PBB153, the primary component of FireMaster, alters the epigenome in human spermatogenic cells. Using our novel stem cell-based spermatogenesis model, we show that PBB153 exposure decreases DNA methylation at regulatory elements controlling imprinted genes. Furthermore, PBB153 affects DNA methylation by reducing de novo DNA methyltransferase activity at increasing PBB153 concentrations as well as reducing maintenance DNA methyltransferase activity at the lowest tested PBB153 concentration. Additionally, PBB153 exposure alters the expression of genes critical to proper human development. Taken together, these results suggest that PBB153 exposure alters the epigenome by disrupting methyltransferase activity leading to defects in imprint establishment causing altered gene expression, which could contribute to health concerns in the children of men exposed to PBB153. While this chemical is toxic to those directly exposed, the results from this study indicate that the epigenetic repercussions may be detrimental to future generations. Above all, this model may be expanded to model a multitude of environmental exposures to elucidate the effect of various chemicals on germline epigenetics and how paternal exposure may impact the health of future generations.


Assuntos
Retardadores de Chama/efeitos adversos , Regulação da Expressão Gênica no Desenvolvimento , Impressão Genômica , Bifenil Polibromatos/efeitos adversos , Espermatozoides/patologia , Criança , DNA (Citosina-5-)-Metiltransferase 1/genética , Epigênese Genética , Feminino , Gametogênese , Humanos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/patologia , RNA Longo não Codificante/genética , Espermatozoides/efeitos dos fármacos , Espermatozoides/metabolismo
15.
Epilepsia ; 61(6): 1291-1300, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32415786

RESUMO

OBJECTIVE: Sodium valproate (VPA), the most effective antiepileptic drug for patients with genetic generalized epilepsy (GGE), is a potent human teratogen that increases the risk of a range of congenital malformations, including spina bifida. The mechanisms underlying this teratogenicity are not known, but may involve genetic risk factors. This study aimed to develop an animal model of VPA-induced birth defects. METHODS: We used three different rat strains: inbred Genetic Absence Epilepsy Rats From Strasbourg (GAERS), a model of GGE with absence seizures; inbred Non-Epileptic Controls (NEC); and outbred nonepileptic Wistars. Female rats were fed standard chow or VPA (20 g/kg food) mixed in standard chow for 2 weeks prior to conception, and then mated with same-strain males. Treatment continued throughout pregnancy. Fetuses were extracted via C-section on gestational day 21 and examined for birth defects, including external assessment and spinal measurements. RESULTS: VPA-exposed pups showed significant reductions in weight, length, and whole-body development compared with controls of all three strains (P < .0001). Gestational VPA treatment altered intravertebral distances, and resulted in underdeveloped vertebral arches between thoracic region T11 and caudal region C2 in most pups (GAERS, 100%; NEC, 95%; Wistar, 80%), more frequently than in controls (9%, 13%, 19%). SIGNIFICANCE: Gestational VPA treatment results in similar developmental and morphological abnormalities in three rat strains, including one with GGE, indicating that the genetic underpinnings of epilepsy do not contribute markedly to VPA-induced birth defects. This model may be used in future studies to investigate mechanisms involved in the pathogenesis of antiepileptic drug-induced birth defects.


Assuntos
Anticonvulsivantes/toxicidade , Modelos Animais de Doenças , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Teratogênios/toxicidade , Ácido Valproico/toxicidade , Anormalidades Induzidas por Medicamentos/patologia , Administração Oral , Animais , Feminino , Masculino , Gravidez , Ratos , Ratos Transgênicos , Ratos Wistar
16.
Toxicology ; 439: 152477, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32360609

RESUMO

We previously reported that exposure during gestation and lactation to a low dose of glyphosate-based herbicide (GBH) reduced the area and perimeter of male offspring mammary gland at postnatal day 60 (PND60), whereas a higher dose increased the longitudinal growth of the gland. Here, our aim was to assess whether perinatal exposure to GBH exhibits endocrine disruptive action in male mammary gland at an early time point (pre-puberty), which could be related to the changes observed after puberty. We also wanted to explore whether an early evaluation of the male rat mammary gland is appropriate to assess exposure to potential endocrine disrupting chemicals (EDCs). Pregnant rats were orally exposed, through the diet, to vehicle (saline solution), 3.5 or 350 mg/kg/day of GBH from gestational day 9 until weaning. At PND21, the male offspring were euthanized, and mammary gland samples were collected. The histology and proliferation index of the mammary glands were evaluated, and the mRNA expression of estrogen (ESR1) and androgen (AR) receptors, cyclin D1 (Ccnd1), amphiregulin (Areg), insulin-like growth factor 1 (IGF1), epidermal growth factor receptor (EGFR) and IGF1 receptor (IGF1R) were assessed. Moreover, the phosphorylated-Erk1/2 (p-ERK1/2) protein expression was determined. No differences were observed in mammary epithelial structures and AR expression between experimental groups; however, the proliferation index was reduced in GBH3.5-exposed males. This result was associated with decreased ESR1, Ccnd1, Areg, IGF1, EGFR and IGF1R mRNA expressions, as well as reduced p-Erk1/2 protein expression in these animals. ESR1, Ccnd1, IGF1R and EGFR expressions were also reduced in GBH350-exposed males. In conclusion, the mammary gland development of pre-pubertal male rats is affected by perinatal exposure to GBH. Although further studies are still needed to understand the molecular mechanisms involved in GBH350 exposure, the present results may explain the alterations observed in mammary gland growth of post-pubertal males exposed to low doses of GBH. Our results also suggest that early evaluation of the male rat mammary gland is useful in assessing exposure to potential EDCs. However, analysis of EDCs effects at later time points should not be excluded.


