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1.
Orv Hetil ; 161(2): 43-49, 2020 Jan.
Artigo em Húngaro | MEDLINE | ID: mdl-31902235

RESUMO

Hormonal imprinting is a physiological process, which is a part of the receptor-hormone complex development. It determines the binding capacity of the receptors across the lifespan. It takes place perinatally in the critical period of hormone receptor development, when the developmental window for imprinting is open and permits the binding of hormone-like molecules (related or synthetic hormones, endocrine disruptors etc.) causing disturbances of the endocrine system, and the systems- influenced organs by it, for life. This is the faulty hormonal imprinting. However, studying the medical database, PubMed, a lot of data can be found on the harmful late (adult age) effects of medication in the critical period of development with non-hormonal molecules, which are manifested later in functional alterations or diseases. This could mean that in the process of faulty imprinting, the openness of the developmental window could be more important than the structural similarity of a molecule to hormones. As developmentally critical period for faulty imprinting by hormone-like molecules is not exclusively the perinatal one (this is justified in the case of faulty hormonal imprinting), the pubertal period was also studied from this aspect and similarities to the impact of perinatal use have been found (this could be called "Pubertal Origin of Health and Disease = POHaD). While in the case of hormonal faulty imprinting, the mechanism seems to be clear (considering the role of receptors), the mechanism of drug-provoked imprinting is presently uncleared (considering the variety of medications which cause late-manifested alterations). The medicaments-caused faulty imprinting conception calls attention to the dangers of medication in the perinatal as well as the pubertal periods. Orv Hetil. 2020; 161(2): 43-49.


Assuntos
Disruptores Endócrinos/efeitos adversos , Impressão Genômica/efeitos dos fármacos , Hormônios/metabolismo , Sistema Endócrino , Feminino , Fertilização , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
2.
Life Sci ; 241: 117154, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31857087

RESUMO

AIM: Insulin resistance and neuroinflammation play roles in Alzheimer's (AD) etiology. Insulin receptors (IR) are developmentally expressed in neurons as well as astrocytes. Moreover, prolonged stress can induce brain insulin resistance and astrogliosis. Also, prenatal stress could advance AD-related abnormalities in a transgenic model of AD. Besides, postnatal maternal care (PMC) has antagonistic effects on prenatal stress (PS)-induced neuronal and immunological malfunctions. Using an icv-STZ subclinical model of sAD, we assessed PS and/or abnormal PMC impacts on advancing sAD-like pathology in adult male rats. We also sought astrocyte- and/or neuron-oriented change in central insulin programming. MAIN METHODS: Pregnant rats were exposed to PS. Thereafter, a group of pups was fostered onto unstressed mothers and the others remained intact. Real-time RT-PCR- for hippocampal IR, Tau, and ChAT transcripts- and immunohistochemistry analysis- for GFAP+ astrocytes- were performed at the first- and forth-postnatal-week, respectively. The other animals received icv-STZ0.5 mg/kg in adulthood and subjected to cognitive tests, molecular, and histological experiments at appropriate time-point post-injection. KEY FINDINGS: PS could advance sAD-related symptoms in icv-STZ-treated animals. PS changed expression levels of hippocampal IR in one-week-old and 5.5-month-old offspring. PS could worsen cognitive, molecular and histological impairments of icv-STZ. Adequate PMC prevented some destructive effects of PS. SIGNIFICANCE: PS can potentially change central insulin programming and induce long-lasting astrogliosis in rat hippocampus. PS-related cognitive and histological pathologies can rescue by PMC probably via IR-dependent pathways. Astrocyte involvement in AD-like neuropathology observed in stressed-animals needs more detailed investigations.


Assuntos
Doença de Alzheimer/patologia , Comportamento Animal , Modelos Animais de Doenças , Resistência à Insulina , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estreptozocina/toxicidade , Estresse Psicológico/complicações , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Animais , Animais Recém-Nascidos , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/toxicidade , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Infusões Intraventriculares , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Gravidez , Ratos , Ratos Wistar , Receptor de Insulina/metabolismo , Transdução de Sinais , Estreptozocina/administração & dosagem
3.
Endocrinology ; 161(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31875912

