RESUMEN

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.

Asunto(s)

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/genética

RESUMEN

Early-life adversities, whether prenatal or postnatal exposure, have been linked to adverse mental health outcomes later in life increasing the risk of several psychiatric disorders. Research on its neurobiological consequences demonstrated an association between exposure to adversities and persistent alterations in the structure, function, and connectivity of the brain. Consistent evidence supports the idea that regulation of gene expression through epigenetic mechanisms are involved in embedding the impact of early-life experiences in the genome and mediate between social environments and later behavioral phenotypes. In addition, studies from rodent models and humans suggest that these experiences and the acquired risk factors can be transmitted through epigenetic mechanisms to offspring and the following generations potentially contributing to a cycle of disease or disease risk. However, one of the important aspects of epigenetic mechanisms, unlike genetic sequences that are fixed and unchangeable, is that although the epigenetic markings are long-lasting, they are nevertheless potentially reversible. In this review, we summarize our current understanding of the epigenetic mechanisms involved in the mental health consequences derived from early-life exposure to malnutrition, maltreatment and poverty, adversities with huge and pervasive impact on mental health. We also discuss the evidence about transgenerational epigenetic inheritance in mammals and experimental data suggesting that suitable social and pharmacological interventions could reverse adverse epigenetic modifications induced by early-life negative social experiences. In this regard, these studies must be accompanied by efforts to determine the causes that promote these adversities and that result in health inequity in the population.

Asunto(s)

Epigénesis Genética , Trastornos Mentales , Humanos , Animales , Trastornos Mentales/genética , Trastornos Mentales/etiología , Salud Mental , Efectos Tardíos de la Exposición Prenatal/genética , Embarazo , Femenino , Experiencias Adversas de la Infancia , Metilación de ADN

RESUMEN

A previous study using miRNA sequencing revealed that exposure to a mixture of phthalates during pregnancy and lactation dysregulated rno-miR-184 and rno-miR-141-3p in the ventral prostate (VP) of offspring. Here, rno-miR-184 and rno-miR-141-3 expressions were obtained by RT-qPCR in the VP of F1 males as well as in F2 offspring, aiming to establish a relationship with possible oncogenic targets through in silico analyses with multigenerational approach. Additionally, some targets were measured by western blots to highlight a possible relationship between the deregulated miRNAs and some of their targets. VP samples from rats exposed to a mixture of phthalates maternally during pregnancy and lactation (GD10 to PND21-F1) and VP from offspring (F2) were examined. The phthalate mixture at both concentrations (20 µg and 200 mg/kg/day) increased the expression of both miRNAs in the F1 (PND22 and 120) and F2 (descendants of F1-treated males) prostate. Target prediction analysis revealed that both microRNAs are responsible for modulating the expression and synthesis of 40 common targets. A phthalate target association analysis and the HPA database showed an interesting relationship among these possible miRNAs modulated targets with prostate adenocarcinoma and other oncogenic processes. Western blots showed alteration in P63, P53, WNT5, and STAT3 expression, which are targeted by the miRNAs, in the VP of F1/F2 males. The data draw attention to the epigenetic modulation in the prostate of descendants exposed to phthalates and adds to one of the few currently found in the literature to point to microRNAs signature as biomarkers of exposure to plasticizers.

Asunto(s)

MicroARNs , Ácidos Ftálicos , Efectos Tardíos de la Exposición Prenatal , Neoplasias de la Próstata , MicroARNs/genética , MicroARNs/metabolismo , Masculino , Animales , Neoplasias de la Próstata/inducido químicamente , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Femenino , Ácidos Ftálicos/toxicidad , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/genética , Exposición Materna/efectos adversos , Próstata/efectos de los fármacos , Próstata/patología , Ratas Wistar , Ratas , Simulación por Computador

RESUMEN

Exposure to heat stress (HS) in utero was postulated to trigger an adaptive molecular response that can be transmitted to the next generation. Hence, this study assessed the impact of HS exposure at different stages of the gestational period of mice on the female F1 population and their offspring. Heat stress exposure (41°C and 65% relative humidity-RH) occurred during the first half (FP), the second half (SP), or the entire pregnancy (TP). A control group (C) was maintained in normothermic conditions (25°C, 45% RH) throughout the experiment. Heat stress had a significant negative effect on intrauterine development, mainly when HS exposure occurred in the first half of pregnancy (FP and TP groups). Postnatal growth of FP and TP mice was hindered until 4 weeks of age. The total number of follicles per ovary did not vary (P > 0.05) between the control and HS-exposed groups. Mean numbers of primordial follicles were lower (P < 0.05) in the sexually mature FP than those in SP and TP F1 females. However, the mean number of viable embryos after superovulation was lower (P < 0.05) in TP compared with C group. The expression of genes associated with physiological and cellular response to HS, autophagy, and apoptosis was significantly affected in the ovarian tissue of F1 females and F2 in vivo-derived blastocysts in all HS-exposed groups. In conclusion, exposure to HS during pregnancy compromised somatic development and reproductive parameters as well as altered gene expression profile that was then transmitted to the next generation of mice.