Assuntos
Disruptores Endócrinos/toxicidade , Glicina/análogos & derivados , Herbicidas/toxicidade , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Actinas/metabolismo , Animais , Feminino , Glicina/toxicidade , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Glândulas Mamárias Humanas/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar , Receptores Estrogênicos/efeitos dos fármacos , Receptores Estrogênicos/genética , Receptores de Fatores de Crescimento/biossíntese , Receptores de Esteroides/biossíntese
17.
Breast Cancer Res ; 22(1): 41, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32370801

RESUMO

BACKGROUND: In utero endocrine disruption is linked to increased risk of breast cancer later in life. Despite numerous studies establishing this linkage, the long-term molecular changes that predispose mammary cells to carcinogenic transformation are unknown. Herein, we investigated how endocrine disrupting compounds (EDCs) drive changes within the stroma that can contribute to breast cancer susceptibility. METHODS: We utilized bisphenol A (BPA) as a model of estrogenic endocrine disruption to analyze the long-term consequences in the stroma. Deregulated genes were identified by RNA-seq transcriptional profiling of adult primary fibroblasts, isolated from female mice exposed to in utero BPA. Collagen staining, collagen imaging techniques, and permeability assays were used to characterize changes to the extracellular matrix. Finally, gland stiffness tests were performed on exposed and control mammary glands. RESULTS: We identified significant transcriptional deregulation of adult fibroblasts exposed to in utero BPA. Deregulated genes were associated with cancer pathways and specifically extracellular matrix composition. Multiple collagen genes were more highly expressed in the BPA-exposed fibroblasts resulting in increased collagen deposition in the adult mammary gland. This transcriptional reprogramming of BPA-exposed fibroblasts generates a less permeable extracellular matrix and a stiffer mammary gland. These phenotypes were only observed in adult 12-week-old, but not 4-week-old, mice. Additionally, diethylstilbestrol, known to increase breast cancer risk in humans, also increases gland stiffness similar to BPA, while bisphenol S does not. CONCLUSIONS: As breast stiffness, extracellular matrix density, and collagen deposition have been directly linked to breast cancer risk, these data mechanistically connect EDC exposures to molecular alterations associated with increased disease susceptibility. These alterations develop over time and thus contribute to cancer risk in adulthood.


Assuntos
Disruptores Endócrinos/toxicidade , Matriz Extracelular/patologia , Glândulas Mamárias Animais/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Células Estromais/patologia , Animais , Compostos Benzidrílicos/toxicidade , Estrogênios não Esteroides/farmacologia , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/imunologia , Feminino , Fibroblastos/imunologia , Fibroblastos/patologia , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/metabolismo , Camundongos , Fenóis/toxicidade , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/imunologia , Transcriptoma
18.
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
19.
Chem Biol Interact ; 323: 109076, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32240654

RESUMO

A growing body of evidence indicates that exposure to nonylphenol (NP), a typical persistent organic pollutant (POP), in early life results in the impairment of the central nervous system (CNS), but the underlying mechanism still remains to be elucidated. High levels of pro-inflammatory cytokines in the brain have been implicated in the CNS damages. The animal model of exposure to NP in early life was established by maternal gavage during the pregnancy and lactation in the present study. We found that exposure to NP in early life increased the levels of pro-inflammatory cytokines in the rat prefrontal cortex. Interestingly, the levels of pro-inflammatory cytokines in the intestine as well as in the serum were also increased by NP exposure. Furthermore, the increased permeability of intestinal barrier and blood-brain barrier (BBB), two critical barriers in the gut to brain communication, was observed in the rats exposed to NP in early lives. The decreased expression of zonula occludens-1 (ZO-1) and claudin-1 (CLDN-1), tight junction proteins (TJs) that responsible for maintaining the permeability of intestinal barrier and BBB, was found, which may underlie these increases in permeability. Taken together, these results suggested that the disturbed gut-brain communication may contribute to the increased levels of pro-inflammatory cytokines in the prefrontal cortex caused by NP exposure in early life.


Assuntos
Citocinas/metabolismo , Trato Gastrointestinal/patologia , Mediadores da Inflamação/metabolismo , Fenóis/toxicidade , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Animais Recém-Nascidos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Líquido Cefalorraquidiano/metabolismo , Claudina-1/metabolismo , Citocinas/sangue , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Mediadores da Inflamação/sangue , Intestinos/efeitos dos fármacos , Intestinos/patologia , Exposição Materna , Permeabilidade , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Ratos Sprague-Dawley , Proteína da Zônula de Oclusão-1/metabolismo
20.
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
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