RESUMO
BACKGROUND: The COVID-19 pandemic constitutes a social crisis that will have long-term health consequences for much of the global population, especially for adolescents. Adolescents are triply affected as they: 1) are experiencing its immediate, direct effects, 2) will carry forward health habits they develop now into adulthood, and 3) as future parents, will shape the early life health of the next generation. It is therefore imperative to assess how the pandemic is influencing adolescent wellbeing, identify sources of resilience, and outline strategies for attenuating its negative impacts. METHODS: We report the results of longitudinal analyses of qualitative data from 28 focus group discussions (FGDs) with 39 Canadian adolescents and of cross-sectional analyses of survey data from 482 Canadian adolescents gathered between September 2020 and August 2021. FGD participants and survey respondents reported on their: socio-demographic characteristics; mental health and wellbeing before and during the pandemic; pre- and during-pandemic health behaviours; experiences living through a crisis; current perceptions of their school, work, social, media, and governmental environments; and ideas about pandemic coping and mutual aid. We plotted themes emerging from FGDs along a pandemic timeline, noting socio-demographic variations. Following assessment for internal reliability and dimension reduction, quantitative health/wellbeing indicators were analyzed as functions of composite socio-demographic, health-behavioural, and health-environmental indicators. RESULTS: Our mixed methods analyses indicate that adolescents faced considerable mental and physical health challenges due to the pandemic, and were generally in poorer health than expected in non-crisis times. Nevertheless, some participants showed significantly better outcomes than others, specifically those who: got more exercise; slept better; were food secure; had clearer routines; spent more time in nature, deep in-person social relationships, and leisure; and spent less time on social media. CONCLUSIONS: Support for youth during times of crisis is essential to future population health because adolescence is a period in the life course which shapes the health behaviours, socio-economic capacities, and neurophysiology of these future parents/carers and leaders. Efforts to promote resilience in adolescents should leverage the factors identified above: helping them find structure and senses of purpose through strong social connections, well-supported work and leisure environments, and opportunities to engage with nature.
Assuntos
COVID-19 , Humanos , Adolescente , COVID-19/epidemiologia , Pandemias , Estudos Transversais , Reprodutibilidade dos Testes , Canadá/epidemiologiaRESUMO
OBJECTIVE: To disrupt cycles of health inequity, traceable to dietary inequities in the earliest stages of life, public health interventions should target improving nutritional wellbeing in preconception/pregnancy environments. This requires a deep engagement with pregnant/postpartum people (PPP) and their communities (including their health and social care providers, HSCP). We sought to understand the factors that influence diet during pregnancy from the perspectives of PPP and HSCP, and to outline intervention priorities. DESIGN: We carried out thematic network analyses of transcripts from ten focus group discussions (FGD) and one stakeholder engagement meeting with PPP and HSCP in a Canadian city. Identified themes were developed into conceptual maps, highlighting local priorities for pregnancy nutrition and intervention development. SETTING: FGD and the stakeholder meeting were run in predominantly lower socioeconomic position (SEP) neighbourhoods in the sociodemographically diverse city of Hamilton, Canada. PARTICIPANTS: All local, comprising twenty-two lower SEP PPP and forty-three HSCP. RESULTS: Salient themes were resilience, resources, relationships and the embodied experience of pregnancy. Both PPP and HSCP underscored that socioeconomic-political forces operating at multiple levels largely determined the availability of individual and relational resources constraining diet during pregnancy. Intervention proposals focused on cultivating individual and community resilience to improve early-life nutritional environments. Participants called for better-integrated services, greater income supports and strengthened support programmes. CONCLUSIONS: Hamilton stakeholders foregrounded social determinants of inequity as main factors influencing pregnancy diet. They further indicated a need to develop interventions that build resilience and redistribute resources at multiple levels, from the household to the state.
