Finally, maternal restriction of proteins, folate, methionine, and B vitamins during periconceptional period, gestation, and lactation increases the risk of lower weight at birth and increased central adiposity, fatty liver, blood pressure dysregulation, and myocardium hypertrophy in offspring as consequences of an altered DNA methylation Wu, ; Gueant et al. In particular, in an experimental mouse model, it has been demonstrated that a low-protein diet in pregnant mothers during a precocious gestational period, such as the preimplantation period, determines cardiovascular and metabolic diseases in offspring adults, through histone modifications of the Gata6 gene Sun et al.
A last consideration must be made regarding alcohol consumption during pregnancy. Hormones play a pivotal role through life in the regulation of fat, carbohydrate, and protein metabolism, and hormonal alterations of these processes are likely to impair metabolism and fat storage. Many natural and synthetic chemicals, found in the environment, contaminating food through food chain, possess hormonal activity.
These compounds, known as endocrine disrupters EDCs , are exogenous substances endowed with the capacity to alter the function s of the endocrine system and thus represent a serious risk to health both in humans and animals International Programme for Chemical Safety Li et al. Endocrine-disrupting chemicals belong to a heterogeneous class of chemicals dispersed in the environment. Several chemicals have comprised obesogens with estrogen properties, such as tributyltin TBT , generally used as biocide in antifouling paints applied to the hulls of ships; diethylstilbestrol, used to enhance fertility in farm animals; dichlorodiphenyltrichloroethane DDT and its breakdown product dichlorodiphenyl-dichloroethylene, used as insecticide; bisphenol A BPA , used in the manufacture of plastics; polybrominated diphenyl ethers and 4-nonylphenol, used for industrial proceedings; parabens, generally used as antimicrobial agents for the preservation of personal care products, foods, pharmaceutical products, and paper products; phytoestrogens, naturally produced by plants and assumed by humans via ingestion of edible plants Darbre, Moreover, many studies highlight that such effects can also be inherited through future generations even in the absence of additional exposure.
Transgenerational studies have revealed that TBT exposure of pregnant mice generates offspring of both genders with larger fat deposits, and this phenotype is inherited up to the third generation, even without further TBT exposure Chamorro-Garcia et al.
Other heritable traits toward obesity in rodents have been observed after exposure to BPA, phthalates Manikkam et al. Obesogens induce weight gain by increasing both the number and size of adipocytes, by altering the endocrine pathways responsible for adipose tissue development, by changing lipid homeostasis, and by promoting adipogenesis and lipid accumulation.
These events might occur through multiple mechanisms, such as interference with Peroxisome Proliferator-Activated Receptors PPARs and steroid receptors, alteration in fat cell recruitment, shifting of appetite, satiety, and food preferences Darbre, In particular, it is thought that early life exposure to EDCs might influence epigenetic programming of obesity via the capacity of these compounds to bind nuclear receptors and other transcription factors and thus to influence consequent gene expression.
For example, nuclear receptors, such as steroid receptors, can directly bind hormone-response elements present in the DNA upon activation by single or multiple ligands. Furthermore, they are able to recruit chromatin-modifying complexes including methyltransferases and acetyltransferases, which directly alter epigenetic marks involved in the regulation of target genes Ozgyin et al. Therefore, EDCs can change the local chromatin state as well as modulate the expression of DNA or histone methyltransferases by activating or inhibiting nuclear receptors and other transcription factors Rissman and Adli, Among EDCs, phytoestrogens represent a diverse group of natural chemicals with structural and functional similarities to endogenously produced mammalian estrogens, able to bind the nuclear receptors and thus endowed of significant estrogen receptor ER modulatory activities.
They are present in fruits, vegetables, and whole grains commonly consumed by humans, as well as in many dietary supplements, and are widely marketed as natural alternatives to estrogen replacement therapy. Recently, the nutritional changes leading to the inclusion of soy-derived products into human diets have consistently enhanced the exposure to these compounds.
In fact, soy products are nowadays important components of food products consumed in both adult and infant human diets McCarver G et al. Phytoestrogens are polyphenolic structures classified as flavonoids or isoflavones , coumestans, lignans, and stilbenes, with isoflavones representing major compounds in dietary sources Rietjens et al. Various beneficial health effects have been ascribed to these compounds including cardiovascular diseases, obesity, metabolic syndrome, and type 2 diabetes, as well as brain function disorders and some types of cancer Guerrero-Bosagna and Skinner, Phytoestrogens exert their potential health effects by different ways.
