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2.
Am J Physiol Endocrinol Metab ; 320(3): E496-E511, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33427049

RESUMO

Tachykinin (TAC) signaling is an important element in the central control of reproduction. TAC family is mainly composed of substance P (SP), neurokinin A (NKA), and NKB, which bind preferentially to NK1, NK2, and NK3 receptors, respectively. While most studies have focused on the reproductive functions of NKB/NK3R, and to a lesser extent SP/NK1R, the relevance of NK2R, encoded by Tacr2, remains poorly characterized. Here, we address the physiological roles of NK2R in regulating the reproductive axis by characterizing a novel mouse line with congenital ablation of Tacr2. Activation of NK2R evoked acute luteinizing hormone (LH) responses in control mice, similar to those of agonists of NK1R and NK3R. Despite the absence of NK2R, Tacr2-/- mice displayed only partially reduced LH responses to an NK2R agonist, which, nonetheless, were abrogated after blockade of NK3R in Tacr2-/- males. While Tacr2-/- mice displayed normal pubertal timing, LH pulsatility was partially altered in Tacr2-/- females in adulthood, with suppression of basal LH levels, but no changes in the number of LH pulses. In addition, trends for increase in breeding intervals were detected in Tacr2-/- mice. However, null animals of both sexes were fertile, with no changes in estrous cyclicity or sex preference in social behavioral tests. In conclusion, stimulation of NK2R elicited LH responses in mice, while congenital ablation of Tacr2 partially suppressed basal and stimulated LH secretion, with moderate reproductive impact. Our data support a modest, albeit detectable, role of NK2R in the control of the gonadotropic axis, with partially overlapping and redundant functions with other tachykinin receptors.NEW & NOTEWORTHY We have explored here the impact of congenital ablation of the gene (Tacr2) encoding the tachykinin receptor, NK2R, in terms of neuroendocrine control of the reproductive axis, using a novel Tacr2 KO mouse line. Our data support a modest, albeit detectable, role of NK2R in the control of the gonadotropic axis, with partially overlapping and redundant functions with other tachykinin receptors.


Assuntos
Receptores da Neurocinina-2/genética , Reprodução/genética , Animais , Feminino , Hormônios Esteroides Gonadais/metabolismo , Hipotálamo/metabolismo , Hormônio Luteinizante/sangue , Masculino , Camundongos , Camundongos Knockout , Camundongos Obesos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Receptores da Neurocinina-2/deficiência , Reprodução/fisiologia , Transdução de Sinais/genética , Transcriptoma
3.
Metabolism ; 116: 154704, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33421507

RESUMO

BACKGROUND: Maternal high-caloric nutrition and related gestational diabetes mellitus (GDM) are associated with a high-risk for developing metabolic complications later in life and in their offspring. In contrast, exercise is recognized as a non-pharmacological strategy against metabolic dysfunctions associated to lifestyle disorders. Therefore, we investigated whether gestational exercise delays the development of metabolic alterations in GDM mothers later in life, but also protects 6-week-old male offspring from adverse effects of maternal diet. METHODS: Female Sprague-Dawley rats were fed with either control (C) or high-fat high-sucrose (HFHS) diet to induce GDM and submitted to gestational exercise during the 3 weeks of pregnancy. Male offspring were sedentary and fed with C-diet. RESULTS: Sedentary HFHS-fed dams exhibited increased gestational body weight gain (p < 0.01) and glucose intolerance (p < 0.01), characteristic of GDM. Their offspring had normal glucose metabolism, but increased early-age body weight, which was reverted by gestational exercise. Gestational exercise also reduced offspring hepatic triglycerides accumulation (p < 0.05) and improved liver mitochondrial respiration capacity (p < 0.05), contributing to the recovery of liver bioenergetics compromised by maternal HFHS diet. Interestingly, liver mitochondrial respiration remained increased by gestational exercise in HFHS-fed dams despite prolonged HFHS consumption and exercise cessation. CONCLUSIONS: Gestational exercise can result in liver mitochondrial adaptations in GDM animals, which can be preserved even after the exercise program cessation. Exposure to maternal GDM programs liver metabolic setting of male offspring, whereas gestational exercise appears as an important preventive tool against maternal diet-induced metabolic alterations.


