Journal Information
Vol. 93. Issue 6.
Pages 551-559 (November - December 2017)
Visits
...
Vol. 93. Issue 6.
Pages 551-559 (November - December 2017)
Review article
Open Access
Obese fathers lead to an altered metabolism and obesity in their children in adulthood: review of experimental and human studies
Pais obesos levam a metabolismo alterado e obesidade em seus filhos na idade adulta: revisão de estudos experimentais e humanos
Visits
...
Fernanda Ornellas, Priscila V. Carapeto, Carlos A. Mandarim-de-Lacerda
Corresponding author
, Marcia B. Aguila
Universidade do Estado do Rio de Janeiro (UERJ), Centro Biomédico, Laboratório de Morfometria, Metabolismo e Doenças Cardiovasculares, Rio de Janeiro, RJ, Brazil
Article information
Abstract
Full Text
Bibliography
Download PDF
Statistics
Figures (1)
Abstract
Objective

To discuss the recent literature on paternal obesity, focusing on the possible mechanisms of transmission of the phenotypes from the father to the children.

Sources

A non-systematic review in the PubMed database found few publications in which paternal obesity was implicated in the adverse transmission of characteristics to offspring. Specific articles on epigenetics were also evaluated. As the subject is recent and still controversial, all articles were considered regardless of year of publication.

Summary of findings

Studies in humans and animals have established that paternal obesity impairs their hormones, metabolism, and sperm function, which can be transmitted to their offspring. In humans, paternal obesity results in insulin resistance/type 2 diabetes and increased levels of cortisol in umbilical cord blood, which increases the risk factors for cardiovascular disease. Notably, there is an association between body fat in parents and the prevalence of obesity in their daughters. In animals, paternal obesity led to offspring alterations on glucose-insulin homeostasis, hepatic lipogenesis, hypothalamus/feeding behavior, kidney of the offspring; it also impairs the reproductive potential of male offspring with sperm oxidative stress and mitochondrial dysfunction. An explanation for these observations (human and animal) is epigenetics, considered the primary tool for the transmission of phenotypes from the father to offspring, such as DNA methylation, histone modifications, and non-coding RNA.

Conclusions

Paternal obesity can induce programmed phenotypes in offspring through epigenetics. Therefore, it can be considered a public health problem, affecting the children's future life.

Keywords:
Paternal obesity
Programming
Obese child
Chronic diseases programming
Epigenetics
Resumo
Objetivo

Discutir a literatura recente sobre obesidade paterna, focalizando os possíveis mecanismos de transmissão dos fenótipos do pai para os filhos.

Fontes

Uma revisão não-sistemática no banco de dados PubMed encontrou poucas publicações com obesidade paterna implicada com a transmissão adversa das características à prole. Artigos específicos sobre epigenética também foram avaliados. Como o assunto é recente e ainda controverso, todos os trabalhos foram considerados independentemente do ano de publicação.

Resumo dos achados

Estudos em seres humanos e animais estabeleceram que a obesidade do pai prejudica seus hormônios, metabolismo e função espermática, que pode ser transmitida à prole. Em humanos, a obesidade paterna resulta em resistência à insulina/diabetes tipo 2 e aumento do nível de cortisol no sangue do cordão umbilical, que aumenta os fatores de risco para doença cardiovascular. Notavelmente, existe associação entre a gordura corporal nos pais e a prevalência de obesidade em suas filhas. Em animais, pais obesos condicionam, na prole, a homeostase glicose-insulina, lipogênese hepática, hipotálamo/comportamento alimentar, rim, prejudicam o potencial reprodutivo da prole masculina com estresse oxidativo espermático e disfunção mitocondrial. Uma explicação para estas observações (humanos e animais) é a epigenética, considerada a ferramenta básica para a transmissão de fenótipos do pai à prole, como a metilação do DNA, modificações nas histonas, e RNA não codificante.

Conclusões

A obesidade paterna pode induzir fenótipos programados na prole através da epigenética. Portanto, a obesidade paterna pode ser considerada um problema de saúde pública, afetando a vida futura das crianças.

Palavras-chave:
Obesidade paterna
Programação
Criança obesa
Programação de doenças crônicas
Epigenética
Full Text
Introduction

Obesity has been growing in a disorderly way, constituting a real epidemic described as “globesity,” which represents a serious public health problem nowadays.1

It is now known that the risk of developing obesity and metabolic syndrome (MS) in adulthood may be influenced by the initial period of life, especially through inadequate nutrition available to the fetus and newborn.2,3 “Programming” is the process by which early life factors may influence the offspring's health in adulthood. Programming is considered an essential mechanism for the establishment of obesity and metabolic changes in the offspring.4,5 Various models are used to understand the mechanisms associated with programming, in which the hormonal and metabolic environment during the prenatal or postnatal period is altered through changes in maternal nutritional status.6–8

Most epidemiological and experimental studies have focused on the maternal influence on offspring's health. However, recent experiments with rodents have demonstrated that the paternal involvement affects glucose homeostasis and the lifetime of pancreatic islets in female offspring.9 Clinical and animal testing have challenged conventional ideas about metabolic programming, suggesting that something else might act in this process via paternal programming. Recent studies now indicate that paternal metabolic health at conception can also impact children's health, and that obese fathers are more likely to generate an obese child.10

This review reports the recent findings and proposed mechanisms involved in paternal programming of the offspring.

