RESUMEN
BACKGROUND: Growing evidence suggests that prenatal alcohol exposure (PAE) has the potential to impact on a wide range of physical outcomes in offspring, including metabolism and body composition, although the evidence to-date is primarily from preclinical studies. The current clinical study examined the association between heavy PAE and indirect measures of adiposity in adolescence. METHODS: Analyses drew on data from the Longitudinal Study of Australian Children, a national prospective cohort of children and their families from birth to adolescence. Participants included children with heavy PAE (≥70 g/week; n = 46), measured via maternal self-report of alcohol use during pregnancy and a comparison group of children without any PAE (n = 782), frequency matched on sex, ethnicity and socio-economic position. Body mass index (BMI) z-scores, waist-to-height ratios and proportion overweight/obese were calculated from height, weight and waist circumference measured at age 12-13 years. Two (PAE) × two (sex) ANCOVA and logistic regression models were performed, controlling for matching variables, adolescent age, pubertal status and birthweight; maternal age at birth and smoking during pregnancy. RESULTS: Female adolescents with heavy PAE during late pregnancy had significantly higher BMI z-scores (M = 0.75, SD = 0.69) and proportion overweight/obese (38.5%) than females not exposed to any prenatal alcohol (M = 0.29, SD = 1.07, P = 0.04; 23.8%, P = 0.03, respectively). There was no significant effect of heavy PAE on male adolescent BMI z-scores and proportion overweight/obese or adolescent waist-to-height ratios (all P > 0.05). CONCLUSIONS: Heavy PAE had a sex-specific effect on measures of adiposity in early adolescence, with girls more likely to have increased BMI and overweight/obesity status. Further longitudinal follow-up of children exposed to PAE is required to confirm if maternal alcohol consumption is a risk factor for later life obesity.
Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Efectos Tardíos de la Exposición Prenatal/etiología , Adolescente , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/fisiopatología , Australia/epidemiología , Índice de Masa Corporal , Niño , Femenino , Humanos , Estudios Longitudinales , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/epidemiología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Relación Cintura-CaderaRESUMEN
Fetal alcohol exposure results in well-characterised neurobehavioural deficits in offspring, which form the basis for diagnosing fetal alcohol spectrum disorder. However, there is increasing interest in the full range of health complications that can arise in children and adults with this disorder. We used a systematic review approach to locate all clinical and preclinical studies across a broad range of health outcomes in offspring exposed to prenatal alcohol. Our search encompassed four databases (PubMed, CINAHL, EMBASE and Web of Science) and titles/abstracts from retrieved studies were screened against strict inclusion/exclusion criteria. This review specifically evaluated studies reporting on reproductive outcomes in both males and females. A total of 23 studies were included, 5 clinical and 18 preclinical. Although there was a wide range in the quality of reporting across both clinical and preclinical studies, and variable results, trends emerged amongst the reproductive measures that were investigated. In females, most studies focussed on age at first menarche/puberty onset, with evidence for a significant delay in alcohol-exposed offspring. In males, offspring exposed to prenatal alcohol had altered testosterone levels, reduced testes and accessory gland weights and reduced sperm concentration and semen volume. However, further studies are required due to the paucity of clinical studies, the narrow scope of female reproductive outcomes examined and inconsistencies in outcomes across preclinical studies. We recommend that adolescents and individuals of reproductive age diagnosed with f-etal alcohol spectrum disorder be assessed for reproductive dysfunction to allow appropriate management of their reproductive health and fertility.
Asunto(s)
Etanol/efectos adversos , Trastornos del Espectro Alcohólico Fetal/diagnóstico , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Maduración Sexual/efectos de los fármacos , Femenino , Humanos , EmbarazoRESUMEN
In western countries, alcohol consumption is widespread in women of reproductive age, and in binge quantities. These countries also continue to have high incidences of unplanned pregnancies, with women often reported to cease drinking after discovering their pregnancy. This suggests the early embryo may be highly exposed to the detrimental effects of alcohol during the periconception period. The periconception and pre-implantation windows, which include maturation of the oocyte, fertilisation, and morphogenesis of the pre-implantation embryo, are particularly sensitive times of development. Within the oviduct and uterus, the embryo is exposed to a unique nutritional environment to facilitate its development and establish de-novo expression of the genome through epigenetic reprogramming. Alcohol has wide-ranging effects on cellular stress, as well as hormonal, and nutrient signalling pathways, which may affect the development and metabolism of the early embryo. In this review, we summarise the adverse developmental outcomes of early exposure to alcohol (prior to implantation in animal models) and discuss the potential mechanisms for these outcomes that may occur within the protected oviductal and uterine environment. One interesting candidate is reduced retinoic acid synthesis, as it is implicated in the control of epigenetic reprogramming and cell lineage commitment, processes that have adverse consequences for the formation of the placenta, and subsequently, fetal programming.
