RESUMO
A new definition of sexual dimorphism is required. The divergent biology of the sexes is still largely ignored, overshadowed by sociocultural considerations and confined to its hormonal organizational and activational effects, while the genes unequally expressed by the sex chromosomes play an important role much earlier, after conception, to set the stage and throughout life. These different components have independent and parallel effects that can interact in a synergistic or antagonistic manner on differentiation and response processes to trigger or erase sex-specific differences. The epigenetic marks and machinery represent the perfect tools to keep the memory of which sex is ours from the very beginning of life. Within the context of the developmental origin of adult health and diseases (DOHaD), owing to their flexibility to the environment, epigenetic marks also represent a support to archive the effects of environments during development, according to the sex of the parent, in a sex-specific mode. In all tissues, including gonads and brain, different trajectories of genes and pathways are used at the basal levels and to modulate/dictate responses according to sex and gender. It is urgent to emphasize the need to take into consideration this new knowledge and to apply less sex-biased approaches in research, medicine and society, to enhance women health and well-being. A critical review and realization of gender-specific social constraints, an indeniably but slowly on-going process, should allow us to "set free our sex biology" while detracting the delusion of hierarchy of the complex mechanisms involved.
Assuntos
Caracteres Sexuais , Diferenciação Sexual/fisiologia , Adulto , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Desenvolvimento Embrionário/genética , Desenvolvimento Embrionário/fisiologia , Epigênese Genética/fisiologia , Feminino , Interação Gene-Ambiente , História do Século XXI , Humanos , Masculino , Modelos Biológicos , Gravidez , Diferenciação Sexual/genética , Fatores SocioeconômicosRESUMO
PURPOSE OF REVIEW: The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli, which result into modified gene expression patterns and phenotypes later in life, is a topic of considerable interest. This review focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, positions and functions of relevant epigenetic marks. RECENT FINDINGS: Animal models, including mice, rats, sheep, pigs and rabbits, remain a vital tool for studying the influence of early nutritional events on adult health and disease. Most epigenetic studies have addressed the long-term effects on a small number of epigenetic marks, at the global or individual gene level, of environmental stressors in humans and animal models. They have demonstrated the existence of a self-propagating epigenetic cycle. In parallel, an increasing number of studies based on high-throughput technologies and focusing on humans and mice have revealed additional complexity in epigenetic processes, by highlighting the importance of crosstalk between the different epigenetic marks. In recent months, a number of studies focusing on the developmental origin of health and disease and metabolic programming have identified links between early nutrition, epigenetic processes and long-term illness. SUMMARY: Despite recent progress, we are still far from understanding how, when and where environmental stressors disturb key epigenetic mechanisms. Thus, identifying the original key marks and their changes throughout development, during an individual's lifetime or over several generations, remains a challenging issue.
Assuntos
Epigênese Genética , Desenvolvimento Fetal/genética , Regulação da Expressão Gênica no Desenvolvimento , Expressão Gênica , Fenômenos Fisiológicos da Nutrição do Lactente/genética , Fenômenos Fisiológicos da Nutrição Pré-Natal/genética , Adulto , Animais , Metilação de DNA , Feminino , Predisposição Genética para Doença , Histonas , Humanos , Lactente , Fenótipo , GravidezRESUMO
Intrauterine growth restriction (IUGR) may be accompanied by inadequate thermoregulation, especially in piglets that are not considered to possess any brown adipose tissue (BAT) and are thus entirely dependent on shivering thermogenesis in order to maintain body temperature after birth. Leptin can stimulate heat production by promoting non-shivering thermogenesis in BAT, but whether this response occurs in piglets is unknown. Newborn female piglets that were characterised as showing IUGR (mean birth weight of approximately 0.98âkg) were therefore administered injections of either saline or leptin once a day for the first 5 days of neonatal life. The dose of leptin was 0.5âmg/kg, which is sufficient to increase plasma leptin by approximately tenfold and on the day of birth induced a rapid increase in body temperature to values similar to those of normal-sized 'control' piglets (mean birth weight of â¼1.47âkg). Perirenal adipose tissue was then sampled from all offspring at 21 days of age and the presence of the BAT-specific uncoupling protein 1 (UCP1) was determined by immunohistochemistry and immunoblotting. UCP1 was clearly detectable in all samples analysed and its abundance was significantly reduced in the IUGR piglets that had received saline compared with controls, but was raised to the same amount as in controls in those IUGR females given leptin. There were no differences in gene expression between primary markers of brown and white adipose tissues between groups. In conclusion, piglets possess BAT that when stimulated exogenously by leptin can promote increased body temperature.