RESUMEN
BACKGROUND: Prenatal and postnatal exposure to drugs such as cocaine is a public health problem that causes deficits in brain development and function in humans and animals. One of the main effects of prenatal and postnatal cocaine exposure is increased vulnerability to developing the substance use disorder at an early age. Furthermore, the negative emotional states associated with cocaine withdrawal increase the fragility of patients to relapse into drug abuse. In this sense, prenatal and postnatal cocaine exposure enhanced the cocaine- and nicotine-induced locomotor activity and locomotor sensitization, and rats exposed prenatally to cocaine displayed an increase in anxiety- and depressive-like behaviors in adulthood (PND 60-70). OBJECTIVE: Therefore, the objective of this study was to determine the effect of prenatal and postnatal cocaine exposure on anxiety- and depressive-like behaviors at different ages (30, 60, 90, and 120 days of age) in rats. METHODS: The study was divided into two stages: prenatal and postnatal. In the prenatal stage, a group of pregnant female Wistar rats was administered daily from GD0 to GD21 cocaine (cocaine pre-exposure group), and another group of pregnant female rats was administered daily saline (saline pre-exposure group). In the postnatal stage, during lactation (PND0 to PND21), pregnant rats received administration of cocaine or saline, respectively. Of the litters resulting from the cocaine pre-exposed and saline pre-exposed pregnant female groups, only the male rats were used for the recording of the anxiety- and depressive-like behaviors at different postnatal ages (30, 60, 90, and 120 days), representative of adolescence, adult, adulthood, and old age. RESULTS: The study found that prenatal and postnatal cocaine exposure generated age-dependent enhancement in anxiety- and depressive-like behaviors, being greater in older adult (PND 120) rats than in adolescent (PND 30) or adults (PND 60-90) rats. CONCLUSIONS: This suggests that prenatal and postnatal cocaine exposure increases anxiety- and depressive-like behaviors, which may increase the vulnerability of subjects to different types of drugs in young and adult age.
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Ansiedad , Cocaína , Depresión , Efectos Tardíos de la Exposición Prenatal , Ratas Wistar , Animales , Embarazo , Cocaína/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Femenino , Ratas , Ansiedad/inducido químicamente , Depresión/inducido químicamente , Masculino , Actividad Motora/efectos de los fármacos , Factores de Edad , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Inhibidores de Captación de DopaminaRESUMEN
Early postnatal administration of antibiotics has been linked to lasting effects on brain development and behavior. Research conducted on animals that are free from germs has demonstrated that the impact of microbiome colonization on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and neuroendocrine pathways is substantial, which play a crucial role in stress management. Nevertheless, it is still uncertain if the exposure to antibiotics in rat dams (F0-generation) before weaning is associated with neurobehavioral changes in rat offspring (F1-generation) during adulthood. In order to investigate the effects, we perturbed the intestinal microbiota of rat dams (F0 generation) by administering cefixime (CEF), an antibiotic commonly used for obstetric purposes, at clinically relevant doses (1 mg/kg, 2.5 mg/kg or 5 mg/kg). Anxiety-like behaviors in adult offspring was evaluated through the utilization of elevated plus maze (EPM) and open field paradigm (OFP) following a six-week interval from birth (PND42). Subsequent to behavioral assessments, the rats were euthanized, and their brains and blood was collected for biochemical analysis. Plasma corticosterone concentration was used to assess HPA activity, whereas the quantitative real-time polymerase chain reaction (PCR) was employed to determine the transcription levels of the glucocorticoid receptor (GR) Nr3c1. The offspring of F1 that were administered antibiotics before being weaned spent less time in the EPM open arm. The alterations were accompanied by increased levels of corticosterone in the bloodstream. The gene expression study revealed a decrease in the levels of mRNA transcription of Nr3c1. This research emphasizes the possible long-term effects of antibiotic exposure before weaning on the development of anxiety in offspring upon adulthood.