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Consumo de Bebidas Alcohólicas/efectos adversos , Blastocisto , Desarrollo Embrionario , Epigénesis Genética , Fertilización , Regulación del Desarrollo de la Expresión Génica , Animales , Femenino , Humanos , MasculinoRESUMEN
The intrauterine environment is critical for the development of the foetus. Barker and colleagues were the first to identify that adverse perturbations during foetal development are associated with an increased risk of developing diseases in adulthood, including cardiorenal disease. Specifically for the kidney, perturbations in utero can lead to nephron deficits and renal dysfunction by a number of mechanisms. Altered programming of nephron number is associated with an increased risk of developing kidney disease via glomerular hypertrophy and reduced vasodilative capacity of the renal blood vessels; both of which would contribute to hypertension in adulthood, with males being more susceptible to disease outcomes. Additionally, alterations in the renin-angiotensin system (RAS) such as an upregulation or downregulation of specific receptors, depending on the nature of the insult, have also been implicated in the development of renal dysfunction. Sex-specific differences in the expression of the RAS during late gestation and in the early postnatal environment have also been identified. Extensive research has demonstrated that both uteroplacental insufficiency and maternal malnutrition alter renal development in utero. Equally, exposure to maternal diabetes and maternal obesity during development are also associated with an increased risk of developing renal disease, however, the mechanism behind this association is poorly understood. Therefore, identifying the link between an adverse intrauterine environment and the programmed kidney disease risk in adulthood may facilitate the development of strategies to alleviate the epidemics of cardiorenal disease worldwide, in addition to understanding why males are more susceptible to adult-onset cardiovascular diseases.
Asunto(s)
Riñón/embriología , Riñón/fisiopatología , Fenómenos Fisiologicos Nutricionales Maternos , Placenta/fisiopatología , Animales , Femenino , Humanos , Riñón/metabolismo , Obesidad , Insuficiencia Placentaria , Embarazo , Complicaciones del EmbarazoRESUMEN
Maternal hypoxia is a common perturbation that can disrupt placental and thus fetal development, contributing to neonatal impairments. Recently, evidence has suggested that physiological outcomes are dependent upon the sex of the fetus, with males more susceptible to hypoxic insults than females. This study investigated the effects of maternal hypoxia during mid- to late gestation on fetal growth and placental development and determined if responses were sex specific. CD1 mice were housed under 21% or 12% oxygen from embryonic day (E) 14.5 until tissue collection at E18.5. Fetuses and placentas were weighed before collection for gene and protein expression and morphological analysis. Hypoxia reduced fetal weight in both sexes at E18.5 by 7% but did not affect placental weight. Hypoxia reduced placental mRNA levels of the mineralocorticoid and glucocorticoid receptors and reduced the gene and protein expression of the glucocorticoid metabolizing enzyme HSD11B2. However, placentas of female fetuses responded differently to maternal hypoxia than did placentas of male fetuses. Notably, morphology was significantly altered in placentas from hypoxic female fetuses, with a reduction in placental labyrinth blood spaces. In addition mRNA expression of Glut1, Igf2 and Igf1r were reduced in placentas of female fetuses only. In summary, maternal hypoxia altered placental formation in a sex specific manner through mechanisms involving placental vascular development, growth factor and nutrient transporter expression and placental glucocorticoid signalling. This study provides insight into how sex differences in offspring disease development may be due to sex specific placental adaptations to maternal insults.
