It is well established that early life environmental signals, including nutrition, set the stage for long-term health and disease risk – effects that span multiple generations. This relationship begins early, in the periconceptional period and extends into embryonic, fetal and early infant phases of life. Now known as the Developmental Origins of Health and Disease (DOHaD), this concept describes the adaptations that a developing organism makes in response to early life cues, resulting in adjustments in homeostatic systems that may prove maladaptive in postnatal life, leading to an increased risk of chronic disease and/or the inheritance of risk factors across generations. Reproductive maturation and function is similarly influenced by early life events. This should not be surprising, since primordial germ cells are established early in life and thus vulnerable to early life adversity. A multitude of ‘modifying’ cues inducing developmental adaptations have been identified that result in changes in reproductive development and impairments in reproductive function. Many types of nutritional challenges including caloric restriction, macronutrient excess and micronutrient insufficiencies have been shown to induce early life adaptations that produce long-term reproductive dysfunction. Many pathways have been suggested to underpin these associations, including epigenetic reprogramming of germ cells. While the mechanisms still remain to be fully investigated, it is clear that a lifecourse approach to understanding lifetime reproductive function is necessary. Furthermore, investigations of the impacts of early life adversity must be extended to include the paternal environment, especially in epidemiological and clinical studies of offspring reproductive function.
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Patrycja A Jazwiec and Deborah M Sloboda
Miguel A Velazquez, Tom P Fleming and Adam J Watkins
The concept emerging from Professor David Barker’s seminal research on the developmental origins of later-life disease has progressed in many directions since it was first published. One critical question being when during gestation might environment alter the developmental programme with such enduring consequences. Here, we review the growing consensus from clinical and animal research that the period around conception, embracing gamete maturation and early embryogenesis might be the most vulnerable period. We focus on four types of environmental exposure shown to modify periconceptional reproduction and offspring development and health: maternal overnutrition and obesity; maternal undernutrition; paternal diet and health; and assisted reproductive technology. These conditions may act through diverse epigenetic, cellular and physiological mechanisms to alter gene expression and cellular signalling and function in the conceptus affecting offspring growth and metabolism leading to increased risk for cardiometabolic and neurological disease in later life.
Trassanee Chatmethakul and Robert D Roghair
Consistent with the paradigm shifting observations of David Barker and colleagues that revealed a powerful relationship between decreased weight through 2 years of age and adult disease, intrauterine growth restriction (IUGR) and preterm birth are independent risk factors for the development of subsequent hypertension. Animal models have been indispensable in defining the mechanisms responsible for these associations and the potential targets for therapeutic intervention. Among the modifiable risk factors, micronutrient deficiency, physical immobility, exaggerated stress hormone exposure and deficient trophic hormone production are leading candidates for targeted therapies. With the strong inverse relationship seen between gestational age at delivery and the risk of hypertension in adulthood trumping all other major cardiovascular risk factors, improvements in neonatal care are required. Unfortunately, therapeutic breakthroughs have not kept pace with rapidly improving perinatal survival, and groundbreaking bench-to-bedside studies are urgently needed to mitigate and ultimately prevent the tsunami of prematurity-related adult cardiovascular disease that may be on the horizon. This review highlights our current understanding of the developmental origins of hypertension and draws attention to the importance of increasing the availability of lactation consultants, nutritionists, pharmacists and physical therapists as critical allies in the battle that IUGR or premature infants are waging not just for survival but also for their future cardiometabolic health.
Clare M Reynolds and Mark H Vickers
Alterations in the environment during critical periods of development, including altered maternal nutrition, can increase the risk for the development of a range of metabolic, cardiovascular and reproductive disorders in offspring in adult life. Following the original epidemiological observations of David Barker that linked perturbed fetal growth to adult disease, a wide range of experimental animal models have provided empirical support for the developmental programming hypothesis. Although the mechanisms remain poorly defined, adipose tissue has been highlighted as playing a key role in the development of many disorders that manifest in later life. In particular, adipokines, including leptin and adiponectin, primarily secreted by adipose tissue, have now been shown to be important mediators of processes underpinning several phenotypic features associated with developmental programming including obesity, insulin sensitivity and reproductive disorders. Moreover, manipulation of adipokines in early life has provided for potential strategies to ameliorate or reverse the adverse sequalae that are associated with aberrant programming and provided insight into some of the mechanisms involved in the development of chronic disease across the lifecourse.