Assuntos
Dieta , Canadá , Feminino , Grupos Focais , Humanos , Período Pós-Parto , Cuidado Pré-Concepcional , Gravidez , Resultado da Gravidez , Cuidado Pré-Natal , Apoio Social , Fatores SocioeconômicosRESUMO
We have previously reported that offspring of mothers fed a high fat (HF) diet during pregnancy and lactation enter puberty early and are hyperleptinaemic, hyperinsulinaemic and obese as adults. Poor maternal care and bonding can also impact offspring development and disease risk.We therefore hypothesized that prenatal nutrition would affect maternal care and that an interaction may exist between a maternal HF diet and maternal care, subsequently impacting on offspring phenotype.Wistar rats were mated and randomized to control dams fed a control diet (CON) or dams fed a HF diet from conception until the end of lactation (HF). Maternal care was assessed by observing maternal licking and grooming of pups between postnatal day (P)3 and P8. Postweaning (P22), offspring were fed a control (con) or HF (hf) diet. From P27, pubertal onset was assessed. At â¼P105 oestrous cyclicity was investigated. Maternal HF diet reduced maternal care; HF-fed mothers licked and groomed pups less than CON dams.Maternal fat:lean ratio was higher in HF dams at weaning and was associated with higher maternal plasma leptin and insulin concentrations, but there was no effect of maternal care on fat:lean ratio or maternal hormone levels. Both female and male offspring of HF dams were lighter from birth to P11 than offspring of CON dams, but by P19, HF offspring were heavier than controls. Prepubertal retroperitoneal fat mass was greater in pups from HF-fed dams compared to CON and was associated with elevated circulating leptin concentrations in females only, but there was neither an effect of maternal care, nor an interaction between maternal diet and care on prepubertal fat mass. Pups from HF-fed dams went into puberty early and this effect was exacerbated by a postweaning HF diet.Maternal and postweaning HF diets independently altered oestrous cyclicity in females: female offspring of HF-fed mothers were more likely to have prolonged or persistent oestrus, whilst female offspring fed a HF diet postweaning were more likely to have irregular oestrous cycles and were more likely to have prolonged or persistent oestrus. These data indicate that maternal HF nutrition during pregnancy and lactation results in a maternal obese phenotype and has significant impact on maternal care during lactation. Maternal and postweaning nutritional signals, independent of maternal care, alter offspring body fat pre-puberty and female reproductive function in adulthood, which may be associated with advanced ovarian ageing and altered fertility.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Comportamento Animal , Dieta Hiperlipídica , Comportamento Materno , Exposição Materna , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/etiologia , Efeitos Tardios da Exposição Pré-Natal , Reprodução , Adiposidade , Fatores Etários , Envelhecimento , Animais , Animais Recém-Nascidos , Biomarcadores/sangue , Peso ao Nascer , Ciclo Estral , Feminino , Fertilidade , Masculino , Obesidade/fisiopatologia , Obesidade/psicologia , Fenótipo , Gravidez , Ratos , Ratos Wistar , Maturidade SexualRESUMO
It is well established that altered maternal nutrition may induce long-term metabolic consequences in offspring. However, the effects of maternal undernutrition during different developmental windows on sex-specific growth and metabolism in offspring are not well defined. We investigated the effect of moderate maternal undernutrition during pregnancy and/or lactation on postnatal growth and metabolic outcomes in offspring. Wistar rats were randomly assigned to one of four groups: (1) control (CONT) dams fed a standard diet throughout pregnancy and lactation; (2) dams undernourished to 50 % of CONT during pregnancy (UNP); (3) dams fed at 50 % of CONT throughout lactation (UNL); (4) dams fed at 50 % of CONT throughout pregnancy and lactation (UNPL). UNP and UNPL offspring were lighter at birth compared to CONT and UNL. UNL and UNPL offspring were growth restricted at weaning and remained smaller into adulthood. UNP males and females developed increased adiposity and hyperleptinaemia in adulthood compared to all other groups. Adiposity in UNL and UNPL males was similar to CONT offspring. In UNL and UNPL females, adiposity was lower than for CONT females. Markers of bone mass, lipid metabolism and hepatic function were altered in UNP offspring but were similar in UNL and UNPL offspring compared to CONT. Lack of catch-up growth during lactation in offspring of undernourished mothers prevented development of adiposity and related metabolic disorders in later life. These data highlight that the timing and duration of undernutrition during critical windows of development exert differential effects on postnatal outcomes in a sex-specific manner.
Assuntos
Adiposidade , Desenvolvimento Fetal , Retardo do Crescimento Fetal/etiologia , Lactação , Desnutrição , Fenômenos Fisiológicos da Nutrição Materna , Adipogenia , Animais , Pesos e Medidas Corporais , Desenvolvimento Ósseo , Feminino , Retardo do Crescimento Fetal/metabolismo , Retardo do Crescimento Fetal/patologia , Retardo do Crescimento Fetal/fisiopatologia , Leptina/sangue , Lipídeos/sangue , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Masculino , Gravidez , Distribuição Aleatória , Ratos , Ratos Wistar , Caracteres SexuaisRESUMO
BACKGROUND: Diagnosing polycystic ovary syndrome (PCOS) in adolescence is clinically challenging. The prevalence of clinical, ultrasound and biochemical features of PCOS in a community-based adolescent population using current diagnostic criteria has not previously been described. METHODS: This was a prospective cohort study with 244 unselected post-menarchal girls, mean age 15.2 years, of whom 91% were Caucasian. Subjects were recruited from a large population-based birth cohort (the Raine cohort). Clinical hyperandrogenism (HA) was quantified using Ferriman-Gallwey scores. In the early follicular phase (Day 2-6), we measured circulating androgens and sex hormone-binding globulin by immunoassay, and ovarian morphology was assessed by transabdominal ultrasound examination. BMI and waist-hip ratio were measured. RESULTS: Normal ranges for early follicular phase androgens in adolescence were derived for this population. The top 5 and 10% of circulating free testosterone levels were 45.6 and 34.5 pmol/l, respectively. Fifty-one percent of girls reported menstrual irregularity. Clinical HA was uncommon, being observed in only 3.5% of girls. Mean ovarian volume was greater than that reported by others in adult women and 35% of girls had polycystic ovary morphology on transabdominal ultrasound. Taking the upper 5% of free testosterone as HA, 42 girls (18.5%) would have met the Rotterdam criteria for PCOS, 11 girls (5%) the Androgen Excess Society criteria and 7 girls (3.1%) the National Institutes of Health criteria. CONCLUSIONS: Menstrual irregularity is common in adolescence and does not relate to clinical or biochemical HA. Diagnostic criteria for PCOS which include ovarian volume and morphology may be of limited use in adolescence.