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Hipoxia/metabolismo , Placenta/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/genética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Sistema de Transporte de Aminoácidos A/genética , Animales , Glucemia/análisis , Corticosterona/sangre , Femenino , Transportador de Glucosa de Tipo 1/genética , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Ratones , Placentación , Embarazo , ARN Mensajero/metabolismo , Receptor IGF Tipo 1/genética , Caracteres SexualesRESUMEN
While fetal alcohol spectrum disorder (FASD) has primarily been thought of as a neurodevelopmental condition, research is beginning to highlight its 'whole-body' implications. Accordingly, the current study sought to provide a snapshot of potential health issues. Caregivers of children (median age of 12 years) with an FASD diagnosis were invited to participate in an online survey. Information relating to sample demographics, FASD status of the child and health outcomes were collected. The prevalence of health conditions reported in the FASD sample was compared against national prevalence data. Multiple linear regression utilising a stepwise approach was used to investigate potential predictors of the number of diagnosed health conditions. Survey data were from an international cohort (n = 197), with the majority of respondents based in Australia (40.2%) or the United States (27.7%). The most commonly reported diagnosed health conditions were eye conditions (44.7%), asthma (34.5%), heart conditions (34.0%) and skin conditions (27.4%). Binomial testing indicated the proportion of children diagnosed with these disorders was generally higher in the current FASD population, compared to national prevalence data. Indicators of metabolic dysfunction including diabetes and obesity were not significantly different compared to national prevalence data. Age of FASD diagnosis, existence of comorbid mental health conditions and the primary caregiver being in paid work were identified as being associated with the prevalence of diagnosed health conditions. Overall, the study has provided an up-to-date snapshot of health problems reported in a sample of children with FASD, confirming their increased risk of adverse health outcomes.
Asunto(s)
Trastornos del Espectro Alcohólico Fetal/epidemiología , Adolescente , Adulto , Australia/epidemiología , Cuidadores , Niño , Preescolar , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Maternal alcohol consumption during pregnancy results in elevated vulnerability to intrauterine growth restriction, preterm birth, miscarriage, and stillbirth. Many of the detrimental effects of fetal alcohol exposure may be mediated through placental dysfunction; however, the exact mechanisms remain unknown. Here, we aimed to determine the effect of maternal alcohol exposure prior to and during early pregnancy on placental glucocorticoid receptor (GR) isoforms, associated GR regulated genes, and infant outcomes. Participants carrying singleton fetuses (n = 113) were recruited during early pregnancy. Amount and type of alcohol consumed over the last 12 months were obtained at 18 weeks of gestation. The level of drinking was separated into none (0 g/day), low (< 10 g/day), moderate (10-100 g/day), and heavy (> 100 g/day). At delivery, placental weight, infant sex, birthweight, and head circumference were recorded. Placental GR isoforms and genes involved in downstream signalling pathways were quantified. The majority of women (70.8%) consumed alcohol. Of these, most consumed low (48.8%) or moderate (37.5%) amounts. Placental weight was unaffected by alcohol consumption, but infants born to heavy drinkers tended to be lighter at birth. In female, but not male, placentae, maternal alcohol consumption resulted in increased GRαC and decreased GRαD1 cytoplasmic expression. In both female and male placentae, a dampened inflammatory response was evident with maternal alcohol consumption, involving downregulated IL6R and upregulated POU2F2 gene expression, respectively. Maternal alcohol consumption in the months prior to, and/or during early, pregnancy alters placental GR isoform and expression of some inflammatory genes in a sex-specific manner.
Asunto(s)
Consumo de Bebidas Alcohólicas , Placenta/metabolismo , Receptores de Glucocorticoides/metabolismo , Adulto , Peso al Nacer , Femenino , Expresión Génica , Humanos , Masculino , Embarazo , Isoformas de Proteínas/metabolismo , Adulto JovenRESUMEN
OBJECTIVE/BACKGROUND: Sleep problems are a common clinically reported area of concern for children and adolescents with fetal alcohol spectrum disorder (FASD). However, limited empirical research has been undertaken investigating sleep problems for children with FASD. The current study aimed to examine the associations between parent-reported sleep problems in children with FASD and child behaviour, caregiver mental health and health-related quality of life and family functioning. PARTICIPANTS: 163 caregivers of children diagnosed with FASD aged 5-17 years were included in the current study. METHOD: Cross-sectional online survey that collected information pertaining to child sleep problems (difficulty falling asleep, difficulty staying asleep and/or frequent waking during the night and waking early in the morning) and standardised caregiver reported measures of child behaviour, caregiver mental wellbeing, caregiver health-related quality of life, and family functioning. RESULTS: Sleep problems were common, affecting 65.6% (n = 107) of participants. Difficulty falling asleep (56.4%) was the most common sleep problem encountered, followed by difficulty staying asleep (44.8%) and waking early (29.4%). Sleep problems were associated with increased rates of child behaviour problems and caregiver anxiety and negative impacts on caregiver and family quality of life. CONCLUSION: Sleep problems in children and adolescents with FASD are common and associated with poorer child, caregiver and family outcomes. Future research needs to determine whether effective identification and management of sleep problems can reduce adverse outcomes.