Asunto(s)

Ovario , Efectos Tardíos de la Exposición Prenatal , Embarazo , Humanos , Animales , Femenino , Ratones , Efectos Tardíos de la Exposición Prenatal/genética , Folículo Ovárico/fisiología , Respuesta al Choque Térmico/genética , Expresión Génica

RESUMEN

AIMS: The developmental Origins of Health and Disease (DOHaD) concept has provided the framework to assess how early life experiences can shape health and disease throughout the life course. Using a model of maternal exposure to a low protein diet (LPD; 6% protein) during the gestational and lactational periods, we demonstrated changes in the ventral prostate (VP) transcriptomic landscape in young rats exposed to maternal malnutrition. Male offspring Sprague Dawley rats were submitted to maternal malnutrition during gestation and lactation, and they were weighed, and distance anogenital was measured, followed were euthanized by an overdose of anesthesia at 21 postnatal days. Next, the blood and the ventral prostate (VP) were collected and processed by morphological analysis, biochemical and molecular analyses. RNA-seq analysis identified 411 differentially expressed genes (DEGs) in the VP of maternally malnourished offspring compared to the control group. The molecular pathways enriched by these DEGs are related to cellular development, differentiation, and tissue morphogenesis, all of them involved in both normal prostate development and carcinogenesis. Abcg1 was commonly deregulated in young and old maternally malnourished offspring rats, as well in rodent models of prostate cancer (PCa) and in PCa patients. Our results described ABCG1 as a potential DOHaD gene associated with perturbation of prostate developmental biology with long-lasting effects on carcinogenesis in old offspring rats. A better understanding of these mechanisms may help with the discussion of preventive strategies against early life origins of non-communicable chronic diseases.

Asunto(s)

Desnutrición , Efectos Tardíos de la Exposición Prenatal , Animales , Femenino , Humanos , Masculino , Ratas , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1/metabolismo , Carcinogénesis/genética , Carcinogénesis/metabolismo , Lactancia , Desnutrición/complicaciones , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Próstata/metabolismo , Ratas Sprague-Dawley

RESUMEN

Several epidemiological, clinical and experimental studies in recent decades have shown the relationship between exposure to stressors during development and health outcomes later in life. The characterization of these susceptible phases, such as preconception, gestation, lactation and adolescence, and the understanding of factors that influence the risk of an adult individual for developing obesity, metabolic and cardiovascular diseases, is the focus of the DOHaD (Developmental Origins of Health and Disease) research line. In this sense, advancements in molecular biology techniques have contributed significantly to the understanding of the mechanisms underlying the observed phenotypes, their morphological and physiological alterations, having as a main driving factor the epigenetic modifications and their consequent modulation of gene expression. The present narrative review aimed to characterize the different susceptible phases of development and associated epigenetic modifications, and their implication in the development of non-communicable diseases. Additionally, we provide useful insights into interventions during development to counteract or prevent long-term programming for disease susceptibility.

Asunto(s)

Enfermedades no Transmisibles , Efectos Tardíos de la Exposición Prenatal , Femenino , Adulto , Humanos , Enfermedades no Transmisibles/epidemiología , Enfermedades no Transmisibles/prevención & control , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/prevención & control , Obesidad/genética , Susceptibilidad a Enfermedades , Útero , Epigénesis Genética