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Antibacterianos , Ansiedad , Regulación hacia Abajo , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Ratas Wistar , Receptores de Glucocorticoides , Animales , Receptores de Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Femenino , Antibacterianos/farmacología , Masculino , Regulación hacia Abajo/efectos de los fármacos , Ratas , Corticosterona/sangre , Embarazo , Efectos Tardíos de la Exposición Prenatal , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Prueba de Campo Abierto/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la Polimerasa , Animales Recién NacidosRESUMEN
Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants produced through the combustion of organic matter, with sources ranging from traffic pollution to diet. Although PAH exposure has been associated with adverse health effects, few studies have examined its impact on neurodevelopmental delay (NDD). Thus, our study aims to investigate the effect of prenatal PAH exposure on the odds of NDD. We measured 7 hydroxylated PAH metabolites in spot urine samples collected up to three times during pregnancy in the PROTECT birth cohort. NDD was identified using score cutoffs from the Ages and Stages Questionnaire, 3rd edition offered in Spanish, across five domains at 12, 24, 36, and 48 months. We utilized logistic regression and mixed effects logistic regression models to assess associations between prenatal PAH concentrations and NDD. Our results showed mostly lower odds of NDD with higher PAH exposure (p < 0.05). However, male children showed higher odds of NDD in relation to PAH exposure, particularly in the Fine Motor domain. For example, 1-hydroxypyrene was associated with 1.11 (1.01, 1.23) times odds of delay in fine motor function in male children versus 0.91 (0.82, 1.00) times odds in female children. Our preliminary sex-specific results suggest that PAH exposure may impact neurodevelopment in male children and prompt further investigation into the potential sex-specific mechanisms of PAHs on motor function.
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Contaminantes Ambientales , Hidrocarburos Policíclicos Aromáticos , Efectos Tardíos de la Exposición Prenatal , Humanos , Hidrocarburos Policíclicos Aromáticos/toxicidad , Hidrocarburos Policíclicos Aromáticos/orina , Femenino , Embarazo , Masculino , Contaminantes Ambientales/orina , Puerto Rico , Preescolar , Exposición Materna/estadística & datos numéricos , Lactante , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/inducido químicamente , Desarrollo Infantil/efectos de los fármacos , Exposición a Riesgos Ambientales/estadística & datos numéricos , AdultoRESUMEN
BACKGROUND: Neurodevelopmental performance tasks are often separately analyzed, even when they tap into a similar construct. This may yield mixed findings for associations of an exposure-neurobehavioral outcome. We develop an item response theory (IRT) approach to integrate multiple task variables together to improve measurement precision of the underlying construct. We apply this approach to create an integrative measure of childhood inhibitory control, and study impacts of pre/post-natal lead exposure. METHODS: Using data from a prospective cohort based in Mexico (N = 533), we created an inhibitory control scale that integrates accuracy and reaction time information from four inhibitory control tasks (Go/NoGo Letter, Go/NoGo Neutral, Go/NoGo Happy, Delis-Kaplan Executive Function System (D-KEFS) Color-Word Interference Test, Condition 3). Using a generalized partial credit item response theory model, we estimated an inhibitory control index for each participant. We then assessed adjusted associations between umbilical cord blood and 4-year lead and childhood inhibitory control. We developed a resampling approach to incorporate error estimates from the inhibitory control variable to confirm the consistency of the lead-inhibitory control associations. We modeled time-varying associations of lead with each inhibitory control measure separately. RESULTS: Participants had a median age of 9 years; 51.4% were males. Umbilical cord blood [-0.06 (95% CI: -0.11, -0.01)] and 4-year lead [-0.07 (95% CI: -0.12, -0.02)] were associated with inhibitory control index at 8-10 years. A resampling approach confirmed that 4-year lead was consistently associated with childhood inhibitory control index. Umbilical cord blood and 4-year lead were each associated with 3 out of 8 measures in separate models. CONCLUSION: This is the first application of IRT in environmental epidemiology to create a latent variable for inhibitory control that integrates accuracy and reaction time information from multiple, related tasks. This framework can be applied to other correlated neurobehavioral assessments or other phenotype data.
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Función Ejecutiva , Inhibición Psicológica , Plomo , Humanos , Plomo/sangre , Masculino , Femenino , México , Preescolar , Embarazo , Efectos Tardíos de la Exposición Prenatal , Contaminantes Ambientales/sangre , Estudios Prospectivos , Niño , Exposición a Riesgos Ambientales/análisisRESUMEN
Changes in maternal gut microbiota due to stress and/or ethanol exposure can have lasting effects on offspring's health, particularly regarding immunity, inflammation response, and susceptibility to psychiatric disorders. The literature search for this review was conducted using PubMed and Scopus, employing keywords and phrases related to maternal stress, ethanol exposure, gut microbiota, microbiome, gut-brain axis, diet, dysbiosis, progesterone, placenta, prenatal development, immunity, inflammation, and depression to identify relevant studies in both preclinical and human research. Only a limited number of reviews were included to support the arguments. The search encompassed studies from the 1990s to the present. This review begins by exploring the role of microbiota in modulating host health and disease. It then examines how disturbances in maternal microbiota can affect the offspring's immune system. The analysis continues by investigating the interplay between stress and dysbiosis, focusing on how prenatal maternal stress influences both maternal and offspring microbiota and its implications for susceptibility to depression. The review also considers the impact of ethanol consumption on gut dysbiosis, with an emphasis on the effects of prenatal ethanol exposure on both maternal and offspring microbiota. Finally, it is suggested that maternal gut microbiota dysbiosis may be significantly exacerbated by the combined effects of stress and ethanol exposure, leading to immune system dysfunction and chronic inflammation, which could increase the risk of depression in the offspring. These interactions underscore the potential for novel mental health interventions that address the gut-brain axis, especially in relation to maternal and offspring health.