Assuntos
Androgênios/sangue , Distúrbios Menstruais/diagnóstico , Síndrome do Ovário Policístico/diagnóstico , Adolescente , Estudos de Coortes , Feminino , Humanos , Ovário/diagnóstico por imagem , Síndrome do Ovário Policístico/diagnóstico por imagem , Síndrome do Ovário Policístico/metabolismo , UltrassonografiaRESUMO
OBJECTIVE: Maternal obesity is associated with obesity and metabolic disorders in offspring. However, there remains a paucity of data on strategies to reverse the effects of maternal obesity on maternal and offspring health. With maternal undernutrition, taurine supplementation improves outcomes in offspring mediated in part via improved glucose-insulin homeostasis. The efficacy of taurine supplementation in the setting of maternal obesity on health and well-being of offspring is unknown. We examined the effects of taurine supplementation on outcomes related to growth and metabolism in offspring in a rat model of maternal obesity. DESIGN: Wistar rats were randomised to: 1) control diet during pregnancy and lactation (CON); 2) CON with 1.5% taurine in drinking water (CT); 3) maternal obesogenic diet (MO); or 4) MO with taurine (MOT). Offspring were weaned onto the control diet for the remainder of the study. RESULTS: At day 150, offspring body weights and adipose tissue weights were increased in MO groups compared to CON. Adipose tissue weights were reduced in MOT versus MO males but not females. Plasma fasting leptin and insulin were increased in MO offspring groups but were not altered by maternal taurine supplementation. Plasma homocysteine concentrations were reduced in all maternal taurine-supplemented offspring groups. There were significant interactions across maternal diet, taurine supplementation and sex for response to an oral glucose tolerance test , a high-fat dietary preference test and pubertal onset in offspring. CONCLUSIONS: These results demonstrate that maternal taurine supplementation can partially ameliorate adverse developmental programming effects in offspring in a sex-specific manner.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Frutose/toxicidade , Doenças Metabólicas/tratamento farmacológico , Obesidade Materna/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Taurina/administração & dosagem , Animais , Animais Recém-Nascidos , Feminino , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos WistarRESUMO
Significant alterations in maternal nutrition may induce long-term metabolic consequences in offspring, in particular obesity and leptin and insulin resistance. Although maternal nutrient deprivation has been well characterized in this context, there is a relative paucity of data on how high fat (HF) nutrition impacts on the subsequent generation. The present study investigated the effects of maternal HF nutrition either throughout the mother's life up to and including pregnancy and lactation or HF nutrition restricted to pregnancy and lactation, on growth and metabolic parameters in male and female offspring. Virgin Wistar rats were assigned to one of three experimental groups: (1) controls (Cont): dams fed a standard chow diet throughout their life and throughout pregnancy and lactation; (2) maternal high fat (MHF) group: dams fed a HF diet from weaning up to and throughout pregnancy and lactation; and (3) pregnancy and lactation high fat (PLHF): dams fed a chow diet through their life until conception and then fed a HF diet throughout pregnancy and lactation. At weaning, all offspring were fed either a chow or HF diet for the remainder of the study (160 days). Litter size and sex ratios were not significantly different between the groups. MHF and PLHF offspring had significantly lower body weights and were hypoleptinaemic and hypoinsulinaemic at birth compared to Cont offspring. As adults however, chow-fed MHF and PLHF offspring were significantly more obese than Cont offspring (DEXA scanning at day 150, P < 0.001 for maternal HF diet). As expected a postweaning HF diet resulted in increased adiposity in all groups; MHF and PLHF offspring, however, always remained significantly more obese than Cont offspring. Increased adiposity in MHF and PLHF offspring was paralleled by hyperinsulinaemia and hyperleptinaemia (P < 0.001; MHF and PLHF versus Cont). It is of interest that a lifetime of HF nutrition produced a similar offspring phenotype to HF nutrition restricted to pregnancy and lactation alone, thus suggesting that the postnatal sequelae of maternal HF nutrition occurs independent of preconceptional diet. These data further reinforce the importance of maternal nutrition during these critical windows of development and show that maternal HF feeding can induce a markedly obese phenotype in male and female offspring completely independent of postnatal nutrition.