Human studies

Studies in humans analyzed the relationship between paternal lifestyle-related factors, environmental exposure factors, and offspring's health outcome in early and later life, suggesting that paternal effects may play a significant role in the pathogenesis of offspring chronic diseases in later life (e.g., insulin resistance and type 2 diabetes). More than 60% of all adults are classified as overweight or obese in most Westernized societies; as the prevalence of obesity increases, it is responsible for an ever-larger proportion of the overall burden of disease.9,11

There is clear evidence that paternal nutritional factors play a significant role in the health of offspring. For example, there is a correlation between paternal absolute and relative amounts of body fat and the same parameters in their daughters aged 4.8–8.9 years.12 Furthermore, paternal body mass index (BMI) might modulate the offspring phenotype in a sex-dependent manner. In the frames of a family cohort study (899 parent–offspring trios), paternal BMI was correlated with birth weight, biparietal diameter, head circumference, abdominal diameter, abdominal circumference, and thoracic diameter in male newborns only.12 Fathers13 or grandfathers14 exposed to either overfeeding or food restriction on the age period of 9–12 years predetermined reduced longevity of their male offspring. The second generation of offspring of these grandfathers had a four-fold risk of diabetes mortality.15

In Northern Sweden, the follow-up of three generations demonstrated that a grandfathers’ surfeit of food is associated with reduced survivability14 and an increased risk of diabetes15 in their grandchildren. Early onset of grandpaternal smoking is also related to increased grandson BMI.16 This evidence indicates that paternal nutritional factors, not only before conception but also as early as in father's puberty, might affect the offspring in a sex-dependent manner.17 Moreover, there is an interaction between parental genes and parental environmental factors that affect the phenotype of the offspring.18 The gene–environment interaction becomes even more complicated, as it is also known that the socioeconomic status of an individual appears to have opposite effects on obesity in poor and rich countries.19

In fathers, the caloric imbalance imposed by lifestyle choices, including high food consumption and low physical activity, are factors to be considered in programming studies. Epigenetic modifications can occur within the lifespan of numerous individuals within a population, and thus be transmitted immediately to a large number of offspring in the next generation, unlike genomic events that spread slowly through a population.20 It is likely that changing circumstances within the individual or over several generations can recruit silent alleles back into the active genome and contribute to the reversibility of adaptive or acquired changes. A recent study in obese men showed changes in circulating microRNA (miRNA) that target VEGF (vascular endothelial growth factor), an adipocyte mitogen, which was reversible following weight loss.21

Paternal BMI during conception was associated with fetal development of the male offspring, but not of the female offspring. It was significantly correlated with birth weight and perinatal biparietal diameter, head circumference, abdominal diameter, abdominal circumference, and thoracic diameter measured in male offspring. There were no significant correlations between paternal BMI and these parameters in female offspring. Cord blood cortisol level was also associated with father's BMI in male offspring only. The authors concluded that a sex-specific transgenerational effect of paternal BMI on fetal cortisol secretion might represent a risk factor for cardiovascular disease in male offspring in later life.12 Furthermore, increased paternal BMI is associated with decreased blastocyst development and live birth rates after in vitro fertilization.22 In obese fathers (BMI>25kg/m2), a higher reactive oxygen species was detected in sperm, as well as increased seminal fluid neopterin (a marker of reproductive tract macrophage activation), decreased sperm counts and serum testosterone, and increased serum estradiol.23

Animal studies

Animal models of male obesity are being used to assess the impact of paternal programming on offspring and to analyze the sperm function of the obese father. Animal models are important due to the difficulties in separating the effects of paternal genetic makeup from those of paternal environmental exposures on the offspring,10 as well as in clustering and interpreting data from human studies. A better understanding of the mechanisms of paternal programming can help in interventions to minimize adverse effects on the offspring.24

A paternal programming (when obese fathers led to disturbance of glucose-insulin homeostasis in the female offspring) was initially described in animals.9 Obese fathers also program liver lipogenesis and beta-oxidation25 and the hypothalamus of the offspring (hypothalamus inflammation was found in offspring, with an increase of interleukin [IL]-6 and tumor necrosis factor [TNF]-alpha expressions).6

Obese fathers also altered the offspring's kidney, with tubular damage and loss of the tubular brush border, but not glomerular damage. The cholesterol acyltransferase-1 (Acat1) gene, involved in the input of fatty acid for beta-oxidation in the tubuli, was up-regulated in the offspring.26

Mammalian male germ cell development is susceptible to damage in different times and in specific diseases in offspring's later life: embryonic development, infancy, and prepubertal age, and preconception and spermatogenesis in adulthood.27–29 Paternal obesity negatively impacts on the reproductive potential of the male offspring not only by altering function, quality, and molecular composition of sperm, but also by increasing sperm's oxidative stress, contributing to DNA damage and mitochondrial dysfunction.30

Many studies in animal model focus on the adverse factors influencing paternal exposure, from the prepubertal period to preconception. Therefore, is more plausible to consider that the epigenome undergoes reprogramming in pre-implantation embryos and in primordial germ cells.31

Environmental exposures in animal models over this period have been suggested to induce intergenerational and transgenerational effects through the sperm epigenome.32 Data demonstrate that numerous metabolic effects observed in the first generation are shown to persist in the second generation, with F1 females producing F2 males with increased adiposity. Paternal obesity modified the expression of various microRNAs, concomitant with alterations in sperm microRNA content and a reduction in global methylation of germ cell DNA.32

From the moment the blastocyst is formed, the pre-implantation is over, and a new stage starts – the in utero development. After entering the gonads, primordial germ cells convert to gonocytes, and in mouse models decreasing decrease in DNA methylation levels is observed.33 The primary responsibilities in this timeframe encompass cell-specific gene expression, tissue differentiation, and tissue-specific epigenomes.27