Although the main mode of action relies on their binding to ER, several other pathways such as rapid nongenomic cellular response, antioxidant action, tyrosine kinase inhibition, PPAR-mediated action, and binding to nonclassic ER gp or aryl hydrocarbon receptor AHR have been largely described Guerrero-Bosagna and Skinner, Compelling evidence suggests that epigenetic modifications link environmental insults occurring during development to disease susceptibility in the adult life.
In this regard, the capacity of phytoestrogens to induce epigenetic effects has been described, in particular for the soy isoflavone genistein and to a lesser extent for daidzein and its microbial metabolite equol Guerrero-Bosagna et al. A direct epigenetic effect of isoflavones was initially demonstrated upon exposure of newborn mice to coumestrol and equol that lead to increased methylation and subsequent inhibition of the proto-oncogene H-ras Lyn-Cook et al.
Furthermore, consumption of genistein was reported to alter DNA methylation pathways in mice Day et al. In addition to direct effects, evidence has been achieved on the capacity of phytoestrogens to affect offspring methylation patterns as a result of maternal exposure.
In this regard, dietary supplementation of pregnant mice with genistein altered coat color and protected A vy mouse offspring from obesity development by modifying the epigenome of the fetus Dolinoy et al.
Several studies have been carried out to assess the obesity-promoting or obesity-protective effect of maternal supplementation with phytoestrogens on the offspring. In this regard, it is of interest that sex differences in human amniotic fluid levels of daidzein and genistein, with significantly higher concentrations among the female fetuses, have been reported Jarrel et al.
Likewise, genistein pharmacokinetics are faster in male rather than female rats Sikker et al. Studies assessing the effects of in utero exposure to phytoestrogens in different preparations genistein as supplement to standard diet, isoflavone-rich diet, soy protein—based diet and for different periods after birth yielded contrasting results.
Whereas some studies reported that in utero exposure results in a lower weight at birth Cederroth et al. Likewise, more than a decade ago, Ruhlen and colleagues Ruhlen et al. Predisposition to diet-induced obesity as a consequence of prenatal following prenatal nutrient restriction has been reported to be gender related, with males more affected than females, as well as age at pubertal development girls earlier than boys Rubin et al. Regardless of the effect induced in the offspring by in utero exposure to phytoestrogens, they appeared to be stronger in the male progeny with respect to females.
Obesity and NCDs are increasing burning health problems that greatly affect worldwide population. Several factors are claimed to play a role in the development and persistence of these metabolic chronic disorders through life, such as altered diet and sedentary life.
Interestingly, in the last decades, several studies have pointed out the importance of perturbance during the early phases of life in the increased number of metabolic chronic disorders. In particular, altered diet and exposure to specific chemicals through food chain appear to play a pivotal role. Further studies, however, are needed to fully characterize and confirm this hypothesis in order to apply preventive actions to successfully approach this global health problem.
All authors have equally contributed in writing, revising, and finalizing the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Barker, D. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. Weight in infancy and death from ischemic heart disease. Bayol, S. Block, T, El-Osta, A. Epigenetic programming, early life nutrition and the risk of metabolic disease.
Atherosclerosis , 31— Cao, J. Soy but not bisphenol A BPA or the phytoestrogen genistin alters developmental weight gain and food intake in pregnant rats and their offspring. Catalano, P. The impact of gestational diabetes and maternal obesity on the mother and her offspring. Health Dis. Cederroth, C. A phytoestrogen-rich diet increases energy expenditure and decreases adiposity in mice.
Health Perspect. Chamorro-Garcia, R. Transgenerational inheritance of increased fat depot size, stem cell reprogramming, and hepatic steatosis elicited by prenatal exposure to the obesogen tributyltin in mice.
Chen, H. Maternal and postnatal overnutrition differentially impact appetite regulators and fuel metabolism. Endocrinology , — Darbre, P. Endocrine Disruption and Human Health. New York: Academic. Google Scholar. Endocrine disruptors and obesity. Day, J. Genistein alters methylation patterns in mice. Dobson, C. Chronic prenatal ethanol exposure increases adiposity and disrupts pancreatic morphology in adult guinea pig offspring.
Diabetes 2, e Dolinoy, D. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Eggersdorfer, M. Emerging nutrition gaps in a world of affluence—micronutrient intake and status globally. Figueira, I. Interventions for age-related diseases: shifting the paradigm. Ageing Dev. Grun, F. Environmental obesogens: organotins and endocrine disruption via nuclear receptor signalling.
Endocrinoloogy S6 , S50—S Gueant, J. Folate and fetal programming: a play in epigenomics? Trends Endocrinol.