RESUMEN

Preclinical genetic studies have related stress early exposures with changes in gene regulatory mechanisms, including epigenetic alterations, such as modifications of DNA methylation, histone deacetylation, and histones acetylation. This study evaluates the effects of prenatal stress on the behavior, hypothalamus-pituitary-adrenal (HPA)-axis, and epigenetic parameters in stressed dams and their offspring. The rats were subjected to a protocol of chronic unpredictable mild stress on the fourteenth day of pregnancy until the birth of offspring. After birth, maternal care was evaluated for six days. Following weaning, the locomotor and depressive-like behaviors of the dams and their offspring (60 days old) were assessed. The HPA axis parameters were evaluated in serum from dams and offspring, and epigenetic parameters (histone acetyltransferase (HAT), histone deacetylase (HDAC), DNA methyltransferase (DNMT) activities, and the levels of histone H3 acetylated at lysine residue 9 (H3K9ac) and histone 3 acetylated at lysine residue 14 (H3K14ac)) were assessed in dams' and offspring' brains. Prenatal stress did not significantly influence maternal care; however, it induced manic behavior in female offspring. These behavioral alterations in the offspring were accompanied by hyperactivity of the HPA-axis, epigenetic adaptations in the activity of HDAC and DNMT, and acetylation in the histones H3K9 and H3K14. In addition, the prenatal stressed female offspring showed increased levels of ACTH compared to their male counterpart. Our findings reinforce the impact of prenatal stress on behavior, stress response, and epigenetic profile of offspring.

Asunto(s)

Sistema Hipotálamo-Hipofisario , Efectos Tardíos de la Exposición Prenatal , Humanos , Embarazo , Ratas , Animales , Masculino , Femenino , Sistema Hipotálamo-Hipofisario/metabolismo , Histonas/metabolismo , Lisina , Efectos Tardíos de la Exposición Prenatal/genética , Sistema Hipófiso-Suprarrenal/metabolismo , Epigénesis Genética , Estrés Psicológico/genética

RESUMEN

In recent years, the background level of environmental pollutants, including metals, has increased. Pollutant exposure during the earliest stages of life may determine chronic disease susceptibility in adulthood because of genetic or epigenetic changes. The objective of this review was to identify the association between prenatal and early postnatal exposure to potentially toxic metals (PTMs) and their adverse effects on the genetic material of offspring. A systematic review was carried out following the Cochrane methodology in four databases: PubMed, Scopus, Web of Science, and the Cochrane Library. Eligible papers were those conducted in humans and published in English between 2010/01/01 and 2021/04/30. A total of 57 articles were included, most of which evaluated prenatal exposure. Most commonly evaluated PTMs were As, Cd, and Pb. Main adverse effects on the genetic material of newborns associated with PTM prenatal exposure were alterations in telomere length, gene or protein expression, mitochondrial DNA content, metabolomics, DNA damage, and epigenetic modifications. Many of these effects were sex-specific, being predominant in boys. One article reported a synergistic interaction between As and Hg, and two articles observed antagonistic interactions between PTMs and essential metals, such as Cu, Se, and Zn. The findings in this review highlight that the problem of PTM exposure persists, affecting the most susceptible populations, such as newborns. Some of these associations were observed at low concentrations of PTMs. Most of the studies have focused on single exposures; however, three interactions between essential and nonessential metals were observed, highlighting that metal mixtures need more attention.

Asunto(s)

Contaminantes Ambientales , Mercurio , Metales Pesados , Efectos Tardíos de la Exposición Prenatal , Masculino , Embarazo , Femenino , Recién Nacido , Humanos , Efectos Tardíos de la Exposición Prenatal/genética , Metales/toxicidad , Intoxicación por Metales Pesados , Contaminantes Ambientales/toxicidad , Metales Pesados/toxicidad , Metales Pesados/metabolismo

RESUMEN

The present study aimed to evaluate the effects of treadmill maternal exercise on alterations induced by prenatal stress in neonatal mice. Female and male Balb/c mice were divided into five groups: control (CON), prenatal restraint stress (PNS), prenatal restraint stress and physical exercise before pregnancy (PNS + EX1), prenatal restraint stress and physical exercise during pregnancy (PNS + EX2), and prenatal restraint stress and physical exercise before and during pregnancy (PNS + EX3). Exercise was performed using a treadmill, at a speed of 10 m/min, for 60 min, 5 days a week. Maternal behavior was assessed on days 3, 4 and 5 postpartum (PPD). Placental gene expression of glucocorticoid receptor (GR), 11-ß-hydroxysteroid dehydrogenase 2 (11ß-HSD2), 5-hydroxytryptamine receptor 1A (5HT1AR), and corticotropin releasing hormone receptor 1 (CRHR1) were analyzed. In neonatal mice, the gene expression of GR, mineralocorticoid receptor (MR), CRHR1, 5HTr1, oxytocin Receptor 1 (OXTr1), tropomyosin related kinase B (TRκB), brain-derived neurotrophic factor exon I (BDNF I), and BDNF IV was analyzed in the brain (PND0) and hippocampus (PND10). Maternal exercise improved (p < 0.05) maternal care. In the placenta, maternal exercise prevented (p < 0.01) the increase in GR expression caused by PNS. In the brain from PND0, exercise before pregnancy prevented (p = 0.002) the decreased CRHR1 expression promoted by PNS. In the hippocampus of PND10 males, PNS decreased (p = 0.0005) GR expression, and exercise before pregnancy prevented (p = 0.003) this effect. In PND10 females, maternal exercise prevented (p < 0.05) the PNS-induced increase in MR expression. PNS + EX2 males showed increased (p < 0.01) BDNF I gene expression and PNS + EX1 females demonstrated increased (p = 0.03) BDNF IV expression. In conclusion, maternal physical exercise may play a role in modulating maternal-fetal health and may contribute to preventing neurodevelopmental changes induced by prenatal stress.