Assuntos
Gorduras na Dieta/administração & dosagem , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Obesidade/etiologia , Obesidade/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fatores Etários , Animais , Animais Recém-Nascidos , Feminino , Masculino , Obesidade/sangue , Valor Preditivo dos Testes , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Ratos , Ratos WistarRESUMO
Evidence supporting the Developmental Origins of Health and Disease (DOHaD) hypothesis indicates that improving early life environments can reduce non-communicable disease risks and improve health over the lifecourse. A widespread understanding of this evidence may help to reshape structures, guidelines and individual behaviors to better the developmental conditions for the next generations. Yet, few efforts have yet been made to translate the DOHaD concept beyond the research community. To understand why, and to identify priorities for DOHaD Knowledge Translation (KT) programs, we review here a portion of published descriptions of DOHaD KT efforts and critiques thereof. We focus on KT targeting people equipped to apply DOHaD knowledge to their everyday home or work lives. We identified 17 reports of direct-to-public DOHaD KT that met our inclusion criteria. Relevant KT programs have been or are being initiated in nine countries, most focusing on secondary school students or care-workers-in-training; few target parents-to-be. Early indicators suggest that such programs can empower participants. Main critiques of DOHaD KT suggest it may overburden mothers with responsibility for children's health and health environments, minimizing the roles of other people and institutions. Simultaneously, though, many mothers-to-be seek reliable guidance on prenatal health and nutrition, and would likely benefit from engagement with DOHaD KT. We thus recommend emphasizing solidarity, and bringing together people likely to one day become parents (youth), people planning pregnancies, expecting couples, care workers and policymakers into empowering conversation about DOHaD and about the importance and complexity of early life environments.
Assuntos
Dieta , Comportamento Alimentar , Promoção da Saúde/métodos , Estilo de Vida , Estado Nutricional , Criança , Humanos , Instituições AcadêmicasRESUMO
BACKGROUND: Abnormal bleeding is common in hormone therapy (HT) users. We aimed to determine how HT alters endometrial blood vessels and stromal factors known to regulate vascular growth and integrity. METHODS: Prospective observational study of 165 post-menopausal women in Western Australia. The following were measured in endometrial biopsies: vascular density (vessels/mm(2)), total vessel area (total area enclosed by peripheral vascular immunostaining for perivascular pericytes in mm(2)), total luminal area (mm(2)) and vessel wall area (total vessel area minus luminal area), stromal expression of matrix metalloproteinases (MMP) -1, -3, -9 and -14, their tissue inhibitors (TIMPs) -1-4 and vascular endothelial growth factor (VEGF) by immunohistochemistry. RESULTS: Total vessel area was greater during bleeding compared with HT users with no bleeding (P = 0.028) or with a prior irregular bleeding (P = 0.039). Total vessel area was greater in non-HT users compared with HT users with no bleeding (P = 0.021). In HT users, vessel luminal area was greater during bleeding compared with HT users with no bleeding (P = 0.030) and vessel wall area was also increased (P = 0.025). During bleeding there was an increase in stromal TIMP-2 staining (P = 0.044). No significant changes in endometrial MMP or VEGF were seen. CONCLUSIONS: Abnormal bleeding in HT users is associated with changes in endometrial vessel size and in stromal expression of factors known to regulate vascular growth and integrity. These changes may contribute to abnormal bleeding.
Assuntos
Endométrio/irrigação sanguínea , Endométrio/efeitos dos fármacos , Terapia de Reposição Hormonal/efeitos adversos , Metrorragia/etiologia , Pós-Menopausa , Adulto , Austrália , Biópsia por Agulha , Endométrio/patologia , Feminino , Expressão Gênica , Humanos , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidores Teciduais de Metaloproteinases/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Inibidor Tecidual 4 de MetaloproteinaseRESUMO
OBJECTIVE: To determine the role of carotid sinus innervation on differential fetal organ growth during maternal nutrient restriction in late pregnancy. DESIGN: Randomised controlled study. SETTING: University research facility. SAMPLE: Thirty-nine Merino ewes. METHODS: At 113 days gestational age (dGA), fetuses were bilaterally carotid sinus denervated or sham denervated. From 118 dGA, the surgery groups were subdivided into two dietary groups, and their ewes were fed 100% of nutrient requirements or 50% until tissue collection at 140 dGA. This provided four groups (sham/control diet, sham/restricted diet, denervated/control diet and denervated/restricted diet). MAIN OUTCOME MEASURES: Fetal organ weights and hormone levels and maternal weight change during the dietary restriction. RESULTS: Adrenal glands were larger in sham/restricted diet fetuses than in sham/control diet or denervated/restricted diet fetuses (P < 0.05). Fetal adrenal weight and brain-to-liver weight ratio were positively related to maternal weight change during the nutritional challenge in sham fetuses only (P < 0.05). Fetal liver weight was negatively related to maternal weight change during nutritional challenge in sham fetuses only (P < 0.05). CONCLUSIONS: We have shown a reduction in liver growth but sparing of adrenal growth in response to moderate maternal undernutrition, which is dependent on intact carotid body innervation. This suggests a new role for the carotid bodies in the control of differential organ growth during such undernutrition.