Asunto(s)
Trastornos del Espectro Alcohólico Fetal , Trastornos del Sueño-Vigilia , Adolescente , Cuidadores , Niño , Conducta Infantil , Estudios Transversales , Femenino , Trastornos del Espectro Alcohólico Fetal/epidemiología , Humanos , Padres , Embarazo , Calidad de Vida , Instituciones Académicas , Trastornos del Sueño-Vigilia/epidemiologíaRESUMEN
The novel environment of a metabolic cage can be stressful for rodents, but few studies have attempted to quantify this stress-response. Therefore, we determined the effects on mean arterial pressure (MAP) and heart rate (HR), of placing mice of both sexes in metabolism cages for 2 days. After surgical implantation of a carotid artery catheter mice recovered individually in standard cages for 5 days. Mice then spent 2 days in metabolism cages. MAP and HR were monitored in the standard cage on Day 5 and in metabolism cages on Days 6-7. MAP increased by 18+/-3 and 22+/-4 %, while HR increased by 27+/-4 and 27+/-6 %, in males and females, respectively, during the first hours after cage switch. MAP decreased to baseline in the fourth and eighth h following metabolism cage switch in males and females, respectively. However, HR remained significantly elevated in both sexes during the entire two-day period in metabolism cages. Females had lower MAP than males both pre- and post-metabolism cage switch, but there were no sex differences in HR. These results demonstrate sustained changes in cardiovascular function when mice are housed in metabolism cages, which could potentially affect renal function.
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Conducta Animal , Vivienda para Animales , Hipertensión/fisiopatología , Estrés Psicológico/complicaciones , Taquicardia/fisiopatología , Animales , Presión Sanguínea , Femenino , Frecuencia Cardíaca , Hipertensión/psicología , Riñón/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Factores Sexuales , Estrés Psicológico/fisiopatología , Taquicardia/psicología , Factores de TiempoRESUMEN
BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a common neurodevelopmental condition. Given that individuals with FASD can experience lifelong challenges, one field of research that could be applicable is the paediatric chronic health literature. AIMS: The aim of the current study was to investigate the utility of the Pediatric Quality of Life Inventory (PedsQL) Family Impact Module, designed to measure the impact of paediatric chronic health conditions on caregivers and families. METHODS AND PROCEDURES: 109 caregivers of children with FASD completed an online survey that assessed a range of areas including, caregiver and family quality of life, caregiver mental health and child behaviour. OUTCOMES AND RESULTS: Overall, caregivers reported the areas most impacted on the PedsQL module were Family Daily Activities and Worry. Caregiver's country of residence, mental health, child gender, and level of child behaviour problems were found to be predictors of caregiver and family quality of life. CONCLUSIONS AND IMPLICATIONS: The results demonstrate that there are multidimensional challenges for caregivers and families. These findings have important implications for policy and practice regarding the provision of supports and services for children with FASD and their families.
Asunto(s)
Cuidadores/psicología , Trastornos del Espectro Alcohólico Fetal , Padres/psicología , Problema de Conducta/psicología , Calidad de Vida , Adaptación Psicológica , Adulto , Niño , Conducta Infantil , Salud de la Familia , Femenino , Trastornos del Espectro Alcohólico Fetal/psicología , Trastornos del Espectro Alcohólico Fetal/rehabilitación , Humanos , Masculino , Salud Mental , Evaluación de NecesidadesRESUMEN
Maternal insufficiency during fetal development can have long-lasting effects on the offspring, most notably on nephron endowment. In polycystic kidney disease (PKD), variability in severity of disease is observed and maternal environment may be a modifying factor. In this study, we first established that in a rodent model of PKD, the Lewis polycystic kidney (LPK) rat's nephron numbers are 25% lower compared with wildtype animals. We then investigated the effects of prenatal and postnatal maternal environment on phenotype and nephron number. LPK pups born from and raised by homozygous LPK dams (control) were compared with LPK pups cross-fostered onto heterozygous LPK dams to improve postnatal environment; with LPK pups born from and raised by heterozygous LPK dams to improve both prenatal and postnatal environment and with LPK pups born from and raised by Wistar Kyoto-LPK heterozygous dams to improve both prenatal and postnatal environment on a different genetic background. Improvement in both prenatal and postnatal environment improved postnatal growth, renal function and reduced blood pressure, most notably in animals with different genetic background. Animals with improved postnatal environment only showed improved growth and blood pressure, but to a lesser extent. All intervention groups showed increased nephron number compared with control LPK. In summary, prenatal and postnatal environment had significant effect in delaying progression and reducing severity of PKD, including nephron endowment.