Natasha N Chattergoon
The fetal heart undergoes its own growth and maturation stages all while supplying blood and nutrients to the growing fetus and its organs. Immature contractile cardiomyocytes proliferate to rapidly increase and establish cardiomyocyte endowment in the perinatal period. Maturational changes in cellular maturation, size and biochemical capabilities occur, and require, a changing hormonal environment as the fetus prepares itself for the transition to extrauterine life. Thyroid hormone has long been known to be important for neuronal development, but also for fetal size and survival. Fetal circulating 3,5,3′-triiodothyronine (T3) levels surge near term in mammals and are responsible for maturation of several organ systems, including the heart. Growth factors like insulin-like growth factor-1 stimulate proliferation of fetal cardiomyocytes, while thyroid hormone has been shown to inhibit proliferation and drive maturation of the cells. Several cell signaling pathways appear to be involved in this complicated and coordinated process. The aim of this review was to discuss the foundational studies of thyroid hormone physiology and the mechanisms responsible for its actions as we speculate on potential fetal programming effects for cardiovascular health.
Carsten T Herz and Florian W Kiefer
In the midst of an obesity epidemic, the promotion of brown adipose tissue (BAT) function and the browning of white adipose tissue (WAT) have emerged as promising therapeutic targets to increase energy expenditure and counteract weight gain. Despite the fact that the thermogenic potential of bone fide BAT in rodents is several orders of magnitudes higher than white fat containing brite/beige adipocytes, WAT browning represents a particularly intriguing concept in humans given the extreme amount of excess WAT in obese individuals. In addition, the clear distinction between classic brown and beige fat that has been proposed in mice does not exist in humans. In fact, studies of human BAT biopsies found controversial results suggesting both classic brown and beige characteristics. Irrespective of the true ‘color’, accumulating evidence suggests the induction of thermogenic adipocytes in human WAT depots in response to specific stimuli, highlighting that WAT browning may occur in both, mice and humans. These observations also emphasize the great plasticity of human fat depots and raise important questions about the metabolic properties of thermogenically active adipose tissue in humans and the potential therapeutic implications. We will first review the cellular and molecular aspects of selected adipose tissue browning concepts that have been identified in mouse models with emphasis on neuronal factors, the microbiome, immune cells and several hormones. We will also summarize the evidence for adipose tissue browning in humans including some experimental pharmacologic approaches.
E J Agnew, A Garcia-Burgos, R V Richardson, H Manos, A J W Thomson, K Sooy, G Just, N Z M Homer, C M Moran, P J Brunton, G A Gray and K E Chapman
Endogenous glucocorticoid action is important in the structural and functional maturation of the fetal heart. In fetal mice, although glucocorticoid concentrations are extremely low before E14.5, glucocorticoid receptor (GR) is expressed in the heart from E10.5. To investigate whether activation of cardiac GR prior to E14.5 induces precocious fetal heart maturation, we administered dexamethasone in the drinking water of pregnant dams from E12.5 to E15.5. To test the direct effects of glucocorticoids upon the cardiovascular system we used SMGRKO mice, with Sm22-Cre-mediated disruption of GR in cardiomyocytes and vascular smooth muscle. Contrary to expectations, echocardiography showed no advancement of functional maturation of the fetal heart. Moreover, litter size was decreased 2 days following cessation of antenatal glucocorticoid exposure, irrespective of fetal genotype. The myocardial performance index and E/A wave ratio, markers of fetal heart maturation, were not significantly affected by dexamethasone treatment in either genotype. Dexamethasone treatment transiently decreased the myocardial deceleration index (MDI; a marker of diastolic function), in control fetuses at E15.5, with recovery by E17.5, 2 days after cessation of treatment. MDI was lower in SMGRKO than in control fetuses and was unaffected by dexamethasone. The transient decrease in MDI was associated with repression of cardiac GR in control fetuses following dexamethasone treatment. Measurement of glucocorticoid levels in fetal tissue and hypothalamic corticotropin-releasing hormone (Crh) mRNA levels suggest complex and differential effects of dexamethasone treatment upon the hypothalamic–pituitary–adrenal axis between genotypes. These data suggest potentially detrimental and direct effects of antenatal glucocorticoid treatment upon fetal heart function.
Madeleine R Di Natale, Alita Soch, Ilvana Ziko, Simone N De Luca, Sarah J Spencer and Luba Sominsky
Chronic stress is a known suppressor of female reproductive function. However, attempts to isolate single causal links between stress and reproductive dysfunction have not yet been successful due to their multi-faceted aetiologies. The gut-derived hormone ghrelin regulates stress and reproductive function and may therefore be pivotal in the neuroendocrine integration of the hypothalamic–pituitary–adrenal (HPA) and –gonadal (HPG) axes. Here, we hypothesised that chronic stress disrupts ovarian follicle maturation and that this effect is mediated by a stress-induced increase in acyl ghrelin and activation of the growth hormone secretatogue receptor (GHSR). We gave C57BL/6J female mice 30 min daily chronic predator stress for 4 weeks, or no stress, and gave them daily GHSR antagonist (d-Lys3-GHRP-6) or saline. Exposure to chronic predator stress reduced circulating corticosterone, elevated acyl ghrelin levels and led to significantly depleted primordial follicle numbers. GHSR antagonism stress-dependently altered the expression of genes regulating ovarian responsiveness to gonadotropins and was able to attenuate the stress-induced depletion of primordial follicles. These findings suggest that chronic stress-induced elevations of acyl ghrelin may be detrimental for ovarian follicle maturation.
Sabashini K Ramchand, Yee-Ming Cheung, Belinda Yeo and Mathis Grossmann
In women with oestrogen receptor (ER)-positive early breast cancer, oestradiol is important for breast cancer development and progression. Endocrine therapy prevents the deleterious effects of oestradiol in breast tissue by systemically depleting oestradiol concentration (aromatase inhibitors) or preventing its local action in breast tissue (selective oestrogen receptor modulators i.e. tamoxifen), thereby improving oncological outcomes. Use of aromatase inhibitors in postmenopausal women and ovarian function suppression with either tamoxifen or aromatase inhibition in premenopausal women, consequent to systemic oestradiol depletion, exerts detrimental effects on skeletal health. The oestradiol-deficient state causes increased bone remodelling and a negative bone balance. This results in bone loss, microstructural deterioration and bone fragility predisposing to fractures. Similar effects are also seen with tamoxifen in premenopausal women. In contrast, use of tamoxifen in postmenopausal women appears to exert protective effects on bone but studies on fracture risk are inconclusive. The longevity of women with ER-positive breast cancer treated with adjuvant endocrine therapy emphasises the need to mitigate the adverse skeletal effects of these therapies in order to maximise benefit. In general, fractures are associated with increased morbidity, mortality and are a high socioeconomic burden. Whilst the efficacy of antiresorptive therapy in preventing bone mineral density loss in postmenopausal women has been established, further clinical trial evidence is required to provide guidance regarding fracture risk reduction, when to initiate and stop treatment, choice of agent and optimal management of bone health in premenopausal women receiving endocrine therapy. In addition, potential oncological benefits of antiresorptive therapies will also need to be considered.
Kumiko Taguchi, Haruka Narimatsu, Takayuki Matsumoto and Tsuneo Kobayashi
Endothelial dysfunction is a hallmark of diabetic vascular complications. Microparticles (MPs) are small vesicles shed from the surface of blood and vascular cells that act as stimuli and during apoptosis. Circulating MPs of diabetic rats have been shown to induce endothelial dysfunction. However, the underlying mechanisms require further study. In this study, we investigated how MPs from diabetic mice affect endothelial function. MPs were collected from streptozotocin-induced diabetic mice and Institute of Cancer Research (ICR) mice as controls. The levels of MPs were assessed and characterized by flow cytometry, enzyme-linked immunosorbent assay and dot blotting. Normal mice aortas were incubated with MPs and expressions of enzymes and vascular relaxation were analyzed. We found that (1) circulating MPs level increased in diabetic mice; (2) MPs impaired endothelial-dependent relaxation in mice aorta, but diabetic mice-derived MPs (diabetes mellitus (DM) MPs) were easier to attach to the endothelial cells than were control MPs; (3) DM MPs had more extracellular signal-regulated kinase (ERK)1/2 than did control mice-derived MPs, and they induced ERK1/2 activation in mice aortas; (4) DM MPs decreased endothelial nitric oxide synthase (eNOS) in mice aortas, and eNOS was emitted from endothelial cells to blood in the shape of endothelial MPs. DM MPs significantly altered endothelial function by activation of ERK1/2, which might provide a therapeutic target for diabetic vascular complications.