Assuntos
Seio Carotídeo/inervação , Dieta Redutora/efeitos adversos , Desenvolvimento Fetal/fisiologia , Desnutrição/embriologia , Complicações na Gravidez/etiologia , Glândulas Suprarrenais/embriologia , Hormônio Adrenocorticotrópico/metabolismo , Animais , Peso Corporal/fisiologia , Encéfalo/embriologia , Seio Carotídeo/embriologia , Seio Carotídeo/cirurgia , Eletrólitos/sangue , Feminino , Sangue Fetal/química , Hidrocortisona/metabolismo , Insulina/metabolismo , Fígado/embriologia , Pulmão/embriologia , Tamanho do Órgão/fisiologia , Gravidez , Distribuição Aleatória , OvinosRESUMO
INTRODUCTION: We have previously shown that even a single course of antenatal betamethasone (BET) as an inductor for lung maturity reduces birth weight and head circumference. Moreover, animal studies link BET administration to alterations of the hypothalamic-pituitary-adrenal-gland-axis (HPA). The unhindered development of the fetal HPA axis is dependent on the function and activity of 11ß-hydroxysteroiddehydrogenase type 2 (11ß-HSD2), a transplacental cortisol barrier. Therefore, we investigated the effects of BET on this transplacental barrier and fetal growth. METHODS: Pregnant women treated with a single course of BET between 23 + 5 to 34 + 0 weeks of gestation were compared to gestational-age-matched controls. Placental size and neonatal anthropometrics were taken. Cortisol and ACTH levels were measured in maternal and umbilical cord blood samples. Placental 11ß-hydroxysteroiddehydrogenase type 1 (11ß-HSD1) protein levels and 11ß-HSD2 protein and activity levels were determined. Parameters were analyzed independent of sex, and in subgroups divided by gender and gestational age. RESULTS: In term born females, BET administration was associated with reduced head circumference and decreased 11ß-HSD2 protein levels and enzyme activity. Males treated with BET, especially those born prematurely, showed increased 11ß-HSD2 protein levels. CONCLUSION: A single course of BET alters placental glucocorticoid metabolism in a sex-specific manner. Decreased 11ß-HSD2 levels in term born females may lead to an increased placental transfer of maternal cortisol and therefore result in a reduced head circumference and a higher risk for altered stress response in adulthood. Further research is needed to conclude the significance of increased 11ß-HSD2 levels in males.
Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Betametasona/farmacologia , Desenvolvimento Fetal/efeitos dos fármacos , Glucocorticoides/farmacologia , Placenta/efeitos dos fármacos , Hormônio Adrenocorticotrópico/sangue , Antropometria , Betametasona/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Cabeça/anatomia & histologia , Humanos , Hidrocortisona/sangue , Masculino , Tamanho do Órgão/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Fatores SexuaisRESUMO
The rise in the occurrence of obesity to epidemic proportions has made it a global concern. Great difficulty has been experienced in efforts to control this growing problem with lifestyle interventions. Thus, attention has been directed to understanding the events of one of the most critical periods of development, perinatal life. Early life adversity driven by maternal obesity has been associated with an increased risk of metabolic disease and obesity in the offspring later in life. Although a mechanistic link explaining the relationship between maternal and offspring obesity is still under investigation, the gut microbiota has come forth as a new factor that may play a role modulating metabolic function of both the mother and the offspring. Emerging evidence suggests that the gut microbiota plays a much larger role in mediating the risk of developing non-communicable disease, including obesity and metabolic dysfunction in adulthood. With the observation that the early life colonization of the neonatal and postnatal gut is mediated by the perinatal environment, the number of studies investigating early life gut microbial establishment continues to grow. This paper will review early life gut colonization in experimental animal models, concentrating on the role of the early life environment in offspring gut colonization and the ability of the gut microbiota to dictate risk of disease later in life.
Assuntos
Modelos Animais de Doenças , Microbioma Gastrointestinal , Obesidade/etiologia , Animais , Animais Recém-Nascidos/microbiologia , Feminino , Gravidez , Complicações na Gravidez/microbiologiaRESUMO
RT-qPCR requires a suitable set of internal control genes (ICGs) for an accurate normalization. The usefulness of 7 previously published ICGs in the human placenta was analyzed according to the effects of betamethasone treatment, sex and fetal age. Raw RT-qPCR data of the ICGs were evaluated using published algorithms. The algorithms revealed that a reliable normalization was achieved using the geometrical mean of PPIA, RPL19, HMBS and SDHA. The use of a different subset ICGs out of the 7 investigated, although not statistically affected by the conditions, biased the results, as demonstrated through changes in expression of glucocorticoid receptor (NR3C1) mRNA as a target gene.