Assuntos
Dieta Hiperlipídica , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , Condicionamento Físico Animal/fisiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Sacarose/administração & dosagem , Animais , Respiração Celular/efeitos dos fármacos , Diabetes Gestacional/metabolismo , Diabetes Gestacional/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Mitocôndrias Hepáticas/efeitos dos fármacos , Mães , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-Dawley
4.
Int J Mol Sci ; 22(2)2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33430368

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication, poor social interactions, and repetitive behaviors. We aimed to examine autism-like behaviors and related gene expressions in rats exposed to diesel exhaust (DE)-origin secondary organic aerosol (DE-SOA) perinatally. Sprague-Dawley pregnant rats were exposed to clean air (control), DE, and DE-SOA in the exposure chamber from gestational day 14 to postnatal day 21. Behavioral phenotypes of ASD were investigated in 10~13-week-old offspring using a three-chambered social behavior test, social dominance tube test, and marble burying test. Prefrontal cortex was collected to examine molecular analyses including neurological and immunological markers and glutamate concentration, using RT-PCR and ELISA methods. DE-SOA-exposed male and female rats showed poor sociability and social novelty preference, socially dominant behavior, and increased repetitive behavior. Serotonin receptor (5-HT(5B)) and brain-derived neurotrophic factor (BDNF) mRNAs were downregulated whereas interleukin 1 ß (IL-ß) and heme oxygenase 1 (HO-1) mRNAs were upregulated in the prefrontal cortex of male and female rats exposed to DE-SOA. Glutamate concentration was also increased significantly in DE-SOA-exposed male and female rats. Our results indicate that perinatal exposure to DE-SOA may induce autism-like behavior by modulating molecules such as neurological and immunological markers in rats.


Assuntos
Poluentes Atmosféricos/toxicidade , Transtorno do Espectro Autista/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Emissões de Veículos/toxicidade , Aerossóis/toxicidade , Animais , Transtorno do Espectro Autista/induzido quimicamente , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase-1/genética , Humanos , Interleucina-1beta/genética , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/genética
5.
Methods Mol Biol ; 2201: 253-258, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32975806

RESUMO

The developmental origins of disease or fetal programming model predict that early (intrauterine and/or postnatal) exposures to external insults of sufficient length and intensity may have enduring or lifelong consequences for physical and psychological health. The method described in this chapter considers an animal model to study the pathophysiological alterations connected to an HPA axis (hypothalamic-pituitary-adrenal) hyperactivity that are induced by an early-life stressful procedure involving the opioid system.


Assuntos
Modelos Animais de Doenças , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/fisiopatologia , Analgésicos Opioides/metabolismo , Analgésicos Opioides/farmacologia , Animais , Feminino , Sistema Hipotálamo-Hipofisário , Hipotálamo , Camundongos , Hipófise , Sistema Hipófise-Suprarrenal , Gravidez , Ratos , Receptores Opioides/metabolismo
6.
Toxicol Lett ; 339: 23-31, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33359558

RESUMO

Interesterified fat (IF) currently substitutes the hydrogenated vegetable fat (HVF) in processed foods. However, the IF consumption impact on the central nervous system (CNS) has been poorly studied. The current study investigated connections between IF chronic consumption and locomotor impairments in early life period and adulthood of rats and access brain molecular targets related to behavior changes in adulthood offspring. During pregnancy and lactation, female rats received soybean oil (SO) or IF and their male pups received the same maternal supplementation from weaning until adulthood. Pups' motor ability and locomotor activity in adulthood were evaluated. In the adult offspring striatum, dopaminergic targets, glial cell line-derived neurotrophic factor (GDFN) and lipid profile were quantified. Pups from IF supplementation group presented impaired learning concerning complex motor skill and sensorimotor behavior. The same animals showed decreased locomotion in adulthood. Moreover, IF group showed decreased immunoreactivity of all dopaminergic targets evaluated and GDNF, along with important changes in FA composition in striatum. This study shows that the brain modifications induce by IF consumption resulted in impaired motor control in pups and decreased locomotion in adult animals. Other studies about health damages induced by IF consumption may have a contribution from our current outcomes.