RESUMO

Changes in gonadotropin-releasing hormone (GnRH) release frequency from the brain help drive reproductive cycles. In polycystic ovary syndrome (PCOS), persistent high GnRH/luteinizing hormone (LH) frequency disrupts cycles and exacerbates hyperandrogenemia. Adult prenatally-androgenized (PNA) mice exhibit increased GnRH neuron firing rate, elevated ovarian androgens, and disrupted cycles, but before puberty, GnRH neuron activity is reduced in PNA mice compared with controls. We hypothesized that ovarian feedback mediates the age-dependent change in GnRH neuron firing rate in PNA vs control mice. Extracellular recordings of green fluorescent protein (GFP)-identified GnRH neurons were made 5 to 7 days after sham-surgery, ovariectomy (OVX), or, in adults, after OVX plus replacement of sub-male androgen levels with dihydrotestosterone implants (OVX + DHT). In 3-week-old mice, OVX did not affect GnRH neuron firing rate in either group. In adult controls, OVX increased GnRH neuron firing rate, which was further enhanced by DHT. In adult PNA mice, however, OVX decreased GnRH neuron firing rate, and DHT restored firing rate to sham-operated levels. In contrast to the differential effects of ovarian feedback on GnRH neuron firing rate, serum LH increased after OVX in both control and PNA mice and was not altered by DHT. Pituitary gene expression largely reflected changes expected with OVX, although in PNA but not control mice, DHT treatment increased Lhb expression. These results suggest prenatal androgen exposure programs marked changes in GnRH neuron regulation by homeostatic steroid feedback. PNA lowers GnRH neuron activity in low-steroid states (before puberty, OVX), and renders activity in adulthood dependent upon ongoing exposure to elevated ovarian androgens.


Assuntos
Androgênios/farmacologia , Hormônio Liberador de Gonadotropina/metabolismo , Neurônios/fisiologia , Ovário/metabolismo , Animais , Di-Hidrotestosterona/farmacologia , Eletrofisiologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ovariectomia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Maturidade Sexual/fisiologia
4.
Nat Med ; 25(12): 1894-1904, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792459

RESUMO

How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case-control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F0) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F1-F3 offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F1-F3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations.


Assuntos
Androgênios/metabolismo , Oócitos/metabolismo , Síndrome do Ovário Policístico/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , Estudos de Coortes , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Núcleo Familiar , /metabolismo , Oócitos/imunologia , Fenótipo , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Análise de Célula Única
5.
Sheng Li Xue Bao ; 71(5): 749-759, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31646329

RESUMO

With the evolution of medical techniques and technology, an increasing number of infants, neonates, and fetuses are exposed to general anesthesia for clinical diagnostic and therapeutic process. The neurotoxic effects of general anesthetics on developing brain have been a subject of concern and considerable research interest. Population-based study confirmed that single short-term general anesthetic exposure does not affect nervous system function, but multiple exposures to general anesthesia could damage cognitive function. Animal studies further discovered the underlying mechanisms. Nervous system is most susceptible to general anesthetics during the brain growth spurt. The time-point is more critical than the duration of exposure to general anesthetics. General anesthetics can induce intracellular calcium overload, disturb energy metabolism, promote cell apoptosis and lead to cell loss. General anesthetics can damage synaptic structure, transmission and plasticity, and impair brain function. High throughput omics technologies have been used to screen the differentially expressed genes induced by general anesthetics, which provide further understanding of the mechanism of general anesthetics affecting cognitive function. This review provides an update on the pathophysiologic mechanisms underlying the anesthesia-neurotoxicity, which will be helpful to provide instructions for the clinical use of general anesthesia in children.


Assuntos
Anestésicos Gerais/efeitos adversos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Cognição , Anestesia Geral/efeitos adversos , Animais , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
6.
Klin Padiatr ; 231(5): 262-268, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31505693

RESUMO

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


Assuntos
Analgésicos Opioides/toxicidade , Desenvolvimento Infantil/efeitos dos fármacos , Cognição/efeitos dos fármacos , Metanfetamina/toxicidade , Atividade Motora/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Comportamento do Lactente/efeitos dos fármacos , Comportamento do Lactente/psicologia , Recém-Nascido , Linguagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia
7.
Ecotoxicol Environ Saf ; 183: 109544, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31400720