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Desarrollo Fetal/genética , Hipertensión/fisiopatología , Quinasas Relacionadas con NIMA/genética , Nefronas/fisiopatología , Enfermedades Renales Poliquísticas/genética , Animales , Animales Recién Nacidos/fisiología , Presión Sanguínea/fisiología , Modelos Animales de Enfermedad , Femenino , Heterocigoto , Homocigoto , Hipertensión/etiología , Lactancia/fisiología , Masculino , Ratones Transgénicos , Mutación , Nefronas/crecimiento & desarrollo , Nefronas/patología , Enfermedades Renales Poliquísticas/complicaciones , Enfermedades Renales Poliquísticas/fisiopatología , Embarazo , Ratas , Ratas Endogámicas Lew , Índice de Severidad de la EnfermedadRESUMEN
Maternal alcohol consumption throughout pregnancy can result in long term behavioural deficits in offspring. However, less is known about the impact of alcohol during the periconceptional period (PC). The aim of this study was to examine the effect of PC ethanol (PC:EtOH) exposure on long term cognitive function; including memory and anxiety. Rats were exposed to a liquid diet containing ethanol (EtOH) (12.5% vol;vol) or a control diet from 4 days prior to mating until day 4 of pregnancy. Separate cohorts of animals were tested at 6 months (adult) or 15-18 months of age (aged). Offspring underwent a series of behavioural tests to assess anxiety, spatial and recognition memory. The hippocampus was collected, and mRNA expression of epigenetic modifiers and genes implicated in learning and memory were examined. PC:EtOH exposure resulted in a subtle anxiety like behaviour in adult female offspring with a significant reduction in directed exploring/head dipping behaviour during holeboard testing. In aged male offspring, PC:EtOH exposure resulted in a tendency for increased directed exploring/head dipping behaviour during holeboard testing. No differences between treatments were observed in the elevated plus maze. Aged female offspring exposed to PC:EtOH demonstrated short term spatial memory impairment (P < 0.05). PC:EtOH resulted in an upregulation of hippocampal mRNA expression of bdnf, grin2a and grin2b at 18 months of age along with increased expression of epigenetic modifiers (dnmt1, dnmt3a and hdac2). In conclusion, PC:EtOH can lead to sex specific anxiety-like behaviour and impairments in spatial memory and altered hippocampal gene expression.
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Consumo de Bebidas Alcohólicas/efectos adversos , Etanol/farmacología , Expresión Génica/efectos de los fármacos , Memoria/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Animales , Ansiedad/etiología , Conducta Animal/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Embarazo , Ratas Sprague-DawleyRESUMEN
There are many reasons why it is timely to review the development of the mammalian kidney. Perhaps the most important of these is the increasing amount of evidence to demonstrate that factors which impinge on/alter the normal developmental processes of this organ can have lifelong consequences for the health of the adult. The'Developmental Origins of Health and Adult Disease' (DOHaD) hypothesis, proposes that changes in the environment during the development of an organ or system, can have permanent deleterious effects leading to increased risk of cardiovascular and/or metabolic disease. The permanent metanephric kidney has been shown to be very vulnerable to such influences with many factors shown to alter both the permanent structure and the level of expression of important functional genes. Thus it is important to understand the precise timing of kidney development in terms of both structure and the genes involved at each stage. Such knowledge has been gained by significant advances in technology, which allow quantification of the number of nephrons by unbiased stereology, detections of both levels and site of gene expression,'knock-out' and knock-in' of genes in animal (mainly mouse) models and by the ability to examine nephron development, in real time, in culture systems.