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Disbiosis , Etanol , Microbioma Gastrointestinal , Efectos Tardíos de la Exposición Prenatal , Estrés Psicológico , Humanos , Embarazo , Femenino , Efectos Tardíos de la Exposición Prenatal/inmunología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/inmunología , Etanol/efectos adversos , Animales , Estrés Psicológico/inmunología , Estrés Psicológico/complicaciones , Disbiosis/inmunología , Trastornos Mentales/etiología , Trastornos Mentales/inmunología , Trastornos Mentales/microbiología , Eje Cerebro-IntestinoRESUMEN
The developmental origins of healthy and disease (DOHaD) concept has demonstrated a higher rate of chronic diseases in the adult population of individuals whose mothers experienced severe maternal protein restriction (MPR). Using proteomic and in silico analyses, we investigated the lung proteomic profile of young and aged rats exposed to MPR during pregnancy and lactation. Our results demonstrated that MPR lead to structural and immune system pathways changes, and this outcome is coupled with a rise in the PI3k-AKT-mTOR signaling pathway, with increased MMP-2 activity, and CD8 expression in the early life, with long-term effects with aging. This led to the identification of commonly or inversely differentially expressed targets in early life and aging, revealing dysregulated pathways related to the immune system, stress, muscle contraction, tight junctions, and hemostasis. We identified three miRNAs (miR-378a-3p, miR-378a-5p, let-7a-5p) that regulate four proteins (ACTN4, PPIA, HSPA5, CALM1) as probable epigenetic lung marks generated by MPR. In conclusion, MPR impacts the lungs early in life, increasing the possibility of long-lasting negative outcomes for respiratory disorders in the offspring.
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Pulmón , MicroARNs , Proteómica , Animales , Femenino , Pulmón/metabolismo , Masculino , Proteómica/métodos , Embarazo , MicroARNs/genética , MicroARNs/metabolismo , Ratas , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/genética , Dieta con Restricción de Proteínas , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Serina-Treonina Quinasas TOR/genética , Longevidad/genética , Ratas Wistar , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteoma/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Envejecimiento/metabolismo , Envejecimiento/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/genéticaRESUMEN
Environmental factors in the early life stages can lead the descendant to adaptations in gene expression, permanently impacting several structures and organs. The amount and quality of fatty acids in the maternal diet in pregnancy and lactation were found to impact offspring metabolism. So, maternal diet and insulin resistance can affect the male and female descendants through distinct pathways and at different time points. We hypothesized that maternal high-fat diet (HFD) intake before conception and an adequate amount of different fatty acids intake during pregnancy and lactation could influence the energy homeostasis system of 21-day-old offspring. Female rats received control diet (C) or HFD (HF) for 8 weeks before pregnancy. During pregnancy and lactation C group remained with same diet (C-C), HF group were distributed into 4 groups and received C diet (HF-C), normolipidic diet based on saturated fatty acids (HF-S) or based on polyunsaturated fatty acids n-3 (HF-P) or remained in same diet (HF-HF). Maternal HFD in preconception, pregnancy, and lactation (HF-HF) led to lower glucagon-like peptide-1 levels in male (HF-HF21) compared to other groups (C-C21, HF-C21, and HF-P21) and compared to HF-HF21 females. Neuropeptide YY levels were higher in the HF-HF21, HF-C21, and HF-S21 male offspring compared to HF-P21. HF-P21 was similar to C-C21. Positive correlations were found among the energy homeostasis markers genes expressed in the offspring hypothalamus. Maternal diet changes to adequate quantities of fatty acids during pregnancy and lactation showed less impaired results but was not entirely avoided. A maternal diet based on PUFA n-3 during pregnancy and lactation seems to reverse the damage of an HFD in preconception. These results of homeostasis energy system disturbance in the offspring at weaning give us clues about changes that precede the onset of the disease in adult life - adding notes to the knowledge for future investigations of prevention and treatment of chronic diseases.