RESUMO

Cigarette smoke can affect female reproductive health by causing follicle destruction and oocyte dysfunction. Third-hand smoke has received increasing attention as a public health issue. However, the effects of third-hand smoke on the female reproductive system, particularly the ovaries, remain unclear. 1-(N-methyl-N-nitrosamino)-1-(3-pyridinyl)-4-butanal (NNA) can be used as a biomarker of third-hand smoke. We studied the in vivo toxic effects of NNA on mice ovaries and offspring development. Three-week-old premature female mice were exposed to NNA at two different concentrations (0.075 µg/kg and 0.15 µg/kg body weight) and tap water (blank control) and diluted dimethylsulfoxide (solvent control) for 30 days. We found that oral administration of NNA (0.075 µg/kg and 0.15 µg/kg) significantly reduced ovary weight (the 0.15 µg/kg group was reduced to 18.69% ±â€¯0.89%) and ovarian follicle number (reduced by about 30%) (p < 0.05). Consumption of 0.15 µg/kg NNA reduced the survival rate of superovulated oocytes from 91.36% to 60.55% (p < 0.05). In addition, treated female mice in each group were mated with normal male mice to observe the effects of NNA on the F1 offspring, and during mating and lactation, all groups were given tap water. Two different concentrations of NNA exposure also significantly reduced body weight and impaired ear opening, tooth eruption and eye opening in F1 offspring, especially those exposed to 0.15 µg/kg NNA (p < 0.05). Our study suggested that NNA exposure had toxic effects on the reproductive health of female mice and their offspring. The results obtained may help evaluate the risks of third-hand smoke to women's reproductive health and to the health of their offspring.


Assuntos
Aldeídos/toxicidade , Ovário/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Piridinas/toxicidade , Reprodução/efeitos dos fármacos , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Lactação , Masculino , Camundongos , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/crescimento & desenvolvimento , Ovário/crescimento & desenvolvimento , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Tabaco/química
8.
Hypertension ; 74(3): 518-525, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31327271

RESUMO

Although maternal high-fructose intake induces cardiometabolic syndrome in adult offspring, whether it induces hypertension in successive multiple generations has not yet been studied. We hypothesized that maternal high-fructose intake induces multigenerational activation of the renin-angiotensin-aldosterone system. Pregnant mice were offered 20% fructose in drinking water, of which subsequent first to fourth generation offspring were raised without being offered fructose. Blood pressure was measured via the tail-cuff method, mRNA expression was determined using the quantitative polymerase chain reaction, and fibrosis was evaluated using trichrome staining. Maternal high-fructose intake statistically significantly increased blood pressure in the first and second, but not the third and fourth, generation offspring as compared to the control group, with maximal increases in serum renin, angiotensin II, and aldosterone in the third generation offspring. It increased the mRNA expression of renin-angiotensin-aldosterone system genes as well as the expression of renin in the kidneys in the first to third generation offspring, with the exception of the vasodilatory Mas1 gene, the mRNA expression of which was the lowest in the second generation offspring. Moreover, it maximally increased fibrosis and the mRNA expression of inflammatory cytokines in the second generation offspring and increased the mRNA expression of oxidative factors in the first to third generation offspring, but maximally decreased the mRNA expression of antioxidant-encoding Sod1 in the second generation offspring. Maternal high-fructose intake induces multigenerational activation of renin-angiotensin-aldosterone system, and the results of this study implicate that it epigenetically induces cardiometabolic syndrome in multiple generations of offspring.


Assuntos
Frutose/efeitos adversos , Hipertensão/etiologia , Prenhez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , RNA Mensageiro/genética , Sistema Renina-Angiotensina/genética , Animais , Animais Recém-Nascidos , Biópsia por Agulha , Modelos Animais de Doenças , Características da Família , Feminino , Frutose/administração & dosagem , Predisposição Genética para Doença/genética , Hipertensão/fisiopatologia , Imuno-Histoquímica , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Distribuição Aleatória , Valores de Referência , Medição de Risco
9.
Life Sci ; 233: 116689, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31348949