Obese mice fathers presented H3 retention and genomic imprints in the sperm, and differences in liver mRNA expression of several fat synthesis-related genes were observed in the offspring. Differences were observed in the liver expression of matallothionein-1 and -2 (Mt1 and Mt2), fatty acid synthase (Fasn), P450 cytochrome oxidoreductase,34 and acetyl-CoA carboxylase-α (Acaca) at the age of 24 weeks. Paternal obesity also increased histone H3 occupancy in the promoters of the genes responsible for the embryonic development and increased monomethylation of lysine 4 on histone H3 (H3K4me1) in genes responsible for embryogenesis regulation in spermatozoa. Altogether, findings suggest that dietary exposure can modulate histone composition at genes involved in the process of development.35

Epigenetics

The mechanisms explaining how the father may affect the development of the offspring are still under debate. Epigenetics is the primary tool for the transmission of paternal phenotypes to offspring, because the transient nutritional stimuli in critical stages of ontogenesis may influence the expression of various genes by changes in chromatin conformation and the accessibility of transcription factors.36

Therefore, the term epigenetic (Greek prefix epi- (??π??): over, outside of, around), proposed by Conrad Waddington, is described as a “process of development of the phenotype from the genotype.”37 In other words, epigenetic is any transmissible and reversible modification in the expression of a gene without structural change in the sequence of DNA.38 Unlike the genetic variation of the germline, which remains unchanged in all cells of the body, epigenetic modification is dynamic and varies among tissues in response to a range of environmental stimuli, including those that direct tissue differentiation during development and growth, and the serious risks that provoke an adaptive response of cells.39

Some epigenetic marks during spermatogenesis may continue throughout the embryonic development. Environmental exposures (diet, lifestyle, and other exposures) that occur in male gametogenesis can cause irreversible epigenetic changes and phenotypic consequences expressed in the offspring.40 Epigenetic processes also modulate the effects through transcription regulation due to several processes, such as DNA methylation, histone alterations, and transcription of non-coding RNA (miRNA, for example).41,42

Epigenetic modifications acting on the cell plasticity capacity prepare the individual for the extrauterine environment and may potentiate a survival advantage by regulating the differential genes encoding proteins involved in energy metabolism and adipogenesis.43 However, in face of a deleterious metabolic condition such as obesity and related metabolic alterations, these modifications can be exacerbated or silenced, especially germ cells program, which constitute the species’ perpetuation and phenotypic transmission.44

Recent hypotheses consider that some paternal dietary patterns reside in spermatozoa bearing epigenetic information.27 The sperm “epigenome” was traditionally considered insignificant, since it was postulated that its DNA methylation profile was erased immediately after fertilization. However, in recent years, there has been an increase in the number of reported cases of apparent epigenetic inheritance through the male germline, suggesting that this epigenome may transmit information between generations.28,40

The development of sperm- and spermatid-derived frog embryos allow the observation that the sperm not only transfers DNA, but also contributes to the epigenetic information required for proper embryonic gene expression, being the key for epigenetic information.45

Methylation

DNA methylation is one of the chemical reactions that occur most frequently in eukaryotes such as plants, fungi, invertebrates, and vertebrates.34 This chemical modification is characterized by the addition of a methyl group at the C5 position of the cytosine ring, catalyzed by the DNA methyltransferases, leading to the formation of 5-methylcytosine.46,47 The frequency of 5-methylcytidine is less than 1% of the total number of nucleotides in the genome.48 This methylation process acts in normal embryonic development, inactivation of the X chromosome, genetic regulation, genomic press, and chromatin modifications.49

Most DNA methylation occurs in regions called CpG islands, which corresponds to genomic regions of more than 1000 base pairs in length and with many GC dinucleotides; about 55% of these islands are in the promoter regions of approximately 40% of mammalian genes. These CpG (cytosine-phosphate-guanine) islands are kept non-methylated, except in imprinting genes or when located on the inactive X chromosome.50,51 Therefore, CpG islands located in the promoter region of housekeeping and developmental regulator genes with dense cytosine and guanine distribution are resistant to DNA methylation.52 The CpG islands, which allow the binding of proteins and enzymes, initiate the cascade of transcription. In contrast, methylated CpG islands are related to transcriptional silencing.53

Hypermethylation of promoter regions rich in dinucleotides has a significant role in the loss of gene expression.54 Typically, hypomethylation of DNA triggers an increase in gene expression, while hypermethylation decreases the expression of target genes.55 Furthermore, transcription factors do not recognize and bind to transcription initiation sites due to the modification of cytosine into 5-methylcytidine. This is the case of adipocyte protein 2 (AP-2), cMYC/murine homolog of max (cMYC/MYN), cyclic adenosine monophosphate response element binding protein (CREB), E2 factor (E2F), and nuclear factor-κB (NF-KB). However, these binding sites may be occupied by other proteins such as methyl-CpG binding protein 2 (MeCP-2) and methyl-CpG-binding domain protein (MBD)1, MBD2, MBD3, and MBD4, which bind to methylated cytosines and stimulate chromatin condensation, inactivating the gene.46,56

The enzymes responsible for the addition of a methyl group to cytosine molecules belong to the family of DNA methyltransferases (DNMTs), including DNMT-1, DNMT3A, DNMT3B and its isoforms, and DNMT3L.47,57 DNMT1 is primarily responsible for maintaining DNA methylation patterns during mitosis. Furthermore, DNMT (differentially methylated regions)-s3 is responsible for de novo methylation of newly synthesized DNA molecules and is most important during the early stages of embryonic development; it could be the process involved in paternal programming for phenotypic transmission.58,59 A schematic view of the main paternal epigenetic modifications can be seen in Fig. 1.