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Dieta Alta en Grasa , Metabolismo Energético , Ácidos Grasos , Intolerancia a la Glucosa , Homeostasis , Lactancia , Fenómenos Fisiologicos Nutricionales Maternos , Destete , Femenino , Animales , Masculino , Embarazo , Ácidos Grasos/metabolismo , Ácidos Grasos/administración & dosificación , Dieta Alta en Grasa/efectos adversos , Ratas , Lactancia/fisiología , Ratas Wistar , Efectos Tardíos de la Exposición Prenatal , Resistencia a la InsulinaRESUMEN
Clinical evidence suggests that early malnutrition promotes symptoms related to psychiatric disorders later in life. Nevertheless, the molecular mechanisms underpinning nutritional injury induce depression remains unknown. The purpose of the present study was to evaluate whether perinatal protein restriction increases vulnerability to developing depressive-like behavior in adulthood by focusing on anhedonia, a core symptom of depression. To this, male adult Wistar rats submitted to a protein restriction schedule at perinatal age (PR-rats), were subjected to the sucrose preference test (SPT), the novel object recognition test (NORT), the forced swim test (FST), and the elevated plus maze (EPM), and compared to animals fed with a normoprotein diet. To investigate neurobiological substrates linked to early protein undernutrition-facilitated depressive-like behavior, we assessed the levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the nucleus accumbens (NAc), and evaluated the reversal of anhedonic-like behavior by infusing ANA-12. We found that early malnutrition decreased sucrose preference, impaired performance in the NORT and increased immobility time in the FST. Furthermore, perinatal protein-restriction-induced anhedonia correlated with increased BDNF and p-TrkB protein levels in the NAc, a core structure in the reward circuit linked with anhedonia. Finally, bilateral infusion of the TrkB antagonist ANA-12 into the NAc shell ameliorated a reduced sucrose preference in the PR-rats. Altogether, these findings revealed that protein restriction during pregnancy and lactation facilitates depressive-like behavior later in life and may increase the risk of developing anhedonia by altering BDNF-TrkB in the NAc shell.
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Anhedonia , Factor Neurotrófico Derivado del Encéfalo , Núcleo Accumbens , Ratas Wistar , Receptor trkB , Transducción de Señal , Animales , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Masculino , Anhedonia/fisiología , Ratas , Receptor trkB/metabolismo , Femenino , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Embarazo , Dieta con Restricción de Proteínas , Efectos Tardíos de la Exposición Prenatal/metabolismo , Depresión/metabolismo , Depresión/psicología , Azepinas , BenzamidasRESUMEN
Autism spectrum disorder (ASD) is known as a group of neurodevelopmental conditions including stereotyped and repetitive behaviors, besides social and sensorimotor deficits. Anatomical and functional evidence indicates atypical maturation of the striatum. Astrocytes regulate the maturation and plasticity of synaptic circuits, and impaired calcium signaling is associated with repetitive behaviors and atypical social interaction. Spontaneous calcium transients (SCT) recorded in the striatal astrocytes of the rat were investigated in the preclinical model of ASD by prenatal exposure to valproic acid (VPA). Our results showed sensorimotor delay, augmented glial fibrillary acidic protein -a typical intermediate filament protein expressed by astrocytes- and diminished expression of GABAA-ρ3 through development, and increased frequency of SCT with a reduced latency that resulted in a diminished amplitude in the VPA model. The convulsant picrotoxin, a GABAA (γ-aminobutyric acid type A) receptor antagonist, reduced the frequency of SCT in both experimental groups but rescued this parameter to control levels in the preclinical ASD model. The amplitude and latency of SCT were decreased by picrotoxin in both experimental groups. Nipecotic acid, a GABA uptake inhibitor, reduced the mean amplitude only for the control group. Nevertheless, nipecotic acid increased the frequency but diminished the latency in both experimental groups. Thus, we conclude that striatal astrocytes exhibit SCT modulated by GABAA-mediated signaling, and prenatal exposure to VPA disturbs this tuning.