RESUMO

BACKGROUND: Maternal metabolic syndrome during gestation and lactation leads to several Se-status-related metabolic changes in offspring. MS leads to hepatomegaly, liver oxidation, resistance to insulin challenges and selenoptroteins expression upregulation, producing an energy imbalance in hepatocytes. As Se is necessary for correct heart function, Se deposits are depleted and selenoproteins expression downregulated in heart; this depletion being related to cardiovascular damage. Recently, selenoproteins have been directly implicated in the central endocrine regulation of appetite and energy homeostasis. METHODS: To obtain information about how Se is involved in regulating endocrine peripheral energy balance during MS process, two experimental groups of dam rats were used: control (Se: 0.1 ppm) and MS (Fructose 65% and Se: 0.1 ppm). At the end of lactation (21d old), the pups' appetite profile, tissular Se deposits and peptides from gastrointestinal tract (including pancreas), leptin, skeletal growth markers and cytokines in serum were measured. RESULTS: MS-exposed pups present changes in Se homeostasis, appetite profile and endocrine energy balance signals related to impaired insulin secretion and high leptin serum values. This profoundly affects the pups' growth profile since muscle and bones are in catabolic process and brown adipose tissue (BAT) mass decreases. CONCLUSION: These results indicate that the pups are suffering a process similar to diabetes type 1 which appeared when dams received low Se dietary supply and they point to Se as an important marker and key treatment for these disorders during gestation and lactation that affect future adult health.


Assuntos
Doenças do Sistema Endócrino/etiologia , Metabolismo Energético/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Síndrome Metabólica/complicações , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Selênio/administração & dosagem , Animais , Biomarcadores/sangue , Doenças do Sistema Endócrino/patologia , Feminino , Homeostase , Resistência à Insulina , Leptina/sangue , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Síndrome Metabólica/tratamento farmacológico , Estresse Oxidativo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Wistar , Selênio/efeitos adversos , Selênio/sangue
10.
Biomed Res Int ; 2019: 3426092, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281833

RESUMO

Anxiety is one of the most frequent psychiatric disorders. Despite the fact that most studies describe an anxiolytic effect of testosterone, hyperandrogenemia in mothers is assumed to be related to an increased risk of mood disorders in their offspring. An increasing body of scientific evidence suggests that an altered expression of interneuronal markers of the hippocampus may be the cause of anxiety. The aim of this study was to examine the influence of maternal hyperandrogenemia on behavioral parameters of anxiety-like behavior, neuropeptide Y (NPY) and parvalbumin (PV) expression in the hippocampus, and the level of the brain-derived neurotrophic factor (BDNF) in the hippocampus and cerebral cortex. Pregnant female Wistar albino rats were treated with testosterone undecanoate on the 20th day of gestation. Anxiety-like behavior in adult female offspring was evaluated by the elevated plus maze test and the open field. The number of PV and NPY immunoreactive cells in the hippocampus was determined immunohistochemically. The level of BDNF expression in the hippocampus and cerebral cortex was analyzed with the Western blot test. Prenatal hyperandrogenization increased anxiety-like behavior in female offspring and decreased expression of NPY+ and PV+ in the CA1 region of the hippocampus as compared to the control group. BDNF expression in the hippocampus and cerebral cortex of prenatally androgenized female offspring was significantly increased in comparison with the controls. Prenatal hyperandrogenization may be the cause of anxiety-like behavior in female offspring. Decrease in NPY and PV expression in the hippocampus may explain the possible mechanism of hyperandrogenization induced anxiety.


Assuntos
Ansiedade/etiologia , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/metabolismo , Interneurônios/fisiologia , Inibição Neural/fisiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Virilismo/complicações , Animais , Ansiedade/sangue , Ansiedade/fisiopatologia , Estradiol/sangue , Feminino , Hipocampo/fisiopatologia , Aprendizagem em Labirinto , Neuropeptídeo Y/metabolismo , Parvalbuminas/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos Wistar , Testosterona/administração & dosagem , Testosterona/sangue , Testosterona/farmacologia , Virilismo/fisiopatologia
11.
Biol Psychol ; 146: 107716, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31176750

RESUMO

We set out to examine the relations between prenatal exposure to the natural disaster Superstorm Sandy, maternal depression, and offspring electrodermal activity (EDA). EDA was measured via skin conductance response (SCR) magnitude in 198 children (M = 42.54 months, SD = 12.76) during a startle paradigm. In keeping with prior research, we expected prenatal depression to be associated with hyporeactive EDA and prenatal stress to be associated with hyperreactive EDA. SCR magnitude was lower in children prenatally exposed to depression alone, when compared to Superstorm Sandy, and controls. SCR magnitude of children prenatally exposed to both maternal depression and the storm was lower than that of all other groups. Our results emphasize the influence of maternal prenatal mental health, support targeted risk assessment for children who experienced an adverse prenatal environment, and highlight the need for a deeper understanding of the interactions between maternal mood and stress on the developing child.