Assuntos
Encéfalo/metabolismo , Gorduras na Dieta/efeitos adversos , Locomoção/fisiologia , Atividade Motora/fisiologia , Sistema Nervoso/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ácidos Graxos Trans/efeitos adversos , Fatores Etários , Fenômenos Fisiológicos da Nutrição Animal , Animais , Gorduras na Dieta/metabolismo , Feminino , Humanos , Fenômenos Fisiológicos da Nutrição Materna , Modelos Animais , Fenômenos Fisiológicos do Sistema Nervoso , Gravidez , Ratos , Ácidos Graxos Trans/metabolismo
7.
Life Sci ; 261: 118364, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32866516

RESUMO

AIMS: Prenatal hypoxia (PH) could affect peripheral vascular tone of the offspring, thus increasing the risk of cardiovascular diseases in adult. However, it's still unknown whether functions of coronary arteries (COA) in adult offspring would be influenced by PH. The present study aimed at effects of PH on vascular tone of COA and its related mechanisms. METHODS: Coronary arteries of adult offspring exposed to hypoxic or normoxic circumstances during gestational day 5 to 21 were collected. Wire myograph system, whole-cell patch clamp technique, IonOptix MyoCam system, PCR, and western blot were used to detect vascular function of adult offspring COA. KEY FINDINGS: PH significantly attenuated serotonin- and phorbol 12, 13-dibutyrate (PDBu)-induced constriction. Iberiotoxin potentiated PDBu-induced constriction and the effect was augmented by PH, however, no significant differences were found in whole-cell BKCa channel currents and its protein expression. Nifedipine inhibited PDBu-mediated constriction and the inhibitory effect was reduced in PH group, and whole-cell calcium channel current was decreased in offspring COA. Besides, PH reduced the capability of calcium release from the endoplasmic reticulum in COA. The phosphorylated PKCß protein expression at Ser660 site, not Thr641 site, was significantly decreased in PH offspring. Chronic hypoxia during pregnancy attenuated PDBu-mediated constriction in offspring COA, presumably through decreased phosphorylated PKCß at serine660 sites and decreased intracellular calcium-related weaker PKC activation. SIGNIFICANCE: The findings provided new information on the influence of prenatal hypoxia on COA, and suggested potential use of PKCß-serine660 for early prevention of coronary heart diseases in developmental origins.


Assuntos
Cálcio/metabolismo , Vasos Coronários/fisiopatologia , Hipóxia/complicações , Espaço Intracelular/metabolismo , Fosfosserina/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Proteína Quinase C beta/metabolismo , Vasoconstrição , Animais , Peso Corporal/efeitos dos fármacos , Cafeína/farmacologia , Canais de Cálcio/metabolismo , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/patologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Feminino , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Gravidez , Ratos Sprague-Dawley , Serotonina/metabolismo , Acetato de Tetradecanoilforbol
8.
PLoS One ; 15(8): e0237708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817646

RESUMO

Parental high-fat diet (HFD) programs for obesity and hypertension in female offspring in rats, but it is unknown how the pregnancies of these offspring are impacted. Therefore, the hypothesis was tested that parental HFD exaggerates obesity and hypertension during pregnancy of the offspring. Wistar Hannover rat dams (the parental, P generation) were maintained on normal-fat diet (NFD) or HFD from weaning and were kept on respective diets through pregnancy and lactation. Their offspring (the first filial, F1 generation) were weaned onto the same diet as the P generation, or they were changed to the other diet to determine if combined HFD in the P and F1 generations exaggerates body weight and blood pressure levels during pregnancy in these offspring. This diet paradigm resulted in the following groups of pregnant F1 offspring: P-NFD/F1-NFD, P-HFD/F1-NFD, P-NFD/F1-HFD, and P-HFD/F1-HFD. Maternal body and adipose tissue weights were greatest in the P-HFD/F1-HFD group compared to the other 3 groups by the end of pregnancy. Plasma leptin and conscious mean arterial blood pressure were not significantly different between any group, although there was a main effect for increased blood pressure in the F1-HFD groups. Circulating levels of the antihypertensive pregnancy factor, placental growth factor (PlGF), were assessed. Although average PlGF levels were similar among all groups, correlative studies revealed that lower levels of PlGF were associated with higher blood pressure only in the P-HFD/F1-HFD group. In summary, HFD feeding from the P generation exaggerated HFD-induced body and adipose tissue weights in the pregnant offspring.