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Enfermedades Renales/etiología , Riñón/embriología , Animales , Investigación Biomédica/métodos , Desarrollo Embrionario/genética , Humanos , Riñón/anomalías , Riñón/fisiologíaRESUMEN
AIM: Uteroplacental insufficiency in rats reduces nephron endowment, leptin concentrations and programmes cardiorenal disease in offspring. Cross-fostering growth-restricted (Restricted) offspring onto a mother with normal lactation restores leptin concentrations and nephron endowment. This study aimed to determine whether the reduced nephron endowment in Restricted offspring is due to delayed glomerular formation and dysregulation of renal genes regulating branching morphogenesis, apoptosis or leptin signalling. Furthermore, we aimed to investigate whether cross-fostering Restricted offspring onto Control mothers could improve glomerular maturation and restore renal gene abundance. METHODS: Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on gestation day 18 (E18). Kidneys were collected at E20, postnatal day 1 (PN1) and PN7. An additional cohort was cross-fostered onto separate mothers at birth and kidneys collected at PN7. RESULTS: Kidneys were lighter in the Restricted group, but weight was restored with cross-fostering. At E20, abundance of Bax, Flt1 and Vegfa was increased in Restricted offspring, while Ret and Bcl2 transcripts were increased only in Restricted females. At PN7, abundance of Gdnf and Ret was higher in Restricted offspring, as was Casp3. Restricted offspring had a wider nephrogenic zone with more immature glomeruli suggesting a delayed or extended nephrogenic period. Cross-fostering had subtle effects on gene abundance and glomerular maturity. CONCLUSION: Uteroplacental insufficiency induced apoptosis in the developing kidney and delayed and extended nephrogenesis. Cross-fostering Restricted offspring onto Control mothers had beneficial effects on kidney growth and renal maturity, which may contribute to the restoration of nephron endowment.
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Apoptosis/fisiología , Riñón/embriología , Riñón/patología , Organogénesis/fisiología , Circulación Placentaria , Animales , Femenino , Retardo del Crecimiento Fetal , Riñón/efectos de los fármacos , Leptina/farmacología , Masculino , Organogénesis/efectos de los fármacos , Embarazo , Complicaciones del Embarazo , Ratas , Ratas Endogámicas WKYRESUMEN
Alcohol consumption around the time of conception is highly prevalent in Western countries. Exposure to ethanol levels during gestation has been associated with altered development of the mesolimbic reward pathway in rats and increased propensity to addiction, however the effect of exposure only around the time of conception is unknown. The current study investigated the effects of periconceptional alcohol exposure (PC:EtOH) on alcohol and palatable food preferences and gene expression in the ventral tegmental area (VTA) and the nucleus accumbens of the adult offspring. Rats were exposed to a liquid diet containing ethanol (EtOH) (12.5% vol/vol) or a control diet from 4 days before mating until 4 days after mating. PC:EtOH had no effect on alcohol preference in either sex. At 15 months of age, however, male PC:EtOH offspring consumed more high-fat food when compared with male control offspring, but this preference was not observed in females. Expression of the dopamine receptor type 1 (Drd1a) was lower in the VTA of male PC:EtOH offspring compared with their control counterparts. There was no effect of PC:EtOH on mRNA expression of the µ-opioid receptor, tyrosine hydroxylase (Th), dopamine receptor type 2 (Drd2) or dopamine active transporter (Slc6a3). These data support the hypothesis that periconceptional alcohol exposure can alter expression of key components of the mesolimbic reward pathway and heighten the preference of offspring for palatable foods and may therefore increase their propensity towards diet-induced obesity. These results highlight the importance of alcohol avoidance when planning a pregnancy.
Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Grasas de la Dieta/administración & dosificación , Preferencias Alimentarias/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Área Tegmental Ventral/efectos de los fármacos , Factores de Edad , Consumo de Bebidas Alcohólicas/metabolismo , Consumo de Bebidas Alcohólicas/tendencias , Animales , Grasas de la Dieta/efectos adversos , Grasas de la Dieta/metabolismo , Etanol/administración & dosificación , Etanol/efectos adversos , Femenino , Preferencias Alimentarias/fisiología , Expresión Génica , Masculino , Núcleo Accumbens/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Recompensa , Área Tegmental Ventral/metabolismoRESUMEN
Exposure of the embryo or fetus to perturbations in utero can result in intrauterine growth restriction, a primary risk factor for the development of adult disease. However, despite similar exposures, males and females often have altered disease susceptibility or progression from different stages of life. Fetal growth is largely mediated by the placenta, which, like the fetus is genetically XX or XY. The placenta and its associated trophoblast lineages originate from the trophectoderm (TE) of the early embryo. Rodent models (rat, mouse, spiny mouse), have been used extensively to examine placenta development and these have demonstrated the growth trajectory of the placenta in females is generally slower compared to males, and also shows altered adaptive responses to stressful environments. These placental adaptations are likely to depend on the type of stressor, duration, severity and the window of exposure during development. Here we describe the divergent developmental pathways between the male and female placenta contributing to altered differentiation of the TE derived trophoblast subtypes, placental growth, and formation of the placental architecture. Our focus is primarily genetic or environmental perturbations in rodent models which show altered placental responsiveness between sexes. We suggest that perturbations during early placental development may have greater impact on viability and growth of the female fetus whilst those occurring later in gestation may preferentially affect the male fetus. This may be of great relevance to human pregnancies which result from assisted reproductive technologies or complications such as pre-eclampsia and diabetes.
Asunto(s)
Placenta/fisiología , Placentación , Caracteres Sexuales , Animales , Femenino , Humanos , Placenta/irrigación sanguínea , EmbarazoRESUMEN
BACKGROUND: A male fetus is suggested to be more susceptible to in utero and birth complications. This may be due in part to altered morphology or function of the XY placenta. We hypothesised that sexual dimorphism begins at the blastocyst stage with sex differences in the progenitor trophectoderm (TE) and its derived trophoblast lineages, as these cells populate the majority of cell types within the placenta. We investigated sex-specific differences in cell allocation in the pre-implantation embryo and further characterised growth and gene expression of the placental compartments from the early stages of the definitive placenta through to late gestation. METHODS: Naturally mated Sprague Dawley dams were used to collect blastocysts at embryonic day (E) 5 to characterise cell allocation; total, TE, and inner cell mass (ICM), and differentiation to downstream trophoblast cell types. Placental tissues were collected at E13, E15, and E20 to characterise volumes of placental compartments, and sex-specific gene expression profiles. RESULTS: Pre-implantation embryos showed no sex differences in cell allocation (total, TE and ICM) or early trophoblast differentiation, assessed by outgrowth area, number and ploidy of trophoblasts and P-TGCs, and expression of markers of trophoblast stem cell state or differentiation. Whilst no changes in placental structures were found in the immature E13 placenta, the definitive E15 placenta from female fetuses had reduced labyrinthine volume, fetal and maternal blood space volume, as well as fetal blood space surface area, when compared to placentas from males. No differences between the sexes in labyrinth trophoblast volume or interhaemal membrane thickness were found. By E20 these sex-specific placental differences were no longer present, but female fetuses weighed less than their male counterparts. Coupled with expression profiles from E13 and E15 placental samples may suggest a developmental delay in placental differentiation. CONCLUSIONS: Although there were no overt differences in blastocyst cell number or early placental development, reduced growth of the female labyrinth in mid gestation is likely to contribute to lower fetal weight in females at E20. These data suggest sex differences in fetal growth trajectories are due at least in part, to differences in placenta growth.