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Astrocitos , Cuerpo Estriado , Animales , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Femenino , Embarazo , Ratas , Ácido Valproico/farmacología , Ratas Wistar , Picrotoxina/farmacología , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Modelos Animales de Enfermedad , Masculino , Calcio/metabolismo , Trastorno del Espectro Autista/metabolismo , Trastorno Autístico/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismoAsunto(s)
Hipertensión , Riñón , Lipopolisacáridos , Efectos Tardíos de la Exposición Prenatal , Sistema Nervioso Simpático , Animales , Sistema Nervioso Simpático/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Ratas , Riñón/inervación , Riñón/efectos de los fármacos , Femenino , Hipertensión/fisiopatología , Embarazo , Lipopolisacáridos/toxicidad , Lipopolisacáridos/farmacología , Presión Sanguínea/efectos de los fármacosRESUMEN
Autism spectrum disorders (ASDs) are characterized by core behavioral symptoms in the domains of sociability, language/communication, and repetitive or stereotyped behaviors. Deficits in the prefrontal and hippocampal excitatory/inhibitory balance due to a functional loss of GABAergic interneurons are proposed to underlie these symptoms. Increasing the postsynaptic effects of GABA with compounds that selectively modulate GABAergic receptors could be a potential target for treating ASD symptoms. In addition, deficits in GABAergic interneurons have been linked to dopamine (DA) system dysregulation, and, despite conflicting evidence, abnormalities in the DA system activity may underly some ASD symptoms. Here, we investigated whether the positive allosteric modulator of α5-containing GABAA receptors (α5-GABAARs) SH-053-2'F-R-CH3 (10 mg/kg) attenuates behavioral abnormalities in rats exposed to valproic acid (VPA) in utero, an established risk factor for autism. We also evaluated if animals exposed to VPA in utero present changes in the ventral tegmental area (VTA) DA system activity using in vivo electrophysiology and if SH-053-2'F-R-CH3 could attenuate these changes. SH-053-2'F-R-CH3 was administered intraperitoneally 30 min before each behavioral test and electrophysiology. In utero VPA exposure caused male and female rats to present increased repetitive behavior (self-grooming) in early adolescence and deficits in social interaction in adulthood. Male, but not female VPA rats, also presented deficits in recognition memory as adults. SH-053-2'F-R-CH3 attenuated the impairments in sociability and cognitive function in male VPA-exposed rats without attenuating the decreased social interaction in females. Adult male and female VPA-exposed rats also showed an increased VTA DA neuron population activity, which was not changed by SH-053-2'F-R-CH3. Despite sex differences, our findings indicate that α5-GABAARs positive allosteric modulators may effectively attenuate some core ASD symptoms.
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Efectos Tardíos de la Exposición Prenatal , Receptores de GABA-A , Conducta Social , Ácido Valproico , Animales , Femenino , Ácido Valproico/farmacología , Ratas , Masculino , Embarazo , Receptores de GABA-A/efectos de los fármacos , Dopamina/metabolismo , Trastorno del Espectro Autista/inducido químicamente , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiopatología , Ratas Sprague-Dawley , Regulación Alostérica/efectos de los fármacos , Modelos Animales de Enfermedad , Conducta Animal/efectos de los fármacos , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/fisiopatologíaRESUMEN
Numerous studies indicate that intrauterine growth restriction (IUGR) can predispose individuals to metabolic syndrome (MetS) in adulthood. Several reports have demonstrated that pharmacological concentrations of biotin have therapeutic effects on MetS. The present study investigated the beneficial effects of prenatal biotin supplementation in a rat model of intrauterine caloric restriction to prevent cardiometabolic risk in adult female offspring fed fructose after weaning. Female rats were exposed to a control (C) diet or global caloric restriction (20%) (GCR), with biotin (GCRB) supplementation (2 mg/kg) during pregnancy. Female offspring were exposed to 20% fructose (F) in drinking water for 16 weeks after weaning (C, C/F, GCR/F, and GCRB/F). The study assessed various metabolic parameters including Lee's index, body weight, feed conversion ratio, caloric intake, glucose tolerance, insulin resistance, lipid profile, hepatic triglycerides, blood pressure, and arterial vasoconstriction. Results showed that GCR and GCRB dams had reduced weights compared to C dams. Offspring of GCRB/F and GCR/F dams had lower body weight and Lee's index than C/F offspring. Maternal biotin supplementation in the GCRB/F group significantly mitigated the adverse effects of fructose intake, including hypertriglyceridemia, hypercholesterolemia, hepatic steatosis, glucose and insulin resistance, hypertension, and arterial hyperresponsiveness. This study concludes that prenatal biotin supplementation can protect against cardiometabolic risk in adult female offspring exposed to postnatal fructose, highlighting its potential therapeutic benefits.