Assuntos
Genes Essenciais/genética , Glucocorticoides/farmacologia , Placenta/efeitos dos fármacos , Receptores de Glucocorticoides/genética , Complexo II de Transporte de Elétrons/genética , Feminino , Perfilação da Expressão Gênica , Glucocorticoides/uso terapêutico , Humanos , Hidroximetilbilano Sintase/genética , Peptidilprolil Isomerase/genética , Placenta/metabolismo , Gravidez , Proteínas Ribossômicas/genéticaRESUMO
Prenatal glucocorticoids, commonly used in women at risk of preterm delivery, can predispose the newborn to disease in later life. Since male reproductive function is likely to reflect testis development during fetal life, we studied the effects of prenatal glucocorticoids on two key intra-testicular factors that play roles in cellular proliferation and differentiation, 3ß-hydroxysteroid dehydrogenase (3ß-HSD) and inhibin-α. Pregnant sheep (n=42) were treated with betamethasone (0.5 mg/kg) or saline (control) at 104, 111 and 118 days of gestation (DG). Testicular tissue was sampled from fetuses at 121 and 132DG, and from lambs at 45 and 90 postnatal days (PD). Within the betamethasone treated group, 3ß-HSD immunostaining area was greater at 121DG than at 90PD (P=0.04), but the intensity of immunostaining was higher at 90PD than at 121DG (P=0.04), 132DG (P=0.04) and 45PD (P=0.03). Control animals showed no changes in 3ß-HSD area or intensity of immunostaining. No significant differences were observed between treated and control animals in immunostaining area, but immunostaining was more intense in the treated group than in the control group at 90PD (P=0.03). For inhibin-α, the proportion of immunostaining area declined in treated offspring from 121DG to 45PD, in contrast to control values, but recovered fully by 90PD, concomitantly with the onset of spermatogenesis. In conclusion, prenatal betamethasone increased the postnatal testicular expression of inhibin-α but reduced the expression of 3ß-HSD. These effects could compromise androgen-mediated testicular development and therefore adult capacity for spermatogenesis.
Assuntos
17-Hidroxiesteroide Desidrogenases/metabolismo , Betametasona/farmacologia , Feto/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inibinas/metabolismo , Testículo/metabolismo , Animais , Feminino , Feto/citologia , Feto/efeitos dos fármacos , Idade Gestacional , Técnicas Imunoenzimáticas , Masculino , Gravidez , Ovinos , Testículo/efeitos dos fármacos , Testículo/crescimento & desenvolvimentoRESUMO
A clear relationship between intrauterine development and later life predisposition to long-term disease is well established. Weight at birth provides a surrogate measure for fetal development and low birth weight predicts changes in most endocrine axes in adulthood. The exposure of the fetus to elevated levels of either endogenous or synthetic glucocorticoids, pre and periconceptional nutritional status and immediate postnatal development including catch-up growth all contribute substantially to the development of adult onset disease. Fetal exposure to high levels of glucocorticoids has direct clinical relevance. Synthetic glucocorticoids (betamethasone/ dexamethasone) are administered to women at risk of preterm delivery to advance fetal maturation and reduce neonatal morbidity and mortality. However, in human pregnancy, evidence suggests that fetal exposure to synthetic glucocorticoids has detrimental effects on birth outcome, childhood cognition and long-term behavior. Studies in animals have established a link between prenatal exposure to synthetic glucocorticoids and alterations in fetal development as well as changes in placental function. These developmental alterations appear to be permanent. Whether this is the case in humans awaits long-term follow-up of children enrolled in randomized controlled trials of prenatal glucocorticoid therapy. The research challenges in this field are now centered on uncovering the mechanisms by which glucocorticoids are involved in programming the fetus for its future life, and discovering ways in which the effectiveness and safety of antenatal glucocorticoids can be enhanced. The purpose of this mini-review is to provide a background into the use of antenatal synthetic corticosteroids and to highlight and summarize recently published clinical and animal-based studies.