Assuntos
Hipertensão/sangue , Leptina/sangue , Obesidade/sangue , Fator de Crescimento Placentário/sangue , Efeitos Tardios da Exposição Pré-Natal/sangue , Adiposidade/genética , Animais , Pressão Sanguínea/genética , Peso Corporal/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Herança Materna/genética , Obesidade/genética , Obesidade/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Desmame
9.
PLoS One ; 15(8): e0238223, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32853260

RESUMO

Being delivered as a low birthweight (LBW) infant is a risk factor for elevated blood pressure and future problems with cardiovascular and cerebellar diseases. Although premature babies are reported to have low numbers of nephrons, some unclear questions remain about the mechanisms underlying elevated blood pressure in full-term LBW infants. We previously reported that glucocorticoids increased miR-449a expression, and increased miR-449a expression suppressed Crhr1 expression and caused negative glucocorticoid feedback. Therefore, we conducted this study to clarify the involvement of pituitary miR-449a in the increase in blood pressure caused by higher glucocorticoids in LBW rats. We generated a fetal low-carbohydrate and calorie-restricted model rat (60% of standard chow), and some individuals showed postnatal growth failure caused by growth hormone receptor expression. Using this model, we examined how a high-fat diet (lard-based 45kcal% fat)-induced mismatch between prenatal and postnatal environments could elevate blood pressure after growth. Although LBW rats fed standard chow had slightly higher blood pressure than control rats, their blood pressure was significantly higher than controls when exposed to a high-fat diet. Observation of glomeruli subjected to periodic acid methenamine silver (PAM) staining showed no difference in number or size. Aortic and cardiac angiotensin II receptor expression was altered with compensatory responses. Blood aldosterone levels were not different between control and LBW rats, but blood corticosterone levels were significantly higher in the latter with high-fat diet exposure. Administration of metyrapone, a steroid synthesis inhibitor, reduced blood pressure to levels comparable to controls. We showed that high-fat diet exposure causes impairment of the pituitary glucocorticoid negative feedback via miR-449a. These results clarify that LBW rats have increased blood pressure due to high glucocorticoid levels when they are exposed to a high-fat diet. These findings suggest a new therapeutic target for hypertension of LBW individuals.


Assuntos
Pressão Sanguínea/fisiologia , Retroalimentação Fisiológica/fisiologia , Glucocorticoides/sangue , Doenças da Hipófise/sangue , Doenças da Hipófise/fisiopatologia , Hipófise/fisiologia , Animais , Peso ao Nascer/efeitos dos fármacos , Peso ao Nascer/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Corticosterona/sangue , Dieta Hiperlipídica/efeitos adversos , Feminino , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Recém-Nascido de Baixo Peso/sangue , Recém-Nascido de Baixo Peso/fisiologia , Recém-Nascido , Masculino , Metirapona/uso terapêutico , Doenças da Hipófise/tratamento farmacológico , Hipófise/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar
12.
Nat Commun ; 11(1): 3593, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681096

RESUMO

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


Assuntos
Relógios Circadianos/efeitos dos fármacos , Glucocorticoides/efeitos adversos , Exposição Materna/efeitos adversos , Transtornos Mentais/etiologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ansiedade , Comportamento/efeitos dos fármacos , Feminino , Glucocorticoides/administração & dosagem , Humanos , Recém-Nascido Prematuro/psicologia , Masculino , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Gravidez , Complicações na Gravidez/tratamento farmacológico , Cuidado Pré-Natal , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo
13.
PLoS One ; 15(6): e0234516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559253

RESUMO

The prevalence of metabolic syndrome is increased worldwide. Tobacco smoking increases the risk of developing metabolic syndrome. Waterpipe tobacco smoking has become a global trend of tobacco consumption and is as common as cigarette smoking. In this study, the effect of waterpipe tobacco smoke (WTS) on the development of metabolic syndrome in rats was evaluated. Adult Wistar rats were exposed for 19 weeks to either fresh air (control) or WTS for 1 hour daily/ 5 days per week (WTS). Central obesity, systolic blood pressure, lipid profile, glucose hemostasis and levels of leptin and adiponectin were evaluated. The WTS exposure increased body weight, abdominal circumference, systolic blood pressure and fasting glucose compared to control animals (P<0.05), consistent with inducing metabolic syndrome. The retroperitoneal fat, lipid profile and levels of insulin, leptin and adiponectin were not affected by WTS exposure (P>0.05). In conclusion, exposure to WTS has detrimental health effects leading to the development of metabolic syndrome in experimental animals.