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Biotina , Restricción Calórica , Suplementos Dietéticos , Retardo del Crecimiento Fetal , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Embarazo , Ratas , Restricción Calórica/métodos , Biotina/administración & dosificación , Biotina/farmacología , Efectos Tardíos de la Exposición Prenatal/prevención & control , Retardo del Crecimiento Fetal/prevención & control , Retardo del Crecimiento Fetal/etiología , Resistencia a la Insulina , Modelos Animales de Enfermedad , Síndrome Metabólico/prevención & control , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Fructosa/efectos adversos , Factores de Riesgo Cardiometabólico , Peso Corporal/efectos de los fármacos , Presión Sanguínea/efectos de los fármacosRESUMEN
AIM: Maternal caffeine crosses the placenta and mammary barriers, reaching the baby and, because his/her caffeine metabolism is immature, our hypothesis is that even a low caffeine intake (250 mg/day), lower than the dose limit recommended by the World Health Organization, can promote caffeine overexposure in the offspring, leading to short- and long-term changes. MAIN METHODS: Pregnant Wistar rats received intragastric caffeine (CAF) (25 mg/Kg/day) or vehicle during the gestation and lactation periods. We evaluated morphometrical, metabolic, hormonal, and behavioral parameters of male and female offspring at different ages. KEY FINDINGS: Even a low caffeine intake promoted lower maternal body mass and adiposity, higher plasma cholesterol and lower plasma T3, without changes in plasma corticosterone. Female CAF offspring exhibited lower birth weight, body mass gain and food intake throughout life, and hyperinsulinemia at weaning, while male CAF offspring showed reduced food intake and lower plasma T3 at weaning. At puberty and adulthood, male CAF showed higher preference for palatable food, aversion to caffeine intake and higher locomotor activity, while female CAF only showed lower preference for high fat diet (HFD) and lower anxiety-like behavior. At adulthood, both male and female offspring showed higher plasma T3. Male CAF showed hypertestosteronemia, while female CAF showed hypoinsulinemia without effect on glucose tolerance. SIGNIFICANCE: A low caffeine intake during the perinatal period affects rat's offspring development, promoting sex-dependent hormonal and behavior changes. Current data suggest the need to review caffeine recommendations during the perinatal period.
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Conducta Animal , Cafeína , Efectos Tardíos de la Exposición Prenatal , Ratas Wistar , Animales , Femenino , Cafeína/administración & dosificación , Masculino , Embarazo , Ratas , Conducta Animal/efectos de los fármacos , Lactancia , Ingestión de Alimentos/efectos de los fármacos , Factores SexualesRESUMEN
Development of the respiratory system can be affected by the use of drugs during pregnancy, as the prenatal phase is highly sensitive to pharmacological interventions, resulting in long-term consequences. The deleterious effects of external cannabinoids during gestation may be related to negative interference in central nervous system formation, cardiorespiratory system function, and behavioral disorders. Nevertheless, the impact of external cannabinoids on cardiorespiratory network development, chemosensitivity, and its future consequences in adulthood is still unclear. We evaluated the effects of prenatal exposure to a synthetic cannabinoid (WIN 55,212-2, 0.5 mg·kg-1·day-1) on the cardiorespiratory control and panic-like behavior of male and female rats in adulthood. Exogenous cannabinoid exposure during pregnancy resulted in a sex-dependent difference in breathing control. Specifically, males showed increased chemosensitivity to CO2 and O2, whereas females exhibited decreased sensitivity. Altered cardiovascular control was evident, with prenatally treated males and females being more susceptible to hypertension and tachycardia under adverse environmental conditions. Moreover, WIN-treated males exhibited higher fragmentation of sleep episodes, whereas females displayed anxiolytic and panicolytic behavioral responses to CO2. However, no changes were observed in the mechanical component of the respiratory system, and there were no neuroanatomical alterations, such as changes in the expression of CB1 receptors in the brainstem or in the quantification of catecholaminergic and serotonergic neurons. These findings highlight that external interference in cannabinoid signaling during fetal development causes sex-specific, long-lasting effects for the cardiorespiratory system and behavioral responses in adulthood.NEW & NOTEWORTHY The surge in recreational cannabis use and cannabinoid-based medication prescription among pregnant women has been notable in recent years, fueled by the misconception that natural products are inherently safe. Significant gaps persist regarding the potential risks of maternal consumption of cannabinoids and the long-term effects on the cardiorespiratory system of their offspring, which may be determined by sex. Accordingly, this research aims to diminish this lack of information and raise a note of caution.
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Cannabinoides , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Embarazo , Masculino , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/patología , Cannabinoides/farmacología , Cannabinoides/efectos adversos , Ratas , Conducta Animal/efectos de los fármacos , Benzoxazinas/farmacología , Benzoxazinas/efectos adversos , Ratas Wistar , Naftalenos/farmacología , Naftalenos/toxicidad , Naftalenos/efectos adversos , Respiración/efectos de los fármacos , Morfolinas/farmacologíaRESUMEN
Pyriproxyfen (PPF) is an insecticide used in agriculture, which is approved for use in drinking water tanks for human consumption. However, some studies indicate that it may act as an endocrine disruptor and affect nontarget organisms. This study aimed to evaluate the effects of PPF on reproduction and general health status in female mice exposed from pre-puberty to adulthood. In the first experiment, females were treated by gavage from postnatal day (PND) 23 to (PND) 75 and were distributed into three experimental groups: control (vehicle), PPF 0.1 mg/kg, and PPF 1 mg/kg. Female mice were assessed for the age of puberty onset, body mass, water and food consumption, and the estrous cycle. On PDN 75, a subgroup was euthanized, when vital and reproductive organs were collected and weighed. The thyroid, ovary, and uterus were evaluated for histomorphometry. The other subgroup was assessed in relation to reproductive performance and fetal parameters. In a second experiment, the uterotrophic assay was performed with juvenile females (PND 18) using doses of 0.01, 0.1, or 1 mg/kg of PPF. PPF treatment reduced thyroid mass and increased liver mass. Furthermore, there was an increase in ovarian interstitial tissue and, in the uterus, a decrease in the thickness of the endometrial stroma with reduced content of collagen fibers. There was also a reduction of 30% in pregnancy rate in the treated groups and an increase in the frequency of fetal death. This study suggests that, based on this experimental model, the insecticide may pose a reproductive risk for females chronically exposed to the substance from the pre-pubertal period until adulthood. These results raise concerns about prolonged exposure of women to the same compound.