Assuntos
Feto/efeitos dos fármacos , Glucocorticoides/uso terapêutico , Síndrome do Desconforto Respiratório do Recém-Nascido/prevenção & controle , Feminino , Feto/embriologia , Glucocorticoides/síntese química , Humanos , Recém-Nascido , Gravidez , Fatores de TempoRESUMO
There is now considerable epidemiological and experimental evidence indicating that early-life environmental conditions, including nutrition, affect subsequent development in later life. These conditions induce highly integrated responses in endocrine-related homeostasis, resulting in persistent changes in the developmental trajectory producing an altered adult phenotype. Early-life events trigger processes that prepare the individual for particular circumstances that are anticipated in the postnatal environment. However, where the intrauterine and postnatal environments differ markedly, such modifications to the developmental trajectory may prove maladaptive in later life. Reproductive maturation and function are similarly influenced by early-life events. This should not be surprising, because the primordial follicle pool is established early in life and is thus vulnerable to early-life events. Results of clinical and experimental studies have indicated that early-life adversity is associated with a decline in ovarian follicular reserve, changes in ovulation rates, and altered age at onset of puberty. However, the underlying mechanisms regulating the relationship between the early-life developmental environment and postnatal reproductive development and function are unclear. This review examines the evidence linking early-life nutrition and effects on the female reproductive system, bringing together clinical observations in humans and experimental data from targeted animal models.
Assuntos
Folículo Ovariano/crescimento & desenvolvimento , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fenômenos Fisiológicos da Nutrição Pré-Natal , Reprodução/fisiologia , Adulto , Animais , Desenvolvimento Embrionário/fisiologia , Feminino , Humanos , Gravidez , Maturidade Sexual/fisiologiaRESUMO
Excessive fructose consumption is associated with insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD), and high fructose intake during pregnancy can lead to compromised fetal development in the rat. Evidence suggests that the amino acid taurine can ameliorate fructose-induced IR and NAFLD in nonpregnant animals. This study investigated the efficacy of taurine supplementation on maternal fructose-induced metabolic dysfunction and neonatal health. Time-mated Wistar rats were randomized to four groups during pregnancy and lactation: (a) control diet (CON), (b) CON supplemented with 1.5% taurine in drinking water (CT), (c) CON supplemented with fructose solution (F) and (d) F supplemented with taurine (FT). Maternal and neonatal weights, plasma cytokines and hepatic gene expression were analyzed. Maternal hyperinsulinemia, increased homeostasis model assessment of IR indices and elevated proinflammatory cytokines were observed in F group and normalized in FT group. Maternal fructose-induced hepatic steatosis accompanied with increased liver weight was ameliorated with taurine supplementation. Maternal hepatic sterol regulatory element-binding protein-1c and fatty acid synthase expression was significantly increased in the F group compared to the CON, CT and FT groups. Neonatal hepatic phosphoenolpyruvate carboxykinase expression was increased in male F neonates compared to the CON, CT and FT groups and was increased in female F and FT neonates compared to CON and CT. Interleukin-1ß expression was decreased in male CT and FT neonates compared to other male groups. Hepatic tumour necrosis factor receptor-1 was lower in the male FT group than the F group. These results demonstrate that maternal taurine supplementation can partially reverse fructose-induced maternal metabolic dysfunction and may ameliorate adverse developmental programming effects in offspring in a sex-specific manner.
Assuntos
Suplementos Nutricionais , Desenvolvimento Fetal , Frutose/efeitos adversos , Lactação , Fenômenos Fisiológicos da Nutrição Materna , Síndrome Metabólica/prevenção & controle , Taurina/uso terapêutico , Animais , Citocinas/sangue , Ácido Graxo Sintases/antagonistas & inibidores , Ácido Graxo Sintases/química , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Resistência à Insulina , Lactação/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Masculino , Síndrome Metabólica/congênito , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Tamanho do Órgão , Gravidez , Distribuição Aleatória , Ratos Wistar , Caracteres Sexuais , Proteína de Ligação a Elemento Regulador de Esterol 1/agonistas , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
INTRODUCTION: Up to 10% of pregnant women take antidepressants, of which selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed. Using a rodent model, we investigated the reproductive impacts of perinatal SSRI treatment on reproductive cyclicity and function in female offspring. METHODS: Virgin Wistar rats were given oral vehicle (n = 10) or fluoxetine hydrochloride (FLX, 10 mg/kg/d; n = 11) from 2 weeks prior to mating until weaning. Pubertal onset and reproductive cyclicity in offspring were assessed. Blood and ovarian tissues were collected for measures of reproductive function. RESULTS: Perinatal FLX tends to induce irregular reproductive cycles in adult offspring, which most commonly manifest as a prolonged estrus phase (FLX 34% vs control [CON] 10%) relative to CON offspring. The FLX offspring tended to have longer cycles (P = .052), had more secondary follicles (P = .0067), more total follicles (P = .0310), and increased apoptotic ovarian cells (P < .001). Prenatally exposed FLX offspring demonstrated elevated ovarian messenger RNA (mRNA) levels of ERß (P = .008), Cry1 (P = .043), and tryptophan hydroxylase 2 (P = .024), independent of stage of cycle. Ovarian mRNA levels of brain and muscle Arnt-like protein 1 (P = .046) and Pet-1 (P = .021) were increased in FLX offspring a manner that was reproductive cycle stage dependent. CONCLUSIONS: This is the first study to investigate the postnatal effects of maternal perinatal exposure to FLX on adult offspring reproduction. We show that genes that regulate serotonin signaling and action in the ovary are altered in prenatally FLX-exposed offspring, which when coupled with increased expression of components of the core Circadian Locomotor Output Cycles Kaput (CLOCK) gene regulatory loop may suggest an interaction between serotonergic signaling and clock gene signaling pathways leading to the altered reproductive phenotype.