Assuntos
Síndrome Metabólica/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fumar Tabaco/efeitos adversos , Tabaco para Cachimbos de Água/efeitos adversos , Animais , Modelos Animais de Doenças , Feminino , Humanos , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Cachimbos de Água
14.
Sci Rep ; 10(1): 7615, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376856

RESUMO

The use of first and second generation antiepileptic drugs during pregnancy doubles the risk of major congenital malformations and other teratogenic defects. Lacosamide (LCM) is a third-generation antiepileptic drug that interacts with collapsing response mediator protein 2, a protein that has been associated with neurodevelopmental diseases like schizophrenia. The aim of this study was to test the potential teratogenic effects of LCM on developing embryos and its effects on behavioural/histological alterations in adult mice. We administered LCM to pregnant mice, assessing its presence, and that of related compounds, in the mothers' serum and in embryonic tissues using liquid chromatography coupled to quadrupole/time of flight mass spectrometry detection. Embryo morphology was evaluated, and immunohistochemistry was performed on adult offspring. Behavioural studies were carried out during the first two postnatal weeks and on adult mice. We found a high incidence of embryonic lethality and malformations in mice exposed to LCM during embryonic development. Neonatal mice born to dams treated with LCM during gestation displayed clear psychomotor delay and behavioural and morphological alterations in the prefrontal cortex, hippocampus and amygdala that were associated with behaviours associated with schizophrenia spectrum disorders in adulthood. We conclude that LCM and its metabolites may have teratogenic effects on the developing embryos, reflected in embryonic lethality and malformations, as well as behavioural and histological alterations in adult mice that resemble those presented by patients with schizophrenia.


Assuntos
Feto/anormalidades , Feto/efeitos dos fármacos , Lacosamida/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Esquizofrenia/fisiopatologia , Afeto/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Incidência , Locomoção/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Gravidez
15.
Nat Commun ; 11(1): 2555, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444624

RESUMO

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


Assuntos
Corpo Estriado/fisiopatologia , Etanol/efeitos adversos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/psicologia , Animais , Cognição/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Etanol/metabolismo , Feminino , Desenvolvimento Fetal , Humanos , Masculino , Camundongos Endogâmicos C57BL , Linhagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
16.
JAMA Netw Open ; 3(5): e204662, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32396192

RESUMO

Importance: Maternal prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) has previously been associated with offspring cardiometabolic risk factors, such as fat mass, glucose and insulin levels, and blood pressure, but these associations appear to be largely mediated by offspring BMI. To our knowledge, no studies have assessed alterations in the retinal microvasculature in association with maternal prepregnancy BMI. Objective: To investigate the association between maternal prepregnancy BMI and anthropometric parameters, blood pressure, and retinal vessel parameters in children age 4 to 6 years. Design, Setting, and Participants: Participants included mother-child pairs of the population-based Environmental Influence on Early Aging (ENVIRONAGE) birth cohort study (Flanders, Belgium) who were recruited at birth from February 2010 to June 2014 and followed-up at age 4 to 6 years between October 2014 and July 2018. Data were analyzed from February 2019 to April 2019. Exposures: Maternal prepregnancy BMI based on height and weight measurements at the first antenatal visit (weeks 7-9 of gestation). Main Outcomes and Measures: Children's anthropometric, blood pressure, and retinal microcirculation measurements at age 4 to 6 years. Retinal vessel diameters and the tortuosity index, a measure for the curvature of the retinal vasculature, were obtained by fundus image analysis. Results: This study included 240 mothers and children with a mean (SD) age of 29. 9 (4.2) years and 54.8 (4.7) months, respectively. Of these, 114 children (47.5%) were boys. Maternal prepregnancy BMI was positively associated with the child's birth weight, BMI, waist circumference, blood pressure, and retinal vessel tortuosity. A 1-point increase in maternal prepregnancy BMI was associated with a 0.26-mm Hg (95% CI, 0.08-0.44) higher mean arterial pressure for their children, with similar estimates for systolic and diastolic blood pressure. Independent from the association with blood pressure, a 1-point increase in maternal prepregnancy BMI was associated with a 0.40 (95% CI, 0.01-0.80) higher retinal tortuosity index (× 103). The hypothesis that these associations reflect direct intrauterine mechanisms is supported by the following observations: associations were independent of the current child's BMI and the estimates for paternal BMI at the follow-up visit did not reach significance. Conclusions and Relevance: Considering that blood pressure tracks from childhood into adulthood and microvascular changes may be early markers of cardiometabolic disease development, our results suggest that maternal prepregnancy BMI is an important modifiable risk factor for later-life cardiovascular health of the offspring.