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Insecticidas , Piridinas , Reproducción , Maduración Sexual , Femenino , Animales , Ratones , Piridinas/toxicidad , Embarazo , Maduración Sexual/efectos de los fármacos , Insecticidas/toxicidad , Reproducción/efectos de los fármacos , Muerte Fetal , Ovario/efectos de los fármacos , Ovario/crecimiento & desarrollo , Útero/efectos de los fármacos , Útero/crecimiento & desarrollo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Disruptores Endocrinos/toxicidad , Glándula Tiroides/efectos de los fármacosRESUMEN
Prenatal SARS-CoV-2 infection may be a risk factor for neurological impairment. This study describes the neuromotor behavior of infants prenatally exposed to SARS-CoV-2 using gold standard tools for early detection of neurological impairment. Sixteen infants were included in this exploratory longitudinal study. Infants were assessed at 3 months using the Prechtl General Movement Assessment, and at 6 months using the Hammersmith Infant Neurological Examination. Infants might have presented neuromotor limitations at 3 months; however, they progressed to a low-risk outcome of neurological impairment at 6 months.
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COVID-19 , Complicaciones Infecciosas del Embarazo , Efectos Tardíos de la Exposición Prenatal , Humanos , Femenino , Embarazo , Lactante , Estudios Longitudinales , Masculino , Examen Neurológico/métodos , SARS-CoV-2 , Desarrollo Infantil/fisiologíaRESUMEN
The aim of this study was to examine the impact of maternal obesity on the reproductive capacity of the female offspring (F1) and on the early development of the second generation (F2). To this end, rats were fed either standard (SD) or cafeteria (CD) diet. CD rats and their offspring were divided into 2 groups: rats with 18% and ≥25% overweight (CD18 and CD25, respectively) and offspring from CD18 and CD25 rats (OCD18 and OCD25, respectively). Both OCD groups achieved greater weight gain than controls, without changes in the serum levels of glucose, cholesterol or triglycerides. However, they showed increased gonadal cholesterol concentration and fat content compared to controls. Female OCD groups showed a slight prolongation of the estrous cycle and different pattern of changes in the weight gain during pregnancy. The OCD25 group displayed an increased fertility index and preimplantation losses, and changes in some fetal measurements. Some OCD25 dams gave birth to a larger litter of pups and displayed a lower viability index and lactation rate than controls. OCD25 dams also showed an increase in estradiol and a decrease in testosterone and anti-Müllerian hormone. OCD25 rats showed increased mRNA levels of steroidogenenic enzymes. The offspring from OCD25 females (F2OCD25 offspring) showed early vaginal opening and higher ovulation rate in females, and lower ano-genital distances in males, compared to controls. In conclusion, these results reflect that maternal obesity impacts on the reproductive health of successive generations, probably as a result of epigenetic changes in different systems, including germ cells.