Asunto(s)
Placenta/embriología , Placentación , Caracteres Sexuales , Animales , Recuento de Células , Diferenciación Celular , Vellosidades Coriónicas/embriología , Vellosidades Coriónicas/metabolismo , Implantación del Embrión , Femenino , Edad Gestacional , Masculino , Placenta/citología , Placenta/metabolismo , Embarazo , ARN Mensajero/metabolismo , Ratas Sprague-DawleyRESUMEN
Maternal stress can impair foetal development and program sex-specific disease outcomes in offspring through the actions of maternally produced glucocorticoids, predominantly corticosterone (Cort) in rodents. We have demonstrated in mice that male but not female offspring prenatally exposed to Cort (33 µg/kg/h for 60 h beginning at E12.5) develop cardiovascular/renal dysfunction at 12 months. At 6 months of age, renal function was normal but male offspring had increased plasma aldosterone concentrations, suggesting that altered adrenal function may precede disease. This study investigated the long-term impact of prenatal exposure to Cort on adrenal growth, morphology and steroidogenic capacity as well as plasma Cort concentrations in offspring at postnatal day 30 (PN30), 6 months and 12 months of age. Prenatal Cort exposure decreased adrenal volume, particularly of the zona fasciculata, in male offspring at PN30 but increased both relative and absolute adrenal weight at 6 months of age. By 12 months of age, male Cort-exposed offspring had reduced absolute adrenal weight in association with increased adrenal plaque deposition (lipogenic pigmentation). Plasma Cort concentrations were elevated in male 6-month offspring but not at other ages. mRNA expression of Mc2r (ACTH receptor) was increased in males at PN30, and Cyp11a1 expression was decreased at 6 and 12 months of age. There were no changes in the adrenals of female Cort-exposed offspring. This study demonstrates that prenatal Cort exposure induces offspring adrenal gland dysfunction in an age- and sex-specific manner, which may contribute to long-term programmed disease in male offspring after maternal stress.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Hormona Adrenocorticotrópica/efectos de los fármacos , Aldosterona/sangre , Corticosterona/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Glándulas Suprarrenales/anatomía & histología , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Animales , Corticosterona/sangre , Femenino , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Factores SexualesRESUMEN
It is well established that maternal undernutrition and micronutrient deficiencies can lead to altered development and behaviour in offspring. However, few studies have explored the implications of maternal Mg deficiency and programmed behavioural and neurological outcomes in offspring. We used a model of Mg deficiency (prior to and during pregnancy and lactation) in CD1 mice to investigate if maternal Mg deficiency programmed changes in behaviour and NMDAR subunit expression in offspring. Hippocampal tissue was collected at postnatal day 2 (PN2), PN8, PN21 and 6 months, and protein expression of NMDAR subunits GluN1, GluN2A and GluN2B was determined. At 6 months of age, offspring were subject to behavioural tasks testing aspects of anxiety-like behaviour, memory, and neophobia. Maternal hypomagnesemia was associated with increased GluN1, GluN2A and GluN2B subunit expression in female offspring at 6 months, but decreased GluN1 and GluN2A expression in males. The GluN2B:GluN2A expression ratio was increased in both sexes. Male (but not female) offspring from Mg-deficient dams showed anxiety-like behaviour, with reduced head dips (Suok test), and reduced exploration of open arms (elevated plus maze). Both male and female offspring from Mg-deficient dams also showed impaired recognition memory (novel object test). These findings suggest that maternal Mg deficiency can result in behavioural deficits in adult life, and that these changes may be related to alterations in hippocampal NMDA receptor expression.
Asunto(s)
Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Deficiencia de Magnesio/fisiopatología , Complicaciones del Embarazo/fisiopatología , Efectos Tardíos de la Exposición Prenatal , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Ansiedad , Estudios de Cohortes , Conducta Exploratoria/fisiología , Femenino , Masculino , Ratones , Actividad Motora/fisiología , Fuerza Muscular/fisiología , Embarazo , Reconocimiento en Psicología/fisiología , Caracteres SexualesRESUMEN
Prenatal hypoxia is associated with growth restriction and adverse cardiovascular outcomes. Here, we describe renal and cardiovascular outcomes in ageing mouse offspring prenatally exposed to hypoxia (12% O2) from embryonic day 14.5 until birth. At 12 months of age, both male and female offspring exposed to prenatal hypoxia had elevated mean arterial pressure. Glomerular number was reduced by 25% in hypoxia-exposed male, but not female, offspring and this was associated with increased urinary albumin excretion, glomerular hypertrophy and renal fibrosis. Hypoxia-exposed offspring of both sexes were more susceptible to salt-induced cardiac fibrosis, however, renal fibrosis was exacerbated by high salt in males only. In male but not female hypoxia-exposed offspring, renal renin mRNA was increased at weaning. By 12 months, renal renin mRNA expression and concentrations were elevated in both sexes. mRNA expression of At 1a R was also elevated in male hypoxia-exposed offspring at 12 months. These results demonstrate that prenatal hypoxia programs elevated blood pressure and exacerbates salt-induced cardiovascular and renal pathology in a sex specific manner. Given sex differences observed in RAS expression and nephron number, future studies may consider RAS blockade as a therapeutic target in this model.