Differential methylation in glucoregulatory genes of offspring born before vs. Guerrero-Bosagna, C. Epigenetic transgenerational effects of endocrine disruptors on male reproduction. Steroid Biochem. Epigenetic and phenotypic changes result from a continuous pre- and post-natal dietary exposure to phytoestrogens in an experimental population of mice. Arachidonic acid is released from cell membrane phospholipids by the action of phospholipase A2 and is converted to eicosanoids by COX or lipoxygenases.
These bioactive lipids, like prostaglandin E 2 PGE 2 , are secreted from cells where they act locally on plasma membrane-associated G-protein linked receptors GPR on target cells Figure These receptors control intracellular second messenger levels, like cAMP and free calcium, which, in turn, control numerous cellular processes through changes in protein phosphorylation.
Consequently, eicosanoid binding to GPR rapidly stimulates protein phosphorylation, leading to changes in metabolism, cytokine production, and production of adhesion molecules. Essential fatty acid deficiency is associated with a decline in arachidonic acid phospholipid content and the production of eicosanoids.
Eicosanoid production is associated with inflammatory responses and host defense. Interestingly, certain dietary fats, particularly the highly unsaturated n-3 fatty acid, are poor substrates for COX. This leads to a decline in eicosanoid production as well as a diminished inflammatory response. A second route for fatty acids to affect gene expression is through the regulation of a family of nuclear receptors called peroxisome proliferator activated receptors, PPAR.
Four PPAR subtypes have been identified i. These are members of the steroid superfamily of nuclear receptors that bind DNA motifs, called peroxisome proliferator regulatory element PPRE. PPARs were first identified as the molecular targets for peroxisome proliferators. Peroxisome proliferators are. Eicosanoid regulation of gene expression. However, certain drugs have as their molecular targets specific PPARs.
PPARs have been associated with the regulation of expression of genes involved in nearly all facets of fatty acid metabolism i.
In addition, these receptors are reported to participate in inflammation as well as cell growth and differentiation. This accelerates the rate of adipocyte differentiation and increases insulin sensitivity of the adipose depot. While PPARs have attracted considerable attention as molecular targets for fatty acid regulation of gene expression, it appears that these factors are not the sole targets for fatty acid effects on the genome.
Several reports appearing in the last 2 years have suggested that SREBP1c plays a major role in both hepatic and adipocyte lipogenesis, i. Because SREBP1c is a key factor in the transcription of several lipogenic genes, its decline leads to a reduction in lipogenic gene expression and de novo lipogenesis. Clearly, fatty acid effects on cell function go far beyond serving as sources of energy and structural components of membranes. Fatty acids enter cells, undergo metabolism, and can serve as ligands for both membrane and nuclear receptors.
Alternatively, fatty acids or their metabolites can regulate the nuclear abundance of SREBP1c, a key transcription factor in the synthesis of fatty acids and triacylglycerols. I have highlighted some of the recent advances in macronutrient regulation of gene expression, and I have provided the detail needed to understand the roles and effects of these nutrients. In addition to their role as an energy source, as structure elements or precursors to signaling molecules, macronutrients clearly have profound effects on gene expression.
This nutrient-genome interaction interfaces with other signaling networks to allow integration of cellular control between dietary intake and internal regulatory mechanisms.
It reflects an adaptive response, allowing cells to adjust to changes in the type, quantity, and duration of nutrients ingested for efficient growth. While pharmacologic agents have been developed to control cholesterol synthesis i. This understanding and ability to design agents to modify metabolism will have benefit to human health, as well as animal production and health.
This could affect both mother and fetus, putting them at higher risk of metabolic conditions, such as type 2 diabetes, later in life. Adjusting nutrition early in pregnancy—or even before conceiving—could potentially help stop or slow down that process.
In a study conducted at the German Research Center for Environmental Health and published in Nature Genetics in , genetically identical mice that consumed a high-fat diet were more likely to produce obese offspring with impaired glucose tolerance, an early sign of type 2 diabetes. Nor are epigenetic impacts limited to obesity and diabetes. A study in Science conducted by the University of Cambridge revealed that undernourished pregnant mice bore offspring with glucose intolerance and pancreatic issues.
He recently contributed to a paper in Biological Psychiatry in February on the connection between maternal infection in pregnant mice and the risk of neurodevelopmental disorders in their offspring. Even so, Szyf says that drawing clear relationships between epigenetic signals and disease is difficult. One complication is the sheer complexity of the epigenome. Along with diet, exercise, environment, and mood may effect gene expression. In a study published in Epigenetics , scientists at the Karolinska Institute in Sweden asked 23 men and women to bicycle using only one leg for 45 minutes, four times a week over three months.
In comparing muscle biopsies before and after the experiment, scientists found that, in the exercised muscle, new patterns had developed on genes associated with insulin response, inflammation and energy metabolism.
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