Assuntos
Mães , Obesidade/complicações , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Retina/fisiologia , Adulto , Pressão Sanguínea , Índice de Massa Corporal , Doenças Cardiovasculares/fisiopatologia , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Microvasos/fisiologia , Gravidez
17.
PLoS One ; 15(5): e0231989, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32369488

RESUMO

BACKGROUND AND OBJECTIVE: Birth weight and post-natal growth are important predictors of adult health. Preeclampsia (PE) is associated with low birth weight and may have long term effects on the health of the children. The current study aims to compare anthropometry and blood pressure between children of mothers with and without PE in an Indian cohort. METHODS: We studied children born to women with (PE; n = 211) and without preeclampsia (non-PE; n = 470) at Bharati Hospital, Pune, India. Anthropometry and blood pressure were measured in children at 3-7 years of age. Weight and height Z-scores were calculated using the WHO 2006 growth reference. Independent t-tests were used to compare means between the two groups, and associations between preeclampsia and child outcomes were analyzed using multiple linear regression, adjusting for potential confounders. RESULTS: Weight and height Z-scores (p = 0.04 and 0.008), and subscapular skinfold thickness (p = 0.03) were higher among children of PE compared with children of non-PE mothers. Systolic blood pressure was also higher in children of PE mothers (1.70 mmHg [95% CI 0.05, 2.90] p = 0.006). BMI and diastolic blood pressure did not differ between groups. In regression models adjusted for newborn weight and gestational age, current age and sex, and maternal height, BMI and socio-economic status, children of PE mothers had higher weight Z-score (0.27 SD [95%CI 0.06, 0.48] p = 0.01), height Z-score (0.28 SD [95%CI 0.09, 0.47] p = 0.005), and subscapular skinfold thickness (0.38 mm [95%CI 0.00, 0.76] p = 0.049). A trend for higher systolic blood pressure (1.59 mmHg [95%CI -0.02, 3.20] p = 0.053) in the children was also observed in the adjusted model. The difference in systolic blood pressure was attenuated after adjusting further for the child's weight and height (1.09 mmHg [95%CI -0.48, 2.67] p = 0.17). There was no evidence of differences in effects between boys and girls. CONCLUSION: Children of PE mothers were taller and heavier, and had higher systolic blood pressure, partly explained by their increased body size, than children of non-PE mothers. In utero exposure to preeclampsia may increase the risk of future cardiovascular disease.


Assuntos
Peso ao Nascer , Pressão Sanguínea , Estatura , Pré-Eclâmpsia/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Determinação da Pressão Arterial , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Índia , Masculino , Idade Materna , Gravidez , Medição de Risco
18.
Life Sci ; 255: 117810, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32473248

RESUMO

AIMS: The aim of the present study was to clarify if in utero exposure to DEX would affect the development of different types of pancreatic endocrine cells during postnatal life. MAIN METHODS: We investigated morphological and transcriptional features of both pancreatic ß- and α-cell populations within the pancreatic islets during the early postnatal life of rats born to mothers treated with DEX (0.1 mg/kg) from day 14 to 19 of pregnancy. Untreated pregnant Wistar rats of the same age (12-week-old) were used as control (CTL). Pups were euthanized on the 1st, 3rd and 21st (PND1, PND3 and PND21, respectively) days of life, regardless of sex. Serum insulin and glucagon levels were also evaluated. KEY FINDINGS: Rats born to DEX-treated mothers exhibited increased pancreatic α-cell mass, circulating glucagon levels and Gcg, Pax6, MafB and Nkx2.2 expression. Rats born to DEX-treated mothers also presented a rise in serum insulin levels on the PND3 that was paralleled by reduced ß-cell mass. Such increase in serum insulin levels, instead, was associated with increased expression of genes associated to insulin secretion such as Gck and Slc2a2. SIGNIFICANCE: Altogether, the present data reveals yet unknown changes in endocrine pancreas during early postnatal life of rats exposed to DEX in utero. Such data may contribute to the understanding of the metabolic features of rats born to DEX-treated mothers.