Asunto(s)

Placenta , Efectos Tardíos de la Exposición Prenatal , Animales , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Femenino , Hipocampo/metabolismo , Humanos , Masculino , Ratones , Placenta/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico/metabolismo

RESUMEN

Aflatoxins are mycotoxins produced as secondary fungal metabolites. Among them, aflatoxin B1 (AFB1) stands out due to its genotoxic and mutagenic potential, being a potent initiator of carcinogenesis. In this review, the outcomes from the published literature in the past 10 years on the effects of AFB1 pathophysiological mechanisms on embryological and fetal development are discussed. In several animal species, including humans, AFB1 has a teratogenic effect, resulting in bone malformations, visceral anomalies, lesions in several organs, and behavioral and reproductive changes, in addition to low birth weight. The mutagenic capacity of AFB1 in prenatal life is greater than in adults, indicating that when exposure occurs in the womb, the risk of the development of neoplasms is higher. Studies conducted in humans indicate that the exposure to this mycotoxin during pregnancy is associated with low birth weight, decreased head circumference, and DNA hypermethylation. However, as the actual impacts on humans are still unclear, the importance of this issue cannot be overemphasized and studies on the matter are essential.

Asunto(s)

Aflatoxina B1/toxicidad , Mutágenos/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Metilación de ADN/efectos de los fármacos , Femenino , Humanos , Neoplasias/inducido químicamente , Neoplasias/genética , Neoplasias/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/patología

RESUMEN

BACKGROUND: Methylmercury (MeHg) remains a public health issue since developing organisms are particularly vulnerable to this environmental contaminant. This study investigated the effect of maternal MeHg exposure on the modulation of proteomic profile of parotid (PA), submandibular (SM), and sublingual (SL) glands of offspring rats. MATERIALS AND METHODS: Pregnant Wistar rats were daily exposed to 40 µg/kg MeHg during both gestational and lactation periods. The proteomic profiles of the major salivary glands of the offspring rats were analyzed through mass spectrometry. RESULTS: The offspring rats exposed to MeHg showed significant alterations in the proteomic profiles of the PA, SM, and SL glands. Altered proteins were associated with cytoskeleton components, tissue morphogenesis, and response to stimulus and stress. CONCLUSION: This original study showed that maternal MeHg exposure significantly modulates the expression of proteins and induces alterations in the proteomic profiles of developing salivary glands.

Asunto(s)

Compuestos de Metilmercurio/toxicidad , Efectos Tardíos de la Exposición Prenatal/genética , Proteoma/efectos de los fármacos , Glándulas Salivales/efectos de los fármacos , Animales , Femenino , Humanos , Lactancia/efectos de los fármacos , Masculino , Espectrometría de Masas , Exposición Materna/efectos adversos , Exposición Materna/prevención & control , Morfogénesis/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/patología , Proteoma/genética , Ratas , Glándulas Salivales/metabolismo

RESUMEN

Maternal overnutrition negatively impacts the offspring's health leading to an increased risk of developing chronic diseases or metabolic syndrome in adulthood. What we eat affects the endocannabinoid system (eCS) activity, which in turn modulates lipogenesis and fatty acids utilization in hepatic, muscle, and adipose tissues. This study aimed to evaluate the transgenerational effect of maternal obesity on cannabinoid receptor 1 knock-out (CB1 KO) animals in combination with a postnatal obesogenic diet on the development of metabolic disturbances on their offspring. CB1 KO mice were fed a control diet (CD) or a high-fat diet (HFD; 33% more energy from fat) for 3 months. Offspring born to control and obese mothers were also fed with CD or HFD. We observed that pups born to an HFD-fed mother presented higher postnatal weight, lower hepatic fatty acid amide hydrolase activity, and increased blood cholesterol levels when compared to the offspring born to CD-fed mothers. When female mice born to HFD-fed CB1 KO mothers were exposed to an HFD, they gained more weight, presented elevated blood cholesterol levels, and more abdominal adipose tissue accumulation than control-fed adult offspring. The eCS is involved in several reproductive physiological processes. Interestingly, we showed that CB1 KO mice in gestational day 15 presented resistance to LPS-induced deleterious effects on pregnancy outcome, which was overcome when these mice were obese. Our results suggest that an HFD in CB1 receptor-deficient mice contributes to a "nutritional programming" of the offspring resulting in increased susceptibility to metabolic challenges both perinatally and during adulthood.