Figure 1.

Epigenetics of paternal programming on the offspring. Paternal metabolic changes related to obesity may result in modifications to genetic information contained in the spermatozoa. DNA methylation in specific promoter regions most often prevents gene transcription by inactivating the gene in question. As for histone modifications, hypermethylation (depending on histone and amino acid) favors the condensation of chromatin, making difficult access to regulatory proteins that promote transcription. However, non-methylated histones ensure decondensed chromatin, supporting gene transcription. In contrast, histone acetylation opens the chromatin, allowing coupling of the transcriptional machinery.

(0.31MB).

In a contrary process, DNA demethylation is also an important epigenetic component of gene transcription and epigenetic programming, which occurs through several enzymatic reactions mediating the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine.60 The presence of 5-hydroxymethylcytosine in promoter regions results in increased transcription, indicating a role in long- and short-term regulation of gene expression.61

Histone modifications

Histone modifications are other biological actions that regulate gene expression. Histones are basic proteins found in eukaryotic cell nuclei, which help in the packaging of DNA into nucleosomes, the binding blocks of chromatin.62 Chromatin should be remodeled, modifying the accessibility of the DNA transcription machinery to control the transcription process.63 Events such as acetylation, methylation, phosphorylation and ubiquitination, often occur in the tail of the histones that extend from the center of the nucleosomes.64 Other chemical modifications also alter histones, such as histone lysine glucosamine acylation (GlcNAcylation), butyrylation, malonylation, and crotonylation.65,66

Histones 3 and 4 (H3 and H4) are commonly studied, and acetylation is the main epigenetic modification considered; it occurs on the lysine and arginine and neutralizes the positive charge of basic residues. The histone acetylase enzymes add acetyl groups to the histone lysine residues, and it is believed that the acetylated histones have a reduced affinity between DNA and histones, leaving chromatin in a relaxed (euchromatin) and transcriptionally active state.66

In contrast, histone deacetylase removes the acetyl groups, which are more condensed, and prevents gene expression.67 These chemical modifications alter the interaction between DNA and histones, changing the degree of chromatin folding and the gene activity.68 Therefore, heterochromatin is related with hypoacetylation for H3 and H4, and di- or trimethylation of the ninth lysine residue on H3 (H3K9me2 or H3K9me3).69

Non-coding RNA (microRNA)

In addition to DNA methylation and histone modification, sperm RNA can be an epigenetic regulator. Spermatozoa contain an array of both mRNAs70 and noncoding RNAs, including miRNA.71 Most of this RNA is delivered to the oocyte. However, the role of miRNA in early preimplantation embryos is still under debate.

Evidence of the direct biological effect of miRNAs in the pre-implantation period is supported by observations in mice with a chromosomal lesion in the Dicer gene. Loss of enzymatic processing of Dicer miRNA in oocytes leads to early lethality in the development process, where the zygotes cannot survive the division in the first place.72 Therefore, this suggests the interference of miRNA in zygote development.

miRNA is a major part of the group of such small non-coding. These components have approximately 21nt-long RNA molecules that repress their target mRNA.73 In males, they are observed in the nucleus of spermatozoa, keeping the DNA connected to histones during spermiogenesis and in early embryonic development.74 miRNA regulates various biological functions, influencing the epigenetic inactivation of genes and the protection of the DNA against viruses and transposons.75

In a general way, miRNA in animals is mostly located within the introns of protein coding or non-coding RNA genes,76 being produced by RNA polymerase II transcription. In humans, miRNA appears to be synthesized by RNA polymerase III.77 In recent years, over- or under-expression of miRNA has been associated with disease development, but the mechanisms and actions are still ambiguous.78

Epigenetics in paternal programming

Several studies in animals and humans have demonstrated the influence of paternal diet on their offspring's phenotype through the epigenome.

Male mice fed a high-fat diet generated female offspring with impaired glucose-insulin homeostasis, associated with an altered expression in one of the 642 pancreatic islet genes and in the hypomethylated interleukin 13 receptor alpha 2 (IL13ra2) gene.9 These alterations were recently observed in the transcriptomes of retroperitoneal adipose and pancreatic islet tissues in female offspring. In retroperitoneal adipose tissue, 5108 genes were differentially expressed due to paternal high-fat diet, whose functions are related to mitochondrial and cellular response to stress, telomerase signaling, cell death and survival, cell cycle, cellular growth and proliferation, and cancer.79

In a mice model of paternal low-protein diet, the offspring showed an elevated methylation in peroxisome proliferator-activated receptor (PPAR)-alpha in the liver, a gene involved in the formation of the first enzymes for the oxidation of lipids in mitochondria, being an essential lipid regulator.80 Also, paternal insulin resistance has altered the methylation status of various insulin-signaling genes in the offspring, increasing the offspring's susceptibility to diabetes through gametic epigenetic alterations. Such includes the genes phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1), phosphoinositide-3-kinase catalytic alpha polypeptide (Pik3ca), Ptpn1 protein tyrosine phosphatase, non-receptor type 1 (Ptpn1), and Pik3ca in sperm.81 In mice models, paternal high-fat diet led to an increase in transfer RNA (tRNA) in sperm as an inherited epigenetic key influenced by paternal diet and related to metabolic impairment in the offspring, leading to glucose intolerance and insulin resistance.82