Assuntos
Dexametasona/toxicidade , Células Secretoras de Glucagon/efeitos dos fármacos , Glucocorticoides/toxicidade , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Dexametasona/administração & dosagem , Feminino , Regulação da Expressão Gênica , Glucagon/sangue , Células Secretoras de Glucagon/citologia , Glucocorticoides/administração & dosagem , Insulina/sangue , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/citologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar
19.
Proc Natl Acad Sci U S A ; 117(18): 10035-10044, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32312804

RESUMO

One factor that contributes to the high prevalence of fetal alcohol spectrum disorder (FASD) is binge-like consumption of alcohol before pregnancy awareness. It is known that treatments are more effective with early recognition of FASD. Recent advances in retrospective motion correction for the reconstruction of three-dimensional (3D) fetal brain MRI have led to significant improvements in the quality and resolution of anatomical and diffusion MRI of the fetal brain. Here, a rhesus macaque model of FASD, involving oral self-administration of 1.5 g/kg ethanol per day beginning prior to pregnancy and extending through the first 60 d of a 168-d gestational term, was utilized to determine whether fetal MRI could detect alcohol-induced abnormalities in brain development. This approach revealed differences between ethanol-exposed and control fetuses at gestation day 135 (G135), but not G110 or G85. At G135, ethanol-exposed fetuses had reduced brainstem and cerebellum volume and water diffusion anisotropy in several white matter tracts, compared to controls. Ex vivo electrophysiological recordings performed on fetal brain tissue obtained immediately following MRI demonstrated that the structural abnormalities observed at G135 are of functional significance. Specifically, spontaneous excitatory postsynaptic current amplitudes measured from individual neurons in the primary somatosensory cortex and putamen strongly correlated with diffusion anisotropy in the white matter tracts that connect these structures. These findings demonstrate that exposure to ethanol early in gestation perturbs development of brain regions associated with motor control in a manner that is detectable with fetal MRI.


Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Encéfalo/fisiopatologia , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Imagem de Difusão por Ressonância Magnética , Modelos Animais de Doenças , Etanol/toxicidade , Feminino , Transtornos do Espectro Alcoólico Fetal/diagnóstico por imagem , Desenvolvimento Fetal/efeitos dos fármacos , Feto/diagnóstico por imagem , Feto/efeitos dos fármacos , Humanos , Macaca mulatta , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/diagnóstico por imagem , Estudos Retrospectivos
20.
Int Rev Neurobiol ; 150: 17-40, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32204831

RESUMO

The impact of stress on brain health begins in the womb. Both animal and human studies have found that prenatal maternal stress affects the brain and behavior of the offspring. Stressful life events, exposure to a natural disaster, and symptoms of maternal anxiety and depression increase the risk for the child having a range of emotional, behavioral and/or cognitive problems in later life. These include depression, anxiety, Attention Deficit Hyperactivity Disorder (ADHD), and/or conduct disorders. There is an increased risk for other outcomes also, including preterm delivery and reduced telomere length, possibly indicative of an accelerated life history. The causal role of prenatal maternal stress on the etiology of the neurodevelopmental disorders is supported by large population cohorts, which have controlled for a wide range of potential confounders, including postnatal maternal mood. More recently, research has begun to explore the biological correlates and mediators of these findings. These studies suggest that the hypothalamic pituitary adrenal (HPA) axis plays a role in mediating the effects of maternal stress on the fetal brain. Further, in vivo brain imaging research reports that maternal stress is associated with changes in limbic and frontotemporal networks, and the functional and microstructural connections linking them. The structural changes include cortical thinning and an enlarged amygdala. While these studies have been conducted on smaller sample sizes and could not control for many confounders, the observed brain changes do plausibly underlie many of the emotional, behavioral and cognitive changes found to be associated with prenatal stress.


Assuntos
Tonsila do Cerebelo , Córtex Cerebral , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário , Transtornos Mentais , Transtornos do Neurodesenvolvimento , Neuroimagem , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/patologia , Animais , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Criança , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Transtornos Mentais/etiologia , Transtornos Mentais/metabolismo , Transtornos Mentais/patologia , Transtornos Mentais/fisiopatologia , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia
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