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Canais Iônicos/metabolismo , Leptina/farmacologia , Proteínas Mitocondriais/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Animais Recém-Nascidos , Temperatura Corporal/efeitos dos fármacos , Esquema de Medicação , Feminino , Retardo do Crescimento Fetal/metabolismo , Immunoblotting , Imuno-Histoquímica , Injeções Intramusculares , Leptina/administração & dosagem , Suínos , Termogênese/efeitos dos fármacos , Proteína Desacopladora 1RESUMO
According to the developmental origins of health and diseases (DOHaD), and in line with the findings of many studies, obesity during pregnancy is clearly a threat to the health and well-being of the offspring, later in adulthood. We previously showed that 20% of male and female inbred mice can cope with the obesogenic effects of a high-fat diet (HFD) for 20 weeks after weaning, remaining lean. However the feeding of a control diet (CD) to DIO mice during the periconceptional/gestation/lactation period led to a pronounced sex-specific shift (17% to 43%) from susceptibility to resistance to HFD, in the female offspring only. Our aim in this study was to determine how, in the context of maternal obesity and T2D, a CD could increase resistance on female fetuses. Transcriptional analyses were carried out with a custom-built mouse liver microarray and by quantitative RT-PCR for muscle and adipose tissue. Both global DNA methylation and levels of pertinent histone marks were assessed by LUMA and western blotting, and the expression of 15 relevant genes encoding chromatin-modifying enzymes was analyzed in tissues presenting global epigenetic changes. Resistance was associated with an enhancement of hepatic pathways protecting against steatosis, the unexpected upregulation of neurotransmission-related genes and the modulation of a vast imprinted gene network. Adipose tissue displayed a pronounced dysregulation of gene expression, with an upregulation of genes involved in lipid storage and adipocyte hypertrophy or hyperplasia in obese mice born to lean and obese mothers, respectively. Global DNA methylation, several histone marks and key epigenetic regulators were also altered. Whether they were themselves lean (resistant) or obese (sensitive), the offspring of lean and obese mice clearly differed in terms of several metabolic features and epigenetic marks suggesting that the effects of a HFD depend on the leanness or obesity of the mother.
Assuntos
Dieta , Epigênese Genética , Perfilação da Expressão Gênica , Obesidade/genética , Transcrição Gênica , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Diabetes Mellitus Experimental/genética , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes/genética , Impressão Genômica/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Fenótipo , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transmissão Sináptica/genéticaRESUMO
Babies with intra-uterine growth restriction (IUGR) are at increased risk for experiencing negative neonatal outcomes due to their general developmental delay. The present study aimed to investigate the effects of a short postnatal leptin supply on the growth, structure, and functionality of several organs at weaning. IUGR piglets were injected from day 0 to day 5 with either 0.5 mg/kg/d leptin (IUGRLep) or saline (IUGRSal) and euthanized at day 21. Their organs were collected, weighed, and sampled for histological, biochemical, and immunohistochemical analyses. Leptin induced an increase in body weight and the relative weights of the liver, spleen, pancreas, kidneys, and small intestine without any changes in triglycerides, glucose and cholesterol levels. Notable structural and functional changes occurred in the ovaries, pancreas, and secondary lymphoid organs. The ovaries of IUGRLep piglets contained less oogonia but more oocytes enclosed in primordial and growing follicles than the ovaries of IUGRSal piglets, and FOXO3A staining grade was higher in the germ cells of IUGRLep piglets. Within the exocrine parenchyma of the pancreas, IUGRLep piglets presented a high rate of apoptotic cells associated with a higher trypsin activity. In the spleen and the Peyer's patches, B lymphocyte follicles were much larger in IUGRLep piglets than in IUGRSal piglets. Moreover, IUGRLep piglets showed numerous CD79(+) cells in well-differentiated follicle structures, suggesting a more mature immune system. This study highlights a new role for leptin in general developmental processes and may provide new insight into IUGR pathology.