Paternal obesity initiates metabolic disturbances in two generations of mice, altering the transcriptional profile of testis and sperm miRNA content. The differential content of canonical miRNAs in the sperm suggested dysregulation in spermatogenesis, embryo development, and metabolic function. Furthermore, paternal high-fat diet affected the metabolic status of offspring through epigenetic changes in the adiponectin and leptin genes for two generations.83 Interestingly, an increase in miR-29 (microRNA 29) has been associated with a decrease in methylation of repeat elements in the male germline.32 Moreover, 13 sperm-borne miRNA were modulated by paternal high-fat diet and transferred off this altered miRNA payload to the embryo at fertilization, changing its growth trajectory and affecting adult offspring phenotype.84

In newborns, an association was observed between preconception obesity and DNA methylation profiles in the offspring, particularly in the differentially methylated region (DMR) of the imprinted insulin-like growth factor 2 (IGF2) gene. The hypomethylation at the IGF2 DMR in the offspring was associated with paternal obesity.85 It is conceivable that additional or novel epigenetic regulators (such as prions) are present in sperm, that sperm quality is affected by diet, and that environment may direct the genetic changes. Although it is important to emphasize that inbred mouse strains were used in this study.80 Furthermore, γ-radiation-induced DNA damage in the sperm has been shown to be heritable, with offspring similarly exhibiting sperm DNA damage.86

Epigenetic modification is a continual process, and some changes may be reversible.20 Combined, these data reveal the impact of paternal programming (in particular through nutritional manipulations) on the future life of the offspring, influenced mainly by phenotype transmission via the epigenetic process.

Final considerations

Data from epidemiological and animal studies provide evidence that paternal feeding and paternal health conditions can program following generations. Thus, the mother is not the only responsible for offspring's health. The father shares the responsibility in providing sperm-specific epigenetic stamp to the oocyte, affecting the embryo developmental trajectory and health of adult offspring. Although the role of paternal influence may be clearly identified, the current knowledge on reprogramming, alteration, and possible prevention of paternal effects remains limited. To date, human studies are not progressing in the same manner as animal studies, so there is little information about the mechanism and contribution of paternal programming in the child's health, as men are widely used as controls in studies with women. Therefore, considering that paternal obesity can also be a public health problem, it is important to improve epidemiological studies to assess the exact role of paternal health on the sperm and on the health of the offspring to propose further interventions.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

This laboratory (www.lmmc.uerj.br) is sponsored by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grant #302.154/2011-6 to CAML, and #306.077/2013-2 to MBA), and Fundação Carlos Chagas Filho de Amparo à Pesquisa do Rio de Janeiro (FAPERJ, grant #102.944/2011 to CAML, #103.062/2011 to MBA).