Assuntos
Tempestades Ciclônicas/história , Depressão/fisiopatologia , Desastres/história , Exposição Materna/efeitos adversos , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Pré-Escolar , Depressão/psicologia , Feminino , Resposta Galvânica da Pele , História do Século XXI , Humanos , Masculino , Exposição Materna/história , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Reflexo de Sobressalto , Medição de Risco , Estados Unidos
12.
Environ Toxicol ; 34(10): 1105-1113, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31240815

RESUMO

The aim of the present study was to evaluate the effects of maternal exposure to triclosan (TCS) during pregnancy and lactation on the uterine morphology of rat offspring. For this, 32 Wistar rat dams were distributed into four dose groups (eight mothers per group), and gavage daily, throughout pregnancy and lactation, as follows: Group I-control (GI): corn oil; Group II (GII): TCS diluted in corn oil at a dose of 75 mg/kg/d; Group III (GIII): TCS diluted in corn oil at a dose of 150 mg/kg/d; Group IV (GIV): TCS diluted in corn oil at a dose of 300 mg/kg/d. A female pup of each mother was selected, and at 90 days the pups were euthanized for weighing and collection of the uterus for histomorphometric analysis. The results showed that the mean litter weight was minor in all the groups treated with TCS, when compared with control. The levels thyroid hormones thyroxine (T4) and triiodothyronine (T3) in TCS mother rats were reduced; however the levels of thyroid stimulating hormone (TSH) were increases. The offspring of all groups exposed to TCS presented deregulation of the estrous cycle, compared with control. Analysis of the uterine histological structure demonstrated that all layers of the uterus were affected by the administration of TCS, and the morphometric analysis showed increased uterine layers thickness in the treated groups. We concluded that maternal exposure to TCS during pregnancy and lactation causes intrauterine development restriction, deregulation of the oestrous cycle, and alters uterine tissue in rat offspring.


Assuntos
Anti-Infecciosos Locais/efeitos adversos , Retardo do Crescimento Fetal/etiologia , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Triclosan/efeitos adversos , Útero/crescimento & desenvolvimento , Animais , Ciclo Estral/efeitos dos fármacos , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Lactação/efeitos dos fármacos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Wistar , Hormônios Tireóideos/metabolismo , Útero/efeitos dos fármacos , Útero/fisiologia
13.
Ann Clin Microbiol Antimicrob ; 18(1): 18, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31226994

RESUMO

BACKGROUND: Prenatal antibiotic exposure has been associated with an altered infant gut microbiome composition and higher risk of childhood obesity, but no studies have examined if prenatal antibiotics simultaneously alter the gut microbiome and adiposity in infants. METHOD: In this prospective study (Nurture: recruitment 2013-2015 in North Carolina, United States), we examined in 454 infants the association of prenatal antibiotic exposure (by any prenatal antibiotic exposure; by trimester of pregnancy; by number of courses; by type of antibiotics) with infant age- and sex-specific weight-for-length z score (WFL-z) and skinfold thicknesses (subscapular, triceps, abdominal) at 12 months of age. In a subsample, we also examined whether prenatal antibiotic exposure was associated with alterations in the infant gut microbiome at ages 3 and 12 months. RESULTS: Compared to infants not exposed to prenatal antibiotics, infants who were exposed to any prenatal antibiotics had 0.21 (95% confidence interval [CI] 0.02, 0.41) higher WFL-z at 12 months, and 0.28 (95% CI 0.02, 0.55) higher WFL-z if they were exposed to antibiotics in the second trimester, after adjustment for potential confounders, birth weight, and gestational age. We also observed a dose-dependent association (P-value for trend = 0.006) with infants exposed to ≥ 3 courses having 0.41 (95% CI 0.13, 0.68) higher WFL-z at 12 months. After further adjustment for delivery method, only second-trimester antibiotic exposure remained associated with higher infant WFL-z (0.27, 95% CI 0.003, 0.54) and subscapular skinfold thickness (0.49 mm, 95% CI 0.11, 0.88) at 12 months. Infants exposed to second-trimester antibiotics versus not had differential abundance of 13 bacterial amplicon sequence variants (ASVs) at age 3 months and 17 ASVs at 12 months (false discovery rate adjusted P-value < 0.05). CONCLUSIONS: Prenatal antibiotic exposure in the second trimester was associated with an altered infant gut microbiome composition at 3 and 12 months and with higher infant WFL-z and subscapular skinfold thickness at 12 months.