Assuntos
Fluoxetina/toxicidade , Folículo Ovariano/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Reprodução/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/toxicidade , Fatores Etários , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Estro/efeitos dos fármacos , Feminino , Fluoxetina/administração & dosagem , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Exposição Materna , Folículo Ovariano/metabolismo , Folículo Ovariano/patologia , Fenótipo , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , DesmameRESUMO
The effects of endogenous cortisol on binucleate cells (BNCs), which promote fetal growth, may be mediated by glucocorticoid receptors (GRs), and exposure to dexamethasone (DEX) in early pregnancy stages of placental development might modify this response. In this article, we have investigated the expression of GR as a determinant of these responses. Pregnant ewes carrying singleton fetuses (n = 119) were randomized to control (2 mL saline/ewe) or DEX-treated groups (intramuscular injections of 0.14 mg/kg ewe weight per 12 hours) at 40 to 41 days of gestation (dG). Placental tissue was collected at 50, 100, 125, and 140 dG. Total glucocorticoid receptor protein (GRt) was increased significantly by DEX at 50 and 125 dG in females only, but decreased in males at 125 dG as compared to controls. Glucocorticoid receptor α (GRα) protein was not changed after DEX treatment. Three BNC phenotypes were detected regarding GRα expression (++, +-, --), DEX increased the proportion of (++) and decreased (--) BNC at 140 dG. Effects were sex- and cell type dependent, modifying the responsiveness of the placenta to endogenous cortisol. We speculate that 3 maturational stages of BNCs exist and that the overall activity of BNCs is determined by the distribution of these 3 cell types, which may become altered through early pregnancy exposure to elevated glucocorticoids.
Assuntos
Dexametasona/toxicidade , Glucocorticoides/toxicidade , Placenta/efeitos dos fármacos , Receptores de Glucocorticoides/agonistas , Animais , Caspase 3/metabolismo , Feminino , Idade Gestacional , Masculino , Fenótipo , Placenta/metabolismo , Placenta/patologia , Lactogênio Placentário/metabolismo , Gravidez , Transporte Proteico , Receptores de Glucocorticoides/metabolismo , Fatores Sexuais , Ovinos , Transdução de Sinais/efeitos dos fármacosRESUMO
Prenatal glucocorticoid exposure has been associated with a reduction in birth weight and postnatal alterations in glucose homeostasis and hypothalamic-pituitary-adrenal (HPA) axis function. The mechanisms underlying these responses are unknown, although changes in fetal hepatic development may play an important role. The fetal liver produces key regulators of fuel metabolism and of the developing HPA axis that are altered by glucocorticoids. The local availability of glucocorticoids is regulated, in part, by corticosteroid-binding protein (CBG), glucocorticoid receptors (GR) and by the enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD), but the effects of maternal glucocorticoid administration on the expression of these genes in the fetal liver are unknown. 11betaHSD1 is the predominant form of this enzyme present in the liver and is responsible for the conversion of cortisone to cortisol. To determine if prenatal glucocorticoid exposure alters fetal hepatic regulation of CBG, 11betaHSD1 and GRs, we treated pregnant ewes with betamethasone (0.5 mg/kg) intramuscularly at 104, 111 and 118 days of gestation (term 150 days). Animals were killed at 125 or 146 days of gestation. Maternal betamethasone administration did not alter mean cord plasma glucose but significantly decreased cord plasma insulin levels (P<0.05) at 125 days of gestation. At 146 days of gestation, cord plasma glucose levels were significantly increased without alterations in insulin levels following maternal betamethasone treatment (P<0.05). Maternal betamethasone administration resulted in a significant increase in fetal hepatic 11betaHSD1 mRNA and protein levels at 125 days of gestation (P<0.05). CBG mRNA levels were significantly elevated over control at 125 days although levels of CBG protein were not significantly different. GR protein levels were not statistically different at either 125 or 146 days of gestation following glucocorticoid administration. These data suggest that prenatal betamethasone exposure in the ovine fetus results in alterations in cord glucose and insulin levels as well as alterations in hepatic 11betaHSD1 mRNA and protein expression. These changes in 11betaHSD1 increase the potential to generate local cortisol from circulating cortisone. We speculate that this could affect expression of glucocorticoid-dependent hepatic enzymes involved with the regulation of glucose production and HPA responsiveness.