References
[1]
H. Huang, Z. Yan, Y. Chen, F. Liu.
A social contagious model of the obesity epidemic.
Sci Rep, 6 (2016), pp. 37961
[2]
D.J. Barker.
The fetal and infant origins of adult disease.
BMJ, 301 (1990), pp. 1111
[3]
D.J. Barker.
The developmental origins of adult disease.
J Am Coll Nutr, 23 (2004), pp. 588S-595S
[4]
M.L. Gusmao-Correia, A.M. Volpato, M.B. Aguila, C.A. Mandarim-de-Lacerda.
Developmental origins of health and disease: experimental and human evidence of fetal programming for metabolic syndrome.
J Hum Hypertens, 26 (2012), pp. 405-419
[5]
A.M. Volpato, A. Schultz, E. Magalhaes-da-Costa, M.L. Correia, M.B. Aguila, C.A. Mandarim-de-Lacerda.
Maternal high-fat diet programs for metabolic disturbances in offspring despite leptin sensitivity.
Neuroendocrinology, 96 (2012), pp. 272-284
[6]
F. Ornellas, V. Souza-Mello, C.A. Mandarim-de-Lacerda, M.B. Aguila.
Combined parental obesity augments single-parent obesity effects on hypothalamus inflammation, leptin signaling (JAK/STAT), hyperphagia, and obesity in the adult mice offspring.
Physiol Behav, 153 (2016), pp. 47-55
[7]
I. Bringhenti, F. Ornellas, C.A. Mandarim-de-Lacerda, M.B. Aguila.
The insulin-signaling pathway of the pancreatic islet is impaired in adult mice offspring of mothers fed a high-fat diet.
Nutrition, 32 (2016), pp. 1138-1143
[8]
F. Ornellas, V.S. Mello, C.A. Mandarim-de-Lacerda, M.B. Aguila.
Sexual dimorphism in fat distribution and metabolic profile in mice offspring from diet-induced obese mothers.
Life Sci, 93 (2013), pp. 454-463
[9]
S.F. Ng, R.C. Lin, D.R. Laybutt, R. Barres, J.A. Owens, M.J. Morris.
Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring.
Nature, 467 (2010), pp. 963-966
[10]
L. Li, C. Law, R. Lo Conte, C. Power.
Intergenerational influences on childhood body mass index: the effect of parental body mass index trajectories.
Am J Clin Nutr, 89 (2009), pp. 551-557
[11]
D.M. Nguyen, H.B. El-Serag.
The epidemiology of obesity.
Gastroenterol Clin North Am, 39 (2010), pp. 1-7
[12]
Y.P. Chen, X.M. Xiao, J. Li, C. Reichetzeder, Z.N. Wang, B. Hocher.
Paternal body mass index (BMI) is associated with offspring intrauterine growth in a gender-dependent manner.
[13]
G. Kaati, L.O. Bygren, M. Pembrey, M. Sjostrom.
Transgenerational response to nutrition, early life circumstances and longevity.
Eur J Hum Genet, 15 (2007), pp. 784-790
[14]
L.O. Bygren, G. Kaati, S. Edvinsson.
Longevity determined by paternal ancestors’ nutrition during their slow growth period.
Acta Biotheor, 49 (2001), pp. 53-59
[15]
G. Kaati, L.O. Bygren, S. Edvinsson.
Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period.
Eur J Hum Genet, 10 (2002), pp. 682-688
[16]
M.E. Pembrey, L.O. Bygren, G. Kaati, S. Edvinsson, K. Northstone, M. Sjostrom, et al.
Sex-specific, male-line transgenerational responses in humans.
Eur J Hum Genet, 14 (2006), pp. 159-166
[17]
J. Li, O. Tsuprykov, X. Yang, B. Hocher.
Paternal programming of offspring cardiometabolic diseases in later life.
J Hypertens, 34 (2016), pp. 2111-2126
[18]
B. Hocher.
More than genes: the advanced fetal programming hypothesis.
J Reprod Immunol, 104–105 (2014), pp. 8-11
[19]
F.C. Pampel, J.T. Denney, Krueger P.M. Obesity.
SES, and economic development: a test of the reversal hypothesis.
Soc Sci Med, 74 (2012), pp. 1073-1081
[20]
Y. Slyvka, Y. Zhang, F.V. Nowak.
Epigenetic effects of paternal diet on offspring: emphasis on obesity.
Endocrine, 48 (2015), pp. 36-46
[21]
F.J. Ortega, J.M. Mercader, V. Catalan, J.M. Moreno-Navarrete, N. Pueyo, M. Sabater, et al.
Targeting the circulating microRNA signature of obesity.
Clin Chem, 59 (2013), pp. 781-792
[22]
H.W. Bakos, R.C. Henshaw, M. Mitchell, M. Lane.
Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology.
Fertil Steril, 95 (2011), pp. 1700-1704
[23]
O. Tunc, H.W. Bakos, K. Tremellen.
Impact of body mass index on seminal oxidative stress.
Andrologia, 43 (2011), pp. 121-128
[24]
N.O. McPherson, J.A. Owens, T. Fullston, M. Lane.
Preconception diet or exercise intervention in obese fathers normalizes sperm microRNA profile and metabolic syndrome in female offspring.
Am J Physiol Endocrinol Metab, 308 (2015), pp. E805-E821
[25]
F. Ornellas, V. Souza-Mello, C.A. Mandarim-de-Lacerda, M.B. Aguila.
Programming of obesity and comorbidities in the progeny: lessons from a model of diet-induced obese parents.
PLOS ONE, 10 (2015), pp. e0124737
[26]
S.S. Chowdhury, V. Lecomte, J.H. Erlich, C.A. Maloney, M.J. Morris.
Paternal high fat diet in rats leads to renal accumulation of lipid and tubular changes in adult offspring.
[27]
U. Schagdarsurengin, K. Steger.
Epigenetics in male reproduction: effect of paternal diet on sperm quality and offspring health.
Nat Rev Urol, 13 (2016), pp. 584-595
[28]
A. Soubry, C. Hoyo, R.L. Jirtle, S.K. Murphy.
A paternal environmental legacy: evidence for epigenetic inheritance through the male germ line.
Bioessays, 36 (2014), pp. 359-371
[29]
H. Wu, R. Hauser, S.A. Krawetz, J.R. Pilsner.
Environmental susceptibility of the sperm epigenome during windows of male germ cell development.
Curr Environ Health Rep, 2 (2015), pp. 356-366
[30]
N.O. Palmer, H.W. Bakos, T. Fullston, M. Lane.
Impact of obesity on male fertility, sperm function and molecular composition.
Spermatogenesis, 2 (2012), pp. 253-263
[31]
M. Saitou, S. Kagiwada, K. Kurimoto.
Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells.
Development, 139 (2012), pp. 15-31
[32]
T. Fullston, E.M. Ohlsson Teague, N.O. Palmer, M.J. DeBlasio, M. Mitchell, M. Corbett, et al.
Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content.
FASEB J, 27 (2013), pp. 4226-4243
[33]
S. Seisenberger, S. Andrews, F. Krueger, J. Arand, J. Walter, F. Santos, et al.
The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells.
Mol Cell, 48 (2012), pp. 849-862
[34]
J.A. Kilgore, S.A. Hoose, T.L. Gustafson, W. Porter, M.P. Kladde.
Single-molecule and population probing of chromatin structure using DNA methyltransferases.
Methods, 41 (2007), pp. 320-332
[35]
M. Terashima, S. Barbour, J. Ren, W. Yu, Y. Han, K. Muegge.
Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression.
Epigenetics, 10 (2015), pp. 861-871
[36]
C. Gallou-Kabani, C. Junien.
Nutritional epigenomics of metabolic syndrome: new perspective against the epidemic.
Diabetes, 54 (2005), pp. 1899-1906
[37]
C. Waddington.
The epigenotype.
Endeavour, 1 (1942), pp. 18-20
[38]
E. Heard, R.A. Martienssen.
Transgenerational epigenetic inheritance: myths and mechanisms.
[39]
A.C. Estampador, P.W. Franks.
Genetic and epigenetic catalysts in early-life programming of adult cardiometabolic disorders.
Diabetes Metab Syndr Obes, 7 (2014), pp. 575-586
[40]
A. Soubry.
Epigenetic inheritance and evolution: a paternal perspective on dietary influences.
Prog Biophys Mol Biol, 118 (2015), pp. 79-85
[41]
N. Li, Q. Shen, J. Hua.
Epigenetic remodeling in male germline development.
Stem Cells Int, 2016 (2016), pp. 3152173
[42]
H. Zhao, Y. Zhao, Y. Ren, M. Li, T. Li, R. Li, et al.
Epigenetic regulation of an adverse metabolic phenotype in polycystic ovary syndrome: the impact of the leukocyte methylation of PPARGC1A promoter.
Fertil Steril, 107 (2017), pp. 467-474
e5
[43]
Q. Gao, J. Tang, J. Chen, L. Jiang, X. Zhu, Z. Xu.
Epigenetic code and potential epigenetic-based therapies against chronic diseases in developmental origins.