Assuntos
Adiposidade/efeitos dos fármacos , Antibacterianos/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Obesidade/microbiologia , Efeitos Tardios da Exposição Pré-Natal/microbiologia , Adulto , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Feminino , Humanos , Lactente , Masculino , Obesidade/etiologia , Obesidade/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estudos Prospectivos , Adulto Jovem
14.
Chaos ; 29(4): 041101, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31042962

RESUMO

It is common knowledge that alcohol consumption during pregnancy would cause cognitive impairment in children. However, recent works suggested that the risk of drinking during pregnancy may have been exaggerated. It is critical to determine whether and up to which amount the consumption of alcohol will affect the cognitive development of children. We evaluate time-varying functional connectivity using magnetoencephalogram data from somatosensory evoked response experiments for 19 teenage subjects with prenatal alcohol exposure and 21 healthy control teenage subjects using a new time-varying connectivity approach, combining renormalised partial directed coherence with state space modeling. Children exposed to alcohol prenatally are at risk of developing a Fetal Alcohol Spectrum Disorder (FASD) characterized by cerebral connectivity deficiency and impaired cognitive abilities. Through a comparison study of teenage subjects exposed to alcohol prenatally with healthy control subjects, we establish that the inter-hemispheric connectivity is deficient for the former, which may lead to disruption in the cortical inter-hemispheric connectivity and deficits in higher order cognitive functions as measured by an IQ test, for example. We provide quantitative evidence that the disruption is correlated with cognitive deficits. These findings could lead to a novel, highly sensitive biomarker for FASD and support a recommendation of no safe amount of alcohol consumption during pregnancy.


Assuntos
Disfunção Cognitiva/induzido quimicamente , Etanol/toxicidade , Potenciais Somatossensoriais Evocados/fisiologia , Transtornos do Espectro Alcoólico Fetal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Adolescente , Consumo de Bebidas Alcoólicas , Encéfalo/fisiologia , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Feminino , Humanos , Magnetoencefalografia , Masculino , Gravidez
15.
Acta Neurobiol Exp (Wars) ; 79(1): 13-24, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038482

RESUMO

Depression is a highly prevalent social disease. Despite significant medical progress, therapeutic solutions for optimising treatment of this disease are still being sought. The aim of this study was to assess, using the forced swimming test, locomotor activity test and two compartment exploratory test, for a reduction in immobility time (a measure of anti-depressant efficacy), locomotor activity and anxiolytic effectiveness after single, repeated, and combined administration of vortioxetine (2.5 mg/kg - a multimodal SMS), dapoxetine (3.0 mg/kg - an SSRI used in premature ejaculation disorders) and fluoxetine (5.0 mg/kg - an SSRI) in non-stressed and prenatally stressed rats. It was found that vortioxetine, fluoxetine and dapoxetine reduced immobility time and rat locomotor activity which suggests anti-depressant efficacy of these drugs both in monotherapy and in combined administration. The results also confirmed an anxiolytic effect of the study drugs in mono and combined therapy. Analysis of the pathomechanism of depression and the mechanisms of action of the individual drugs tested resulted in a prediction that combined administration of these drugs may be effective in the treatment of depressive disorders, although possible interactions between the drugs used must be assessed for. Considering the fact that dapoxetine is not currently used in depression treatment and vortioxetine is a relatively new drug, further research in this direction is vital, including within animal models.


Assuntos
Antidepressivos/uso terapêutico , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/etiologia , Animais , Benzilaminas/uso terapêutico , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada , Comportamento Exploratório/efeitos dos fármacos , Feminino , Fluoxetina/uso terapêutico , Resposta de Imobilidade Tônica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Naftalenos/uso terapêutico , Gravidez , Ratos , Ratos Wistar , Estatísticas não Paramétricas , Natação/psicologia , Fatores de Tempo , Resultado do Tratamento , Vortioxetina/uso terapêutico
16.
Depress Anxiety ; 36(8): 753-765, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31066992