Asunto(s)

Lipopolisacáridos/efectos adversos , Obesidad Materna/genética , Receptor Cannabinoide CB1/genética , Animales , Animales Recién Nacidos , Dieta Alta en Grasa/efectos adversos , Femenino , Fenómenos Fisiologicos Nutricionales Maternos , Enfermedades Metabólicas/etiología , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/metabolismo , Ratones , Ratones Noqueados , Obesidad , Obesidad Materna/metabolismo , Embarazo , Resultado del Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Receptor Cannabinoide CB1/metabolismo

RESUMEN

Using a rabbit model, we investigated whether maternal intake of a high-fat and high-carbohydrate diet (HFCD) before and during pregnancy induces an increase in micronuclei frequency and oxidative stress in offspring during adulthood. Female rabbits received a standard diet (SD) or HFCD for two months before mating and during gestation. The offspring from both groups were nursed by foster mothers fed SD until postnatal day 35. After weaning, all the animals received SD until postnatal day 440. At postnatal day 370, the frequency of micronuclei in peripheral blood reticulocytes (MN-RETs) increased in the male offspring from HFCD-fed mothers compared with the male offspring from SD-fed mothers. Additionally, fasting serum glucose increased in the offspring from HFCD-fed mothers compared with the offspring from SD-fed mothers. At postnatal day 440, the offspring rabbits were challenged with HFCD or continued with SD for 30 days. There was an increase in MN-RET frequency in the male rabbits from HFCD-fed mothers, independent of the type of challenging diet consumed during adulthood. The challenge induced changes in serum cholesterol, LDL and HDL that were influenced by the maternal diet and offspring sex. We measured malondialdehyde in the liver of rabbits as an oxidative stress marker after diet challenge. Oxidative stress in the liver only increased in the female offspring from HFCD-fed mothers who were also challenged with this same diet. The data indicate that maternal overnutrition before and during pregnancy is able to promote different effects depending on the sex of the animals, with chromosomal instability in male offspring and oxidative stress and hypercholesterolemia in female offspring. Our data might be important in the understanding of chronic diseases that develop in adulthood due to in utero exposure to maternal diet.

Asunto(s)

Daño del ADN , Hipernutrición/genética , Efectos Tardíos de la Exposición Prenatal/genética , Animales , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Femenino , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Hipernutrición/complicaciones , Hipernutrición/patología , Estrés Oxidativo/fisiología , Embarazo , Complicaciones del Embarazo/genética , Complicaciones del Embarazo/patología , Efectos Tardíos de la Exposición Prenatal/patología , Conejos , Caracteres Sexuales

RESUMEN

To explore in mice if a 15% food restriction protocol during pregnancy programs the offspring postnatal development, with emphasis on reproductive function, and to assess if ghrelin (Ghrl) administration to mouse dams exerts effects that mimic those obtained under mild caloric restriction. Mice were 15% food-restricted, injected with 4 nmol/animal/day of Ghrl, or injected with the vehicle (control) thorough pregnancy. After birth, the pups did not receive further treatment. Pups born from food-restricted dams (FR pups) were lighter than Ghrl pups at birth, but reached normal weight at adulthood. Ghrl pups were heavier at birth and gained more weight than control pups (C pups). This effect was not associated with plasma IGF-1. FR pups showed a delay in pinna detachment and eye opening, while an advance was observed in Ghrl pups. FR pups showed also impairment in the surface-righting reflex. In both female FR and Ghrl pups, there was an advance in vaginal opening and, in adulthood, FR pups showed a significant decrease in their own litter size and plasma progesterone, and an increase in embryo loss. A delay in testicular descent was evident in male Ghrl pups. Changes in puberty onset were not associated with differences in the expression of Kiss1 in hypothalamic nuclei. Finally, in adulthood, FR pups showed a significant decrease in sperm quality. In conclusion, a mild food restriction thorough gestation exerted programming effects on the offspring, affecting also their reproductive function in adulthood. These effects were not similar to those of intragestational Ghrl administration.

Asunto(s)

Restricción Calórica/métodos , Desarrollo Fetal/fisiología , Ghrelina/administración & dosificación , Efectos Tardíos de la Exposición Prenatal/genética , Desarrollo Sexual/fisiología , Animales , Animales Recién Nacidos , Vías de Administración de Medicamentos , Femenino , Desarrollo Fetal/efectos de los fármacos , Masculino , Ratones , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Desarrollo Sexual/efectos de los fármacos

RESUMEN

BACKGROUND: Arterial hypertension in children is considered a common alteration nowadays, mainly because obesity is a growing worldwide problem closely related to increased blood pressure. Childhood hypertension can be classified as primary or secondary, depending on the etiology. Primary or essential hypertension still has its pathophysiology not fully elucidated, and there is no consensus in the literature on most underlying mechanisms. In this review, genetic and environmental factors, including sodium and potassium intake, socioeconomic status, ethnicity, family structure, obesity, sedentary lifestyle, prematurity and low birth weight, prenatal and postnatal exposures are highlighted. OBJECTIVE: The present study aimed to perform an update on primary hypertension in childhood, providing clinicians and researchers an overview of the current state of the literature regarding the influence of genetic and environmental factors. METHODS: This integrative review searched for articles on genetic and environmental factors related to primary hypertension in pediatric patients. The databases evaluated were PubMed and Scopus. RESULTS: The studies have provided insights regarding many genetic and environmental factors, in addition to their association with the pathophysiology of primary hypertension in childhood. Findings corroborated the idea that primary hypertension is a multifactorial disease. Further studies in the pediatric population are needed to elucidate the underlying mechanisms. CONCLUSION: The study of primary hypertension in pediatrics has utmost importance for the adoption of preventive measures and the development of more efficient treatments, therefore reducing childhood morbidity and the incidence of cardiovascular diseases and other health consequences later in life.

Asunto(s)

Hipertensión Esencial/etiología , Adolescente , Niño , Exposición a Riesgos Ambientales/efectos adversos , Hipertensión Esencial/diagnóstico , Hipertensión Esencial/fisiopatología , Familia , Femenino , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Humanos , Obesidad Infantil/complicaciones , Obesidad Infantil/fisiopatología , Embarazo , Efectos Tardíos de la Exposición Prenatal/diagnóstico , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Factores de Riesgo , Conducta Sedentaria , Determinantes Sociales de la Salud , Factores Socioeconómicos

RESUMEN

In rats, maternal nicotine exposure during lactation induces obesity, thyroid dysfunction, brown adipose tissue (BAT) hypofunction and liver alterations in adult offspring. Both thyroid function and lipid metabolism are influenced by gene silencing mediated by microRNAs (miRNAs). Here we investigated long-term effects of early nicotine exposure on molecular and epigenetic mechanisms closely related to thyroid and lipid metabolism, through the expression of mRNAs and miRNAs in BAT and liver of adult male and female offspring. At postnatal day 2 (PND2), lactating control (CON) or nicotine (NIC) dams were subcutaneously implanted with osmotic minipumps containing, respectively, saline or 6 mg/kg nicotine. Litters were adjusted to 3 males and 3 females. Offspring's euthanasia occurred at PND180. In the BAT, NIC females showed higher Dio2 mRNA expression, while miR-382* expression was not altered in both sexes. In the liver, NIC offspring of both sexes showed lower Dio1 mRNA expression and higher miR-224 expression, while only NIC females had higher miR-383 and miR-21 expressions. NIC offspring of both sexes showed higher mRNA expression of SCD1 in the liver; NIC males had decreased CPT1 expression, whereas NIC females had increased FASN, miR-370 and miR-122 expressions. Regardless of sex, alterations in liver Dio1, miR-224 and SCD1 expressions are involved in the disturbances caused by maternal nicotine exposure during breastfeeding. Interestingly, females had more altered miRs in the liver. Early nicotine exposure induces a sex dimorphism, particularly regarding hepatic lipid metabolism, through miRs expression.