Drug Discov Today, 19 (2014), pp. 1744-1750
[44]
C. Guerrero-Bosagna, M.K. Skinner.
Environmentally induced epigenetic transgenerational inheritance of male infertility.
Curr Opin Genet Dev, 26 (2014), pp. 79-88
[45]
M. Teperek, A. Simeone, V. Gaggioli, K. Miyamoto, G.E. Allen, S. Erkek, et al.
Sperm is epigenetically programmed to regulate gene transcription in embryos.
Genome Res, 26 (2016), pp. 1034-1046
[46]
P. Caiafa, M. Zampieri.
DNA methylation and chromatin structure: the puzzling CpG islands.
J Cell Biochem, 94 (2005), pp. 257-265
[47]
H. Fan, Z.J. Zhao, J. Cheng, X.W. Su, Q.X. Wu, Y.F. Shan.
Overexpression of DNA methyltransferase 1 and its biological significance in primary hepatocellular carcinoma.
World J Gastroenterol, 15 (2009), pp. 2020-2026
[48]
C.Y. Yen, H.W. Huang, C.W. Shu, M.F. Hou, S.S. Yuan, H.R. Wang, et al.
DNA methylation, histone acetylation and methylation of epigenetic modifications as a therapeutic approach for cancers.
Cancer Lett, 373 (2016), pp. 185-192
[49]
A. Bird.
DNA methylation patterns and epigenetic memory.
Genes Dev, 16 (2002), pp. 6-21
[50]
X. Deng, W. Ma, V. Ramani, A. Hill, F. Yang, F. Ay, et al.
Bipartite structure of the inactive mouse X chromosome.
Genome Biol, 16 (2015), pp. 152
[51]
S.K. Kota, D. Roy Chowdhury, L.K. Rao, V. Padmalatha, L. Singh, U. Bhadra.
Uncoupling of X-linked gene silencing from XIST binding by DICER1 and chromatin modulation on human inactive X chromosome.
Chromosoma, 124 (2015), pp. 249-262
[52]
W. Xu, F. Wang, Z. Yu, F. Xin.
Epigenetics and cellular metabolism.
Genet Epigenet, 8 (2016), pp. 43-51
[53]
G. Egger, G. Liang, A. Aparicio, P.A. Jones.
Epigenetics in human disease and prospects for epigenetic therapy.
Nature, 429 (2004), pp. 457-463
[54]
M.W. Luczak, P.P. Jagodzinski.
The role of DNA methylation in cancer development.
Folia Histochem Cytobiol, 44 (2006), pp. 143-154
[55]
R.A. Liddle, R.L. Jirtle.
Epigenetic silencing of genes in human colon cancer.
Gastroenterology, 131 (2006), pp. 960-962
[56]
A. Weyrich, D. Lenz, M. Jeschek, T.H. Chung, K. Rubensam, F. Goritz, et al.
Paternal intergenerational epigenetic response to heat exposure in male Wild guinea pigs.
Mol Ecol, 25 (2016), pp. 1729-1740
[57]
M.M. Sarabi, F. Naghibalhossaini.
Association of DNA methyltransferases expression with global and gene-specific DNA methylation in colorectal cancer cells.
Cell Biochem Funct, 33 (2015), pp. 427-433
[58]
D.C. Dolinoy, J.R. Weidman, R.L. Jirtle.
Epigenetic gene regulation: linking early developmental environment to adult disease.
Reprod Toxicol, 23 (2007), pp. 297-307
[59]
T.J. Moss, L.L. Wallrath.
Connections between epigenetic gene silencing and human disease.
Mutat Res, 618 (2007), pp. 163-174
[60]
L. Scourzic, E. Mouly, O.A. Bernard.
TET proteins and the control of cytosine demethylation in cancer.
[61]
G. Ficz, M.R. Branco, S. Seisenberger, F. Santos, F. Krueger, T.A. Hore, et al.
Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation.
Nature, 473 (2011), pp. 398-402
[62]
D.K. Sarkar.
Male germline transmits fetal alcohol epigenetic marks for multiple generations: a review.
Addict Biol, 21 (2016), pp. 23-34
[63]
C.R. Clapier, B.R. Cairns.
The biology of chromatin remodeling complexes.
Annu Rev Biochem, 78 (2009), pp. 273-304
[64]
P.M. Howell Jr., S. Liu, S. Ren, C. Behlen, O. Fodstad, A.I. Riker.
Epigenetics in human melanoma.
Cancer Control, 16 (2009), pp. 200-218
[65]
T. Jenuwein, C.D. Allis.
Translating the histone code.
Science, 293 (2001), pp. 1074-1080
[66]
K.A. Gelato, W. Fischle.
Role of histone modifications in defining chromatin structure and function.
Biol Chem, 389 (2008), pp. 353-363
[67]
J. Ausio, D.B. Levin, G.V. De Amorim, S. Bakker, P.M. Macleod.
Syndromes of disordered chromatin remodeling.
Clin Genet, 64 (2003), pp. 83-95
[68]
D.D. Deobagkar, H.S. Chandra.
The inactive X chromosome in the human female is enriched in 5-methylcytosine to an unusual degree and appears to contain more of this modified nucleotide than the remainder of the genome.
J Genet, 82 (2003), pp. 13-16
[69]
K.L. Arney, A.G. Fisher.
Epigenetic aspects of differentiation.
J Cell Sci, 117 (2004), pp. 4355-4363
[70]
D.T. Carrell.
Contributions of spermatozoa to embryogenesis: assays to evaluate their genetic and epigenetic fitness.
Reprod Biomed Online, 16 (2008), pp. 474-484
[71]
W. Yan, K. Morozumi, J. Zhang, S. Ro, C. Park, R. Yanagimachi.
Birth of mice after intracytoplasmic injection of single purified sperm nuclei and detection of messenger RNAs and microRNAs in the sperm nuclei.
Biol Reprod, 78 (2008), pp. 896-902
[72]
E. Bernstein, S.Y. Kim, M.A. Carmell, E.P. Murchison, H. Alcorn, M.Z. Li, et al.
Dicer is essential for mouse development.
Nat Genet, 35 (2003), pp. 215-217
[73]
S.S. Bhat, A. Jarmolowski, Z. Szweykowska-Kulinska.
MicroRNA biogenesis: epigenetic modifications as another layer of complexity in the microRNA expression regulation.
Acta Biochim Pol, 63 (2016), pp. 717-723
[74]
T. Hamatani.
Human spermatozoal RNAs.
Fertil Steril, 97 (2012), pp. 275-281
[75]
M.J. Luteijn, R.F. Ketting.
PIWI-interacting RNAs: from generation to transgenerational epigenetics.
Nat Rev Genet, 14 (2013), pp. 523-534
[76]
V.N. Kim, J. Han, M.C. Siomi.
Biogenesis of small RNAs in animals.
Nat Rev Mol Cell Biol, 10 (2009), pp. 126-139
[77]
G.M. Borchert, W. Lanier, B.L. Davidson.
RNA polymerase III transcribes human microRNAs.
Nat Struct Mol Biol, 13 (2006), pp. 1097-1101
[78]
Y. Li, K.V. Kowdley.
MicroRNAs in common human diseases.
Genomics Proteomics Bioinform, 10 (2012), pp. 246-253
[79]
S.F. Ng, R.C. Lin, C.A. Maloney, N.A. Youngson, J.A. Owens, M.J. Morris.
Paternal high-fat diet consumption induces common changes in the transcriptomes of retroperitoneal adipose and pancreatic islet tissues in female rat offspring.
FASEB J, 28 (2014), pp. 1830-1841
[80]
B.R. Carone, L. Fauquier, N. Habib, J.M. Shea, C.E. Hart, R. Li, et al.
Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals.
Cell, 143 (2010), pp. 1084-1096
[81]
Y. Wei, C.R. Yang, Y.P. Wei, Z.A. Zhao, Y. Hou, H. Schatten, et al.
Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals.
Proc Natl Acad Sci U S A, 111 (2014), pp. 1873-1878
[82]
Q. Chen, M. Yan, Z. Cao, X. Li, Y. Zhang, J. Shi, et al.
Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder.
Science, 351 (2016), pp. 397-400
[83]
H. Masuyama, T. Mitsui, T. Eguchi, S. Tamada, Y. Hiramatsu.
The effects of paternal high-fat diet exposure on offspring metabolism with epigenetic changes in the mouse adiponectin and leptin gene promoters.
Am J Physiol Endocrinol Metab, 311 (2016), pp. E236-E245
[84]
T. Fullston, E.M. Ohlsson-Teague, C.G. Print, L.Y. Sandeman, M. Lane.
Sperm microRNA content is altered in a mouse model of male obesity, but the same suite of microRNAs are not altered in offspring's sperm.
PLOS ONE, 11 (2016), pp. e0166076
[85]
A. Soubry, J.M. Schildkraut, A. Murtha, F. Wang, Z. Huang, A. Bernal, et al.
Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort.
[86]
S.K. Adiga, D. Upadhya, G. Kalthur, S.R. Bola Sadashiva, P. Kumar.
Transgenerational changes in somatic and germ line genetic integrity of first-generation offspring derived from the DNA-damaged sperm.
Fertil Steril, 93 (2010), pp. 2486-2490