RESUMO

BACKGROUND: Prenatal maternal depression (PMD) and selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with increased developmental risk in infants. Reports suggest that PMD is associated with hyperconnectivity of the insula and the amygdala, while SSRI exposure is associated with hyperconnectivity of the auditory network in the infant brain. However, associations between functional brain organization and PMD and/or SSRI exposure are not well understood. METHODS: We examined the relation between PMD or SSRI exposure and neonatal brain functional organization. Infants of control (n = 17), depressed SSRI-treated (n = 20) and depressed-only (HAM-D ≥ 8) (n = 16) women, underwent resting-state functional magnetic resonance imaging at postnatal Day 6. At 6 months, temperament was assessed using Infant Behavioral Questionnaire (IBQ). We applied GTA and partial least square regression (PLSR) to the resting-state time series to assess group differences in modularity, and connector and provincial hubs. RESULTS: Modularity was similar across all groups. The depressed-only group showed higher connector hub values in the left anterior cingulate, insula, and caudate as well as higher provincial hub values in the amygdala compared to the control group. The SSRI group showed higher provincial hub values in Heschl's gyrus relative to the depressed-only group. PLSR showed that newborns' hub values predicted 10% of the variability in infant temperament at 6 months, suggesting different developmental patterns between groups. CONCLUSIONS: Prenatal exposures to maternal depression and SSRIs have differential impacts on neonatal functional brain organization. Hub values at 6 days predict variance in temperament between infant groups at 6 months of age.


Assuntos
Encéfalo/fisiopatologia , Transtorno Depressivo/tratamento farmacológico , Mães/psicologia , Complicações na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Inibidores de Captação de Serotonina/uso terapêutico , Adulto , Antidepressivos/uso terapêutico , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico/métodos , Desenvolvimento Infantil/efeitos dos fármacos , Transtorno Depressivo/fisiopatologia , Transtorno Depressivo/psicologia , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética/métodos , Vias Neurais/diagnóstico por imagem , Vias Neurais/efeitos dos fármacos , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/psicologia , Temperamento/efeitos dos fármacos
17.
Ups J Med Sci ; 124(2): 125-134, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31063006

RESUMO

Background: Although pregestational obesity has been associated with increased risk of adverse fetal outcome, the mechanisms behind are not known. We aimed to investigate the influence of the maternal metabolic state on fetal outcome in rats exposed to either a high-fat diet (HFD) or a control diet (CD). We also investigated the impact of serum collected from HFD/CD pregnant rats on CD embryonic development in whole-embryo cultures. Material and methods: On gestational day 0, 9, 10, or 20 maternal plasma/serum samples were collected as pregnancies were terminated for the estimations of maternal metabolic state and embryo-fetal development. We measured embryonic gene expression of ROS scavenger enzymes as well as genes involved in inflammation in maternal adipose tissue. Results: In HFD maternal plasma/serum, concentrations of glucose, ß-hydroxybutyrate, branched-chain amino acids, and leptin were increased, whereas those of triacylglycerol, cholesterol, and palmitic, oleic, linoleic, and α-linolenic acids were decreased. Gene expression of CuZnSOD, IL-6, IL-10, and resistin was increased in HFD maternal adipose tissue, whereas that of CuZnSOD and MnSOD was decreased in HFD-exposed embryos. HFD caused retention of most fatty acids in the maternal liver as well. Conclusion: HFD alters the maternal metabolic state, increases fetal resorptions in vivo, and increases the rate of fetal/embryonic malformations both in vivo and in vitro. These findings suggest that metabolic disturbances in HFD pregnant rats have profound adverse developmental effects in the offspring.


Assuntos
Dieta Hiperlipídica , Prenhez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Tecido Adiposo/metabolismo , Animais , Glicemia/análise , Colesterol/sangue , Técnicas de Cultura Embrionária , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Feminino , Desenvolvimento Fetal , Feto/metabolismo , Perfilação da Expressão Gênica , Humanos , Inflamação , Fígado/metabolismo , Troca Materno-Fetal , Modelos Animais , Obesidade , Gravidez , RNA/análise , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase-1/metabolismo , Triglicerídeos/sangue
18.
Life Sci ; 229: 251-260, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31112711