Asunto(s)

Tejido Adiposo Pardo/metabolismo , Envejecimiento/genética , Metabolismo de los Lípidos/genética , Hígado/metabolismo , MicroARNs/genética , Nicotina/administración & dosificación , Efectos Tardíos de la Exposición Prenatal/genética , Glándula Tiroides/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Femenino , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , MicroARNs/metabolismo , Nicotina/farmacología , Embarazo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Wistar , Glándula Tiroides/efectos de los fármacos

RESUMEN

Hyperoxia-hypoxia exposure is a proposed cause of alveolar developmental arrest in bronchopulmonary dysplasia in preterm infants, where mitochondrial reactive oxygen species and oxidative stress vulnerability are increased. The aryl hydrocarbon receptor (AhR) is one of the main activators of the antioxidant enzyme system that protects tissues and systems from damage. The present study aimed to determine if the activation of the AhR signaling pathway by prenatal administration of indole-3-carbinol (I3C) protects rat pups from hyperoxia-hypoxia-induced lung injury. To assess the activation of protein-encoding genes related to the AhR signaling pathway (Cyp1a1, Cyp1b1, Ugt1a6, Nqo1, and Gsta1), pup lungs were excised at 0, 24, and 72 h after birth, and mRNA expression levels were quantified by reverse transcription-quantitative polymerase chain reaction assays (RT-qPCR). An adapted Ratner's method was used in rats to evaluate radial alveolar counts (RACs) and the degree of fibrosis. The results reveal that the relative expression of AhR-related genes in rat pups of prenatally I3C-treated dams was significantly different from that of untreated dams. The RAC was significantly lower in the hyperoxia-hypoxia group (4.0 ± 1.0) than that in the unexposed control group (8.0 ± 2.0; P < 0.01). When rat pups of prenatally I3C-treated dams were exposed to hyperoxia-hypoxia, an RAC recovery was observed, and the fibrosis index was similar to that of the unexposed control group. A cytokine antibody array revealed an increase in the NF-κB signaling cascade in I3C-treated pups, suggesting that the pathway could regulate the inflammatory process under the stimulus of this compound. In conclusion, the present study demonstrates that I3C prenatal treatment activates AhR-responsive genes in pup's lungs and hence attenuates lung damage caused by hyperoxia-hypoxia exposure in newborns.

Asunto(s)

Displasia Broncopulmonar/tratamiento farmacológico , Displasia Broncopulmonar/genética , Indoles/administración & dosificación , Lesión Pulmonar/tratamiento farmacológico , Lesión Pulmonar/genética , Efectos Tardíos de la Exposición Prenatal/genética , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Animales Recién Nacidos , Displasia Broncopulmonar/complicaciones , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Fibrosis , Hiperoxia/complicaciones , Hiperoxia/genética , Hipoxia/complicaciones , Hipoxia/genética , Indoles/uso terapéutico , Mediadores de Inflamación/metabolismo , Pulmón/patología , Lesión Pulmonar/complicaciones , Embarazo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Aumento de Peso

RESUMEN

Glyphosate-based formulations are the most popular herbicide used around the world. These herbicides are widely applied in agriculture to control weeds on genetically modified crops. Although there is much evidence showing that glyphosate-based herbicides induce toxic effect on reproductive and hepatic systems, and also cause oxidative damage on cells, studies from recent years revealed that the nervous system may represent a key target for their toxicity. In the present work, we evaluated the effect of glyphosate (without adjuvants) in neonate rats after gestational exposure. Particularly, we examined whether glyphosate during gestation affected the nervous system function at early development. Pregnant Wistar rats were treated with 24 or 35 mg/kg of pure glyphosate every 48 h and neurobehavioral studies were performed. Our results indicated that gestational exposure to glyphosate induced changes in reflexes development, motor activity and cognitive function, in a dose-dependent manner. To go further, we evaluated whether prenatal exposure to glyphosate affected the Ca+2-mediated Wnt non-canonical signaling pathway. Results indicated that embryos exposed to glyphosate showed an inhibition of Wnt5a-CaMKII signaling pathway, an essential cascade controlling the formation and integration of neural circuits. Taken together, these findings suggest that gestational exposure to glyphosate leads to a downregulation of Wnt/Ca+2 pathway that could induce a developmental neurotoxicity evidenced by deficits at behavioral and cognitive levels in rat pups.

Asunto(s)

Glicina/análogos & derivados , Herbicidas/toxicidad , Síndromes de Neurotoxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cognición/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Femenino , Glicina/toxicidad , Hipocampo/efectos de los fármacos , Hipocampo/embriología , Hipocampo/metabolismo , Masculino , Intercambio Materno-Fetal , Actividad Motora/efectos de los fármacos , Síndromes de Neurotoxicidad/genética , Síndromes de Neurotoxicidad/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo , Glifosato

RESUMEN

Clinical and experimental evidences indicate that epigenetic modifications induced by the prenatal environment are related to metabolic and reproductive derangements in polycystic ovary syndrome (PCOS). Alterations in the leptin and adiponectin systems, androgen signalling and antimüllerian hormone (AMH) levels have been observed in PCOS women and in their offspring. Using a targeted Next-Generation Sequencing (NGS), we studied DNA methylation in promoter regions of the leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), adiponectin receptor 1 and 2 (ADIPOR1 and ADIPOR2), AMH and androgen receptor (AR) genes in 24 sons and daughters of women with PCOS (12 treated with metformin during pregnancy) and 24 children born to non-PCOS women during early infancy (2-3 months of age). Genomic DNA was extracted from whole blood, bisulphite converted and sequenced by NGS. Girls showed differences between groups in 1 CpG site of LEPR, 2 of LEP, 1 of ADIPOR2 and 2 of AR. Boys showed differences in 5 CpG sites of LEP, 3 of AMH and 9 of AR. Maternal metformin treatment prevented some of these changes in LEP, ADIPOR2 and partially in AR in girls, and in LEP and AMH in boys. Maternal BMI at early pregnancy was inversely correlated with the methylation levels of the ChrX-67544981 site in the whole group of girls (r = -0.530, p = 0.008) and with the global Z-score in all boys (r = -0.539, p = 0.007). These data indicate that the intrauterine PCOS environment predisposes the offspring to acquire certain sex-dependent DNA methylation patterns in the promoter regions of metabolic and reproductive genes.

Asunto(s)

Metilación de ADN , Epigénesis Genética , Síndrome del Ovario Poliquístico/genética , Efectos Tardíos de la Exposición Prenatal/genética , Adiponectina/genética , Adiponectina/metabolismo , Adulto , Femenino , Humanos , Lactante , Leptina/genética , Leptina/metabolismo , Masculino , Embarazo , Regiones Promotoras Genéticas , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Receptores Androgénicos/genética , Receptores Androgénicos/metabolismo , Receptores de Leptina/genética , Receptores de Leptina/metabolismo

RESUMEN

Three relevant, interrelated scientific advances are described: the concept of critical periods (CPs), the Barker Hypothesis (BH), and the underlying epigentic mechanisms involved. Critical periods are genetically programmed, highly sensitive time intervals during which the interaction between environment and individuals generates the development of physiological processes related to physical growth and development, survival (breastfeeding), social behavior, and learning. Barker hypothesis is based on the finding that prenatal malnutrition (for example, lowbirthweight) is closely related to mortality due to cardiovascular disease CVD) in the adult, and to the risk conditions leading to it: insuline resistence, metabolic syndrome, obesity, and high blood pressure. This association is no due to genetical causes, but secondary to nutritional deficits which in turn generate epigenetic mechanisms of methylation of DNA basis and cromatine proteines (histones), which do not modify the genetic code but modulate its expresion, reinforcing some genes, inhibiting others, regulating when and where they are expressed. These genes participate in the process called programming, consisting of permanent changes in the response to stimulation of metabolic and hormone regulators, such as, for example, increasing insuline resistence. Epigenetic changes persist even when original conditions (fetal or perinatal malnutrition) are no longer present. This, in turn, affects health of the offspring later in adult life, creating thus the same environmental prenatal conditions to the next generation. This transgenerational effects of early nutritional experiences are more frequent in population groups of por socioeconomic level, and consequently have serious implications in the future health of Latin American populations.

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Se describen tres adelantos interrelacionados: el concepto de períodos críticos, la hipótesis de Barker y los mecanismos epigenéticos involucrados. Los primeros son intervalos temporales genéticamente programados, vinculados a procesos fisiológicos ligados al crecimiento y desarrollo físico del individuo (habilitación de vías nerviosas, replicación neuronal), a procesos relacionados con el apego madre-hijo, la lactancia, la socialización y el aprendizaje. La hipótesis de Barker sostiene que la desnutrición, en la etapa perinatal, se asocia a mayor mortalidad por enfermedad cardiovascular y a las alteraciones metabólicas que condicionan dicha enfermedad (síndrome metabólico, resistencia a la insulina, hipertensión). Esta asociación es secundaria a las alteraciones nutricionales que desencadenan mecanismos epigenéticos de metilación de bases del ADN o de histonas. Los cambios epigenéticos son permanentes y pueden tener efectos transgeneracionales, al afectar el ambiente perinatal en donde crece la descendencia, hecho relevante en países con poblaciones que viven en condiciones socioeconómicas desfavorables.

Asunto(s)

Epigénesis Genética , Complicaciones del Embarazo/epidemiología , Efectos Tardíos de la Exposición Prenatal/epidemiología , Adulto , Femenino , Humanos , Trastornos Nutricionales/epidemiología , Trastornos Nutricionales/genética , Fenómenos Fisiológicos de la Nutrición , Estado Nutricional , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Factores de Tiempo