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Obesidad Materna , Efectos Tardíos de la Exposición Prenatal , Reproducción , Animales , Femenino , Embarazo , Obesidad Materna/metabolismo , Ratas , Masculino , Dieta Alta en Grasa/efectos adversos , Testosterona/sangre , Ciclo Estral , Dieta/efectos adversos , Estradiol/sangre , Obesidad/metabolismo , Obesidad/etiologíaRESUMEN
The state of Maternal Protein Malnutrition (MPM) is associated with several deleterious effects, including inflammatory processes and dysregulation in oxidative balance, which can promote neurodegeneration. On the other hand, it is known that aerobic exercise can promote systemic health benefits, combating numerous chronic diseases. Therefore, we evaluate the effect of aerobic exercise training (AET) on indicators of mitochondrial bioenergetics, oxidative balance, endoplasmic reticulum stress, and neurotrophic factor in the prefrontal cortex of malnourished juvenile Wistar rats. Pregnant Wistar rats were fed with a diet containing 17% or 8% casein during pregnancy and lactation. At 30 days of life, male offspring were divided into 4 groups: Low-Protein Control (LS), Low-Protein Trained (LT), Normoprotein Control (NS), and Normoprotein Trained (NT). The trained groups performed an AET for 4 weeks, 5 days a week, 1 h a day per session. At 60 days of life, the animals were sacrificed and the skeletal muscle, and prefrontal cortex (PFC) were removed to evaluate the oxidative metabolism markers and gene expression of ATF-6, GRP78, PERK and BDNF. Our results showed that MPM impairs oxidative metabolism associated with higher oxidative and reticulum stress. However, AET restored the levels of indicators of mitochondrial bioenergetics, in addition to promoting resilience to cellular stress. AET at moderate intensity for 4 weeks in young Wistar rats can act as a non-pharmacological intervention in fighting against the deleterious effects of a protein-restricted maternal diet.
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Factor Neurotrófico Derivado del Encéfalo , Mitocondrias , Estrés Oxidativo , Condicionamiento Físico Animal , Ratas Wistar , Animales , Femenino , Ratas , Mitocondrias/metabolismo , Embarazo , Masculino , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Estrés del Retículo Endoplásmico , Biomarcadores/metabolismo , Corteza Prefrontal/metabolismo , Músculo Esquelético/metabolismo , Desnutrición/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Factor de Transcripción Activador 6/metabolismoRESUMEN
This study investigated the impact of maternal protein restriction (MPR) and early postnatal sugar consumption (SUG) on the liver health of adult male descendant rats. Male offspring of mothers fed a normal protein diet (NPD) or a low protein diet (LPD) were divided into four groups: Control (CTR), Sugar Control (CTR + SUG), LPD during gestation and lactation (GLLP), and LPD with sugar (GLLP + SUG). Sugar consumption (10% glucose diluted in water) began after weaning on day 21 (PND 21), and at 90 days (PND 90), rats were sacrificed for analysis. Sugar intake reduced food intake and increased water consumption in CTR + SUG and GLLP + SUG compared to CTR and GLLP. GLLP and GLLP + SUG groups showed lower body weight and total and retroperitoneal fat compared to CTR and CTR + SUG. CTR + SUG and GLLP + SUG groups exhibited hepatocyte vacuolization associated with increased hepatic glycogen content compared to CTR and GLLP. Hepatic catalase activity increased in GLLP compared to CTR. Proteomic analysis identified 223 differentially expressed proteins (DEPs) among experimental groups. While in the GLLP group, the DEPs enriched molecular pathways related to cellular stress, glycogen metabolic pathways were enriched in the GLLP + SUG and CTR + SUG groups. The association of sugar consumption amplifies the effects of MPR, deregulating molecular mechanisms related to metabolism and the antioxidant system.
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Dieta con Restricción de Proteínas , Hígado , Proteómica , Animales , Hígado/metabolismo , Hígado/efectos de los fármacos , Masculino , Femenino , Dieta con Restricción de Proteínas/efectos adversos , Embarazo , Proteómica/métodos , Ratas , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/patología , Redes y Vías Metabólicas/efectos de los fármacos , Proteoma/metabolismo , Fenómenos Fisiologicos Nutricionales Maternos , Ratas Wistar , Animales Recién Nacidos , Lactancia , Peso Corporal/efectos de los fármacosRESUMEN
BACKGROUND: Prenatal alcohol exposure (PAE) has serious physical consequences for children such as behavioral disabilities, growth disorders, neuromuscular problems, impaired motor coordination, and decreased muscle tone. However, it is not known whether loss of muscle strength occurs, and which interventions will effectively mitigate physical PAE impairments. We aimed to investigate whether physical alteration persists during adolescence and whether exercise is an effective intervention. RESULTS: Using paradigms to evaluate different physical qualities, we described that early adolescent PAE animals have significant alterations in agility and strength, without alterations in balance and coordination compared to CTRL animals. We evaluated the effectiveness of 3 different exercise protocols for 4 weeks: Enrichment environment (EE), Endurance exercise (EEX), and Resistance exercise (REX). The enriched environment significantly improved the strength in the PAE group but not in the CTRL group whose strength parameters were maintained even during exercise. Resistance exercise showed the greatest benefits in gaining strength, and endurance exercise did not. CONCLUSION: PAE induced a significant decrease in strength compared to CTRL in PND21. Resistance exercise is the most effective to reverse the effects of PAE on muscular strength. Our data suggests that individualized, scheduled, and supervised training of resistance is more beneficial than endurance or enriched environment exercise for adolescents FASD.