RESUMO

AIMS: Cardiovascular diseases may originate from suboptimal intrauterine environments. We aimed to examine the effects of prenatal androgen exposure (PAE) on heart basal hemodynamic parameters and tolerance to ischemia/reperfusion (I/R) injury, in PAE adult females and males. MAIN METHODS: Pregnant Wistar rats in the experimental group (n = 8) received 5 mg of testosterone (s.c. injection) on the 20th day of pregnancy, while controls received solvent. The hearts of adult female and male offspring were isolated and perfused in a Langendorff apparatus, values of left ventricular systolic pressure(LVSP), left ventricular developed pressure(LVDP), rate pressure product(RPP) and peak rates of positive and negative changes in left ventricular pressure(±dp/dt) were recorded using a power lab system. KEY FINDINGS: At baseline, PAE adult males demonstrated significant higher values of LVSP, LVDP, RPP and ±â€¯dp/dt, compared to controls and PAE adult females (p < 0.05), while PAE adult females showed no significant differences compared to controls. In PAE adult males, LVSP, LVDP, RPP and ±â€¯dp/dt had significant decreasing trends per phases after I/R, compared to their controls and PAE females, while these decreasing trends were not statistically significant in PAE adult female rats vs. their controls. SIGNIFICANCE: The impact of prenatal androgen exposure on adulthood cardiac function and tolerance to I/R is gender dependent, which may be partly explained by different cardiac effects of hyperandrogenism in males versus females. After prenatal androgen exposure, the baseline hemodynamic parameters of the hearts of adult males are increased; although they had less tolerance to I/R, findings however not observed in females.


Assuntos
Androgênios/administração & dosagem , Tolerância a Medicamentos , Coração/fisiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Pressão Sanguínea , Feminino , Coração/efeitos dos fármacos , Hemodinâmica , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Ratos , Ratos Wistar
19.
Mol Brain ; 12(1): 29, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935412

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males. In the medial prefrontal cortex (mPFC), a key region regulating these behaviors, we found augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons. Fast-spiking interneurons in mPFC exhibited enhanced intrinsic excitability and serotonin-induced excitability due to upregulated serotonin (5-HT) 2A receptor (5-HT2AR) signaling. More importantly, the behavioral deficits in prenatal fluoxetine treated mice were reversed by the application of a 5-HT2AR antagonist. Taken together, our findings suggest that alterations in inhibitory neuronal modulation are responsible for the behavioral alterations following prenatal exposure to SSRIs.


Assuntos
Memória de Curto Prazo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Inibidores de Captação de Serotonina/efeitos adversos , Comportamento Social , Sinapses/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Animal , Feminino , Fluoxetina/efeitos adversos , Interneurônios/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Inibição Neural/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Sinapses/efeitos dos fármacos
20.
Mol Autism ; 10: 19, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31011411

RESUMO

Background: Autism spectrum disorders (ASD) affect around 1.5% of people worldwide. Symptoms start around age 2, when children fail to maintain eye contact and to develop speech and other forms of communication. Disturbances in glutamatergic and GABAergic signaling that lead to synaptic changes and alter the balance between excitation and inhibition in the developing brain are consistently found in ASD. One of the hallmarks of these disorders is hypersensitivity to sensory stimuli; however, little is known about its underlying causes. Since the retina is the part of the CNS that converts light into a neuronal signal, we set out to study how it is affected in adolescent mice prenatally exposed to valproic acid (VPA), a useful tool to study ASD endophenotypes. Methods: Pregnant female mice received VPA (600 mg/kg, ip) or saline at gestational day 11. Their male adolescent pups (P29-35) were behaviorally tested for anxiety and social interaction. Proteins known to be related with ASD were quantified and visualized in their retinas by immunoassays, and retinal function was assessed by full-field scotopic electroretinograms (ERGs). Results: Early adolescent mice prenatally exposed to VPA displayed impaired social interest and increased anxiety-like behaviors consistent with an ASD phenotype. The expression of GABA, GAD, synapsin-1, and FMRP proteins were reduced in their retinas, while mGluR5 was increased. The a-wave amplitudes of VPA-exposed were smaller than those of CTR animals, whereas the b-wave and oscillatory potentials were normal. Conclusions: This study establishes that adolescent male mice of the VPA-induced ASD model have alterations in retinal function and protein expression compatible with those found in several brain areas of other autism models. These results support the view that synaptic disturbances with excitatory/inhibitory imbalance early in life are associated with ASD and point to the retina as a window to understand their subjacent mechanisms.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Retina/metabolismo , Potenciais de Ação , Animais , Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/metabolismo , Endofenótipos , Feminino , Proteína do X Frágil de Retardo Mental/genética , Proteína do X Frágil de Retardo Mental/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Receptores de GABA/genética , Receptores de GABA/metabolismo , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Retina/fisiopatologia , Comportamento Social , Sinapsinas/genética , Sinapsinas/metabolismo , Ácido Valproico/toxicidade
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