In today′s society, with the rapid development of economy and the continuous improvement of living standards, people′s lifestyle and diet have undergone major changes, followed by overweight and obesity show a sharp rise. Obesity has become a widespread public health problem worldwide. According to the World Health Organization data, the number of obese people worldwide has nearly tripled since 1975. World Health Organization data of 2016 showed that there were 39% and 13% of adults aged 18+ overweight or obese, respectively, with no gender difference. In addition, more than 18% of children and adolescents aged 5 to 19 were overweight or obesity in 2016. Obesity has become one of the most important factors for the increasing incidence of chronic diseases, such as type 2 diabetes, cardiovascular diseases, osteoarthritis, respiratory disorders, and cancer.
In the 1990s, British scientist David Barker proposed the “thrifty phenotype hypothesis” to explain the observation of intrauterine exposure to maternal malnutrition as a factor in determining type 2 diabetes in offspring. This theory has evolved into an emerging field of the developmental origins of health and disease, reflecting the early-life origins of adult chronic diseases, such as obesity and metabolic disorders. In view of the rapid growth of obesity in the world, increasing studies are devoted to explaining the mechanism of obesity and its related complications, brings new insight into the prevention and treatment of obesity and its complications. Besides, recent studies focusing on the long-term effects of parental obesity upon offspring health have become particularly interesting. The relationship between maternal obesity and offspring health has been reported in many studies.[4–8] However, there are relatively few studies focusing on the effects of father obesity upon the long-term health of offspring. Therefore, considering the increasing incidence of obesity among young men, research in this area should be given more attention.
In this review, we will focus on the recent studies on the effects of paternal obesity upon sperm function and offspring health. In addition, we also discuss the effects of diet and exercise interventions, as well as the potential epigenetic mechanisms implicated in epigenetic inheritance. Finally, we try to put forward the key scientific issues which need to be solved in the future development of this field.
Effects on sperm parameters and molecular composition
There have been increasing studies focusing on the effects of male obesity upon the conventional sperm parameters, mainly including sperm concentration, morphology, and motility. However, the results of studies on the effects of male obesity upon sperm parameters remain controversial. For example, Jensen et al examined 1558 military recruits and showed that body mass index (BMI) was associated with sperm parameters. Compared with men with a BMI between 20 and 25 kg/m2, men with a BMI greater than 25 kg/m2 had a 21.6% and 23.9% reduction in sperm concentration and sperm count, respectively, while semen volume and sperm motility did not change. In a large single-center study including 10,665 men, Belloc et al showed that increased BMI was associated with decreased sperm concentration, sperm count and progressive motility. However, a review included 31 studies showed no evidence of a link between BMI and sperm concentration or total sperm count. Most recently, Campbell et al reported that meta-analysis of 30 papers including a total of 115,158 participants showed that although the results of conventional semen parameters indicated normal fertility, obese men were more prone to be infertile. Moreover, male obesity was associated with increased abnormal morphology and DNA fragmentation as well as low mitochondrial membrane potential in sperm.
In addition to conventional sperm parameters, the molecular composition of sperm was evaluated in many recent studies. Sperm DNA integrity is critical for successful fertilization and normal embryonic development.[13,14] Many studies have measured sperm DNA integrity by using different methodologies (terminal dexynucleotidyl transferase-mediated dUTP nick end labeling, single-cell gel electrophoresis, sperm chromatin structure assay), revealing the adverse effects of obesity on sperm DNA integrity.[15–19] Sperm oxidative stress is associated with increased DNA damage, reduced sperm motility, decreased acrosome reaction as well as in vitro fertilization implantation rates.[20–22] Tunc et al showed a positive correlation between BMI and sperm reactive oxygen species (ROS) in humans. Bakos et al demonstrated that sperm DNA damage and ROS were increased in the high fat induced obese mice. Therefore, the inclusion of sperm DNA integrity and ROS evaluation into semen examination may be beneficial for obese men whose conventional sperm parameters indicate normal fertility.
Effects on offspring health: human studies
Although the association between maternal obesity and offspring health has been widely documented, few epidemiological studies investigate the potential impact of paternal obesity upon offspring health. In 2000, Figueroa-Colon et al reported that paternal body fat in humans was associated with the total and percentage body fat in their prepubertal girls. Subsequently, more and more epidemiological data showed the association between paternal BMI and childhood BMI.[26,27] In addition, Loomba et al showed that early-onset paternal obesity was associated with increased serum alanine aminotransferase levels in offspring, which may potentially be correlated with obesity and metabolic disorders in offspring.