Please cite this article as: Ornellas F, Carapeto PV, Mandarim-de-Lacerda CA, Aguila MB. Obese fathers lead to an altered metabolism and obesity in their children in adulthood: review of experimental and human studies. J Pediatr (Rio J). 2017;93:551–9.

Copyright © 2017. Sociedade Brasileira de Pediatria
Idiomas
Jornal de Pediatria (English Edition)

Subscribe to our newsletter

Article options
Tools
en pt
Taxa de publicaçao Publication fee
Os artigos submetidos a partir de 1º de setembro de 2018, que forem aceitos para publicação no Jornal de Pediatria, estarão sujeitos a uma taxa para que tenham sua publicação garantida. O artigo aceito somente será publicado após a comprovação do pagamento da taxa de publicação. Ao submeterem o manuscrito a este jornal, os autores concordam com esses termos. A submissão dos manuscritos continua gratuita. Para mais informações, contate assessoria@jped.com.br. Articles submitted as of September 1, 2018, which are accepted for publication in the Jornal de Pediatria, will be subject to a fee to have their publication guaranteed. The accepted article will only be published after proof of the publication fee payment. By submitting the manuscript to this journal, the authors agree to these terms. Manuscript submission remains free of charge. For more information, contact assessoria@jped.com.br.
Cookies policy Política de cookies
To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here. Utilizamos cookies próprios e de terceiros para melhorar nossos serviços e mostrar publicidade relacionada às suas preferências, analisando seus hábitos de navegação. Se continuar a navegar, consideramos que aceita o seu uso. Você pode alterar a configuração ou obter mais informações aqui.