Assuntos
Retardo do Crescimento Fetal/metabolismo , Gônadas/efeitos dos fármacos , Sistema Imunitário/efeitos dos fármacos , Leptina/farmacologia , Organogênese/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antígenos CD79/genética , Antígenos CD79/imunologia , Feminino , Retardo do Crescimento Fetal/imunologia , Retardo do Crescimento Fetal/patologia , Feto , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica no Desenvolvimento , Gônadas/crescimento & desenvolvimento , Gônadas/metabolismo , Humanos , Sistema Imunitário/crescimento & desenvolvimento , Sistema Imunitário/metabolismo , Recém-Nascido , Injeções Intramusculares , Fígado/efeitos dos fármacos , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Pâncreas/crescimento & desenvolvimento , Pâncreas/metabolismo , SuínosRESUMO
Males and females responses to gestational overnutrition set the stage for subsequent sex-specific differences in adult onset non communicable diseases. Placenta, as a widely recognized programming agent, contibutes to the underlying processes. According to our previous findings, a high-fat diet during gestation triggers sex-specific epigenetic alterations within CpG and throughout the genome, together with the deregulation of clusters of imprinted genes. We further investigated the impact of diet and sex on placental histology, transcriptomic and epigenetic signatures in mice. Both basal gene expression and response to maternal high-fat diet were sexually dimorphic in whole placentas. Numerous genes showed sexually dimorphic expression, but only 11 genes regardless of the diet. In line with the key role of genes belonging to the sex chromosomes, 3 of these genes were Y-specific and 3 were X-specific. Amongst all the genes that were differentially expressed under a high-fat diet, only 16 genes were consistently affected in both males and females. The differences were not only quantitative but remarkably qualitative. The biological functions and networks of genes dysregulated differed markedly between the sexes. Seven genes of the epigenetic machinery were dysregulated, due to effects of diet, sex or both, including the Y- and X-linked histone demethylase paralogues Kdm5c and Kdm5d, which could mark differently male and female epigenomes. The DNA methyltransferase cofactor Dnmt3l gene expression was affected, reminiscent of our previous observation of changes in global DNA methylation. Overall, this striking sexual dimorphism of programming trajectories impose a considerable revision of the current dietary interventions protocols.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Epigênese Genética , Expressão Gênica , Placenta/metabolismo , Efeitos Tardios da Exposição Pré-Natal/genética , Animais , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica , Histona Desmetilases , Masculino , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Oxirredutases N-Desmetilantes/genética , Oxirredutases N-Desmetilantes/metabolismo , Placenta/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fenômenos Fisiológicos da Nutrição Pré-Natal , Caracteres Sexuais , TranscriptomaRESUMO
The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli that result in modified gene expression patterns and phenotypes later in life, are a topic of considerable interest. This article focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, positions, and functions of epigenetic marks. Most epigenetic studies have addressed the long-term effects of environmental stressors on a small number of epigenetic marks, at the global or individual gene level, in humans and in animal models. In parallel, increasing numbers of studies based on high-throughput technologies are revealing additional complexity in epigenetic processes by highlighting the importance of crosstalk between different epigenetic marks in humans and mice. A number of studies focusing on metabolic programming and the developmental origin of health and disease have identified links between early nutrition, epigenetic processes, and long-term illness. The existence of a self-propagating epigenetic cycle has been shown. Moreover, recent studies have shown an obvious sexual dimorphism both for programming trajectories and in response to the same environmental insult. Despite recent progress, however, we are still far from understanding how, when, and where environmental stressors disturb key epigenetic mechanisms. Thus, the need to identify original key marks and monitor the changes they undergo throughout development, during an individual's lifetime, or over several generations remains a challenging issue.
Assuntos
Epigênese Genética , Desenvolvimento Fetal/genética , Animais , Cromatina/genética , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , Metilação de DNA , Exposição Ambiental/efeitos adversos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Hormônios Esteroides Gonadais/genética , Hormônios Esteroides Gonadais/metabolismo , Histonas/metabolismo , Humanos , Fígado/metabolismo , Masculino , Camundongos , Filogenia , Placenta/metabolismo , GravidezRESUMO
The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli, which result in modified gene expression patterns and phenotypes later in life, is a topic of considerable interest. This review focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, position and functions of epigenetic marks. Most epigenetic studies have addressed the long-term effects on a small number of epigenetic marks, at the global or individual gene level, of environmental stressors in humans and animal models. In parallel, increasing numbers of studies based on high-throughput technologies and focusing on humans and mice have revealed additional complexity in epigenetic processes, by highlighting the importance of crosstalk between the different epigenetic marks. A number of studies focusing on the developmental origin of health and disease and metabolic programming have identified links between early nutrition, epigenetic processes and long-term illness. The existence of a self-propagating epigenetic cycle has been demonstrated. Moreover, recent studies demonstrate an obvious sexual dimorphism both for programming trajectories and in response to the same environmental insult. Despite recent progress, we are still far from understanding how, when and where environmental stressors disturb key epigenetic mechanisms. Thus, identifying the original key marks and their changes throughout development during an individual's lifetime or over several generations remains a challenging issue.
RESUMO
The postnatal leptin surge, described particularly in rodents, has been demonstrated to be crucial for hypothalamic maturation and brain development. In the present study, the possible general effects of this hormone on maturation of numerous peripheral organs have been explored. To test this hypothesis, we used a leptin antagonist (L39A/D40A/F41A) to investigate the effects of the blockage of postnatal leptin action on neonatal growth and maturation of organs involved in metabolism regulation, reproduction and immunity. For that purpose, newborn female pups were subcutaneously injected from days 2-13 with either saline or leptin antagonist and sacrificed at weaning. Organs were submitted to histological and immunohistochemical analyses. Leptin antagonist treatment clearly impaired the maturation of pancreas, kidney, thymus and ovary. All these alterations, at the organ level, occurred without changes in the whole-body mass of the animals. Leptin antagonist treatment induced: (1) a reduction in b cell area and a concomitant increase of a cells in Langherans islets in the pancreas, (2) a reduction in the number of glomeruli and a persistence of immature glomeruli in kidney, (3) an increase in the thymic cortical layer thickness, reflecting an unmatured stage, (4) a drastic reduction of the pool of primordial follicles, in ovaries. All these results strongly argue for a crucial role of leptin for the achievement of organ maturation, opening new perspectives in the field of leptin physiology and organ development.
Assuntos
Leptina/metabolismo , Organogênese , Animais , Animais Recém-Nascidos , Animais Lactentes/crescimento & desenvolvimento , Feminino , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/crescimento & desenvolvimento , Rim/citologia , Rim/crescimento & desenvolvimento , Leptina/antagonistas & inibidores , Tamanho do Órgão , Especificidade de Órgãos , Ovário/citologia , Ovário/crescimento & desenvolvimento , Ratos , Ratos Wistar , Timo/citologia , Timo/crescimento & desenvolvimentoRESUMO
The phenotype of an individual is the result of complex interactions between genotype and current, past and ancestral environment leading to a lifelong remodelling of our epigenomes. The vast majority of common diseases, including atherosclerosis, diabetes, osteoporosis, asthma, neuropsychological and autoimmune diseases, which often take root in early development, display some degree of sex bias, very marked in some cases. This bias could be explained by the role of sex chromosomes, the different regulatory pathways underlying sexual development of most organs and finally, lifelong fluctuating impact of sex hormones. A substantial proportion of dimorphic genes expression might be under the control of sex-specific epigenetic marks. Environmental factors such as social behaviour, nutrition or chemical compounds can influence, in a gender-related manner, these flexible epigenetic marks during particular spatiotemporal windows of life. Thus, finely tuned developmental program aspects, for each sex, may be more sensitive to specific environmental challenges, particularly during developmental programming and gametogenesis, but also throughout the individual's life under the influence of sex steroid hormones and/or sex chromosomes. An unfavourable programming could thus lead to various defects and different susceptibility to diseases between males and females. Recent studies suggest that this epigenetic programming could be sometimes transmitted to subsequent generations in a sex-specific manner and lead to transgenerational effects (TGEs). This review summarizes the current understanding in the field of epigenetic programming and highlights the importance of studying both sexes in epidemiological protocols or dietary interventions both in humans and in experimental animal models.