In addition, Swedish historical data have revealed transgenerational effects of paternal availability of food during the slow growth period (SGP). Decreased longevity was related to exposure of excessive food to grandfather or father during SGP.[29,30] Furthermore, food abundance during the grandfather's SGP was correlated with the increased risk of death from diabetes in resulting generations.
Studies in humans measuring epigenetic effects in offspring triggered by paternal obesity are even rarer. In 2013, Soubry et al first reported the paternal obesity-induced methylation alteration in human offspring. They analyzed DNA methylation in the umbilical cord blood leukocytes of 79 newborns and showed that the imprinted gene insulin-like growth factor-2 hypomethylation was associated with paternal obesity. In addition, they found that other imprinted genes hypomethylation was correlated with paternal obesity.
Effects on offspring health: animal studies
Considering many confounding factors, such as genetic factors, shared diet, and lifestyle in human studies, most evidence for the long-term effects of paternal obesity upon offspring health originates from animal data. Increasingly, experiments in animals have showed that high fat diet (HFD)-induced paternal obesity can modulate the phenotype of offspring. In 2010, Ng et al demonstrated that paternal HFD consumption impaired glucose tolerance and insulin secretion in F1 female rat offspring, possibly due to decreased β-cell abundance. Mechanistically, paternal HFD reprogrammed gene expression patterns in islet of female offspring. Moreover, an important gene, the interleukin-13 receptor a2, was shown to decrease promoter methylation and increase mRNA expression. In 2014, Ng et al further reported that paternal HFD also reprogrammed gene expression patterns in retroperitoneal white adipose tissue in rat offspring. However, they did not analyze epigenetic information in sperm, which potentially mediate the father-offspring effects. In 2015, de Castro Barbosa et al found that paternal HFD exposure led to glucose intolerant in female rat offspring in 2 generations. They further found sperm DNA methylation patterns and sncRNAs in HFD-fed male rats were altered. In addition, Fullston et al found that paternal obesity induced insulin resistance in 2 successive generations. Mechanistically, a HFD altered sperm microRNA expression and global DNA methylation, indicating potential epigenetic carriers that transmit metabolic disorders to future generations. Besides, Terashima et al showed that paternal HFD altered sperm histone composition at genes involved in the regulation of developmental processes. They also found 7 differentially expressed liver genes in HFD male offspring. Ornellas et al found that diet-induced paternal obesity led to impaired glucose metabolism and exacerbated lipogenesis in both male and female mice offspring. They also found that paternal obesity induced hypothalamic inflammation with an increase in interleukin-6 and tumor necrosis factor-alpha expression in offspring, possibly predicting metabolic disorders in adulthood.
In addition to metabolic dysfunction in offspring of paternal obesity, there are also animal studies focusing on other adverse offspring outcomes. For example, Chowdhury et al showed that paternal HFD exposure in rats induced kidney damage in offspring, including increased cell sloughing and decreased brush border. The cholesterol acyltransferase-1 gene, which was associated with fatty acid entry into beta-oxidation, was significantly upregulated in offspring. Another study by Fullston et al reported that paternal obesity impaired fertility of male and female mice offspring, perpetuating in 2 successive generations. Paternal obesity reduced sperm function in F1 and F2 male offspring, including increased sperm ROS and DNA damage, as well as reduced motility. Similarly, paternal obesity induced reproductive impairment in F1 and F2 female offspring, including reduced meiotic competence, altered mitochondrial function, as well as increased oxidative stress in oocytes. Interestingly, F2 male offspring from F1 females displayed marked subfertility phenotypes similar to F0 fathers, including reduced testicular weights and testosterone levels, reduced sperm motility, as well as increased sperm ROS. More recently, Zhou et al showed that male mice offspring from obese fathers exhibited impaired hippocampus-dependent learning and memory, which was associated with reduced brain-derived neurotrophic factor expression in offspring hippocampus. Moreover, brain-derived neurotrophic factor promoter methylation showed upregulated both in F0 sperm and F1 hippocampus.
In recent years, some experiments using in vitro fertilization RNA microinjection have also suggested that in the absence of semen, the epigenetic information contained in the sperm is sufficient to inherit the acquired phenotype of the father, further supporting the idea of sperm-transfer acquired traits. For example, in 2015, Grandjean et al found that male mice exposed to a Western-like diet increased body weight and impaired glucose tolerance in offspring. Furthermore, microinjecting sperm RNAs from Western-like diet fathers into one-cell embryos can establish the similar metabolic disorders in offspring, indicating the role of sperm RNAs in transmitting metabolic dysfunction to offspring. Similarly, Chen et al reported that paternal HFD exposure altered a subset of sperm transfer RNA-derived small RNAs (tsRNAs) expression. Moreover, by injecting sperm tsRNAs from HFD fathers into normal zygotes, they conferred paternally acquired metabolic disorder to F1 offspring and altered gene expression of metabolic pathways in F1 islets.
Diet or exercise interventions
While there is now growing evidence that paternal obesity exerts adverse effects upon sperm function and offspring health, the question is whether these effects are reversible. Diet and exercise are the most reasonable and cost-effective interventions for obese fathers. Recently, studies have found that exercise and dietary intervention in obese fathers can improve sperm function and offspring health. For instance, Palmer et al showed that abnormal sperm function in HFD-induced obese mice can be reversed by diet and exercise interventions. They found that diet and/or exercise improved sperm motility, sperm morphology, sperm binding, and reduced sperm ROS, DNA damage and mitochondrial membrane potential. One cohort study in humans included 43 men with a BMI > 33 kg/m2 found an increase in sperm volume, sperm count, normal sperm morphology, and sex hormones through a 14-week weight loss task. Another human study included 20 morbidly obese men showed that gastric bypass surgery intervention increased serum total testosterones and follicle-stimulating hormones and reduced prolactin. Moreover, erectile function improved despite no changes in sperm quality. In addition, using diet and exercise as interventions for HFD-induced paternal obesity, McPherson et al found that diet and/or exercise improved embryo and fetal development. Diet and/or exercise interventions increased blastocyst, inner cell mass, and epiblast cell numbers and increased contact between cells, as well as increased fetal weights. Furthermore, McPherson et al demonstrated that 8-week paternal interventions improved metabolic disorders in female mice offspring. Mechanistically, dietary and exercise interventions restored the abundance of X-linked sperm microRNAs, which target genes regulating apoptosis and the cell cycle. In addition, Denham et al found significant changes in the overall and genome-wide DNA methylation of sperm from 24 men after 3 months of exercise training. Donkin et al analyzed the sperm DNA patterns in obese men before and after bariatric surgery and found that surgery-induced weight loss remodeled DNA methylation in sperm. Notably, numerous differentially methylated genes were involved in the regulation of appetite control.
Although there is substantial evidence that the paternal diet can influence the phenotype of offspring, it is not clear what substance the inheritance of this acquired trait is passed on. The epigenetic information carried in germ cells and its function in progeny have become the focus of intergenerational genetic research in recent years. In order to make the individual adapt to the complex and diverse environment, flexible gene expression regulation becomes particularly important when the organism is stimulated by the outside world. The epigenetic modification of the genome can effectively affect gene expression over time without changing the sequence of the DNA itself. Throughout life, organisms can acquire new traits through epigenetic inheritance in their living environment, and some of the epigenetic information accumulated in the environment may accumulate in gametes and escape from epigenetic reprogramming after fertilization, which can be passed on from one generation to the next. While mothers may influence offspring through intrauterine exposure during pregnancy, the biological mechanisms underlying epigenetic inheritance through germ line are often investigated in fathers. Mechanistically, DNA methylation, chromatin histone modifications, and non-coding RNAs expression have been involved in the mechanism of epigenetic inheritance.
DNA methylation is the earliest known epigenetic regulation mechanism, which refers to the reaction of methyl groups covalently binding to CpG dinucleotide cytosine 5’carbon position to transform cytosine into 5-methylcytosine under the catalysis of DNA methyltransferase. CpG is often clustered in the vicinity of gene promoters, called “CpG islands”. DNA methylation patterns are reprogrammed between generations through 2 events in mammals, which occur in primordial germ cells and zygote. During the development of primordial germ cells into gametes, DNA methylation is almost completely erased and re-established. In the initial early embryo stage, DNA methylation patterns are erased, but genomic imprints are maintained, indicating that imprinted genes are protected from the large-scale DNA methylation erasure after fertilization. In addition, recent studies have shown that non-imprinted genes can also escape from postfertilization reprogramming. For example, using methylated DNA immunoprecipitation, Borgel et al found that numerous non-imprinted genes can retain the parental gametes promoter DNA methylation, indicating a way to escape from the postfertilization reprogramming event. Another study reported that although few methylated CpG islands can fully escape from the global demethylation after fertilization, a majority of methylated CpG islands displayed incomplete demethylation in preimplantation embryos. Moreover, Jiang et al showed that paternal DNA methylation patterns persisted during the early embryogenesis, while maternal DNA methylation patterns remained until the 16-cell stage. Wei et al demonstrated that paternal prediabetes predisposed offspring to diabetes through the epigenetic modification in sperm. Moreover, they analyzed DNA methylation patterns in F0 sperm and F1 pancreatic islets, and identified a big part of differentially methylated genes overlap, indicating an epigenetic transmission from paternal sperm to specific tissues in offspring. In humans, a cross-sectional study of 67 young and healthy volunteers showed that sperm from overweight or obese men displayed significantly different DNA methylation at differentially methylated regions of imprinted genes, compared with normal weight men. Donkin et al reported that obesity remodeled human sperm DNA methylation of genes that regulate the development and function of the central nervous system. These results support the hypothesis that DNA methylation patterns can be inherited through sperm, thereby affecting the development and health of offspring. However, other studies have shown that DNA methylation was not a major genetic factor in intergenerational inheritance caused by parental diet, suggesting that there are still other factors in addition to DNA methylation.[45,59]
During gametogenesis, sperm cells undergo intense chromatin remodeling. In the process of producing haploid sperm cells, chromatin histones throughout the genome are gradually replaced by protamine. Whether the remodeling process can proceed smoothly is very important for gamete meiosis. The normal formation of gametes can directly affect the development of the embryo. However, about 10% and 1% of human and mouse histones, respectively, remain in mature sperm. These retained histones are not randomly distributed but are concentrated in gene regulatory elements.[61,62] These sites and their modifications may affect embryonic development after fertilization. At present, histone modification and chromatin remodeling on intergenerational inheritance are mainly studied in lower animals. In 2010, Greer et al reported that H3K4 methyltransferase/demethylase complex was involved in the transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Seong et al found that heat shock or osmotic stress resulted in heterochromatic disruption over multiple consecutive generations in flies, though it gradually returned to the normal state. Recently, using a Drosophila model of paternal intergenerational metabolic reprogramming, Öst et al found that paternal diet reprogrammed chromatin-state-defined regions of the genome in both mature sperm and offspring embryos, thereby modifying offspring phenotype via the male germline. Terashima et al found that paternal HFD consumption altered sperm histone composition at genes associated with the regulation of developmental processes. These results suggest that histone modifications also play an important role in intergenerational inheritance.
When exposed to the adverse environment, either DNA methylation, histone modifications or the expression of non-coding RNA may be altered, affecting the phenotype of offspring. However, it is extremely challenging to verify what changes are actually affecting future generations. It is more experimental to study the effects of specific RNA changes on intergenerational inheritance than to modify specific DNA methylation or histone modifications. Sperm has a highly condensed nucleus and little cytoplasm, which is almost silent in transcription. However, it has been shown that sperm-derived RNAs can be delivered to post-fertilization embryos. Sperm contains numerous types of non-coding RNAs, including microRNAs, small interfering RNAs, and Piwi-interacting RNAs. There are many lines of evidence supporting the RNA-dependent transmission of epigenetic effects. For example, Rechavi et al showed that starvation can induce the generation of small RNAs that act on nutrition-related genes in C elegans, an effect inherited through at least 3 successive generations. Moreover, the prolonged lifespan of F3 progeny in starved animals confirmed the transgenerational memory of past conditions. In 2006, Rassoulzadegan et al reported that sperm RNA can act as an epigenetic carrier to modify offspring phenotype in mammals. They found that the kit+/− knockout mouse testicles and sperm accumulated large amounts of RNA fragments that come from the abnormal location of the kit gene. In male offspring of kit+/− mice, some mice whose genotype was kit+/+ also showed a kit+/− phenotype. They believe that this phenotype is due to the presence of these abnormal RNA fragments in kit+/+ sperm. By injecting these RNA fragments into normal fertilized eggs, a similar phenotype can be induced, thus demonstrating that RNA carried in sperm has a role in regulating the phenotype of offspring. Recently, Fullston et al found that in addition to the phenotypic intergenerational inheritance, the microRNAs in the father's sperm also changed in diet-induced obese mice. Gapp et al showed that 5 microRNAs expression were changed in the sperm of mice exposed to fetal stress, and their offspring showed depressive behavioral patterns and abnormal glucose metabolism. Furthermore, RNAs from the sperm of stressed mice were microinjected into normal fertilized eggs and a consistent phenotype was found to repeat itself in the offspring. Notably, although the microRNAs alteration disappeared in F2 sperm of mice exposed to fetal stress, their behavioral and metabolic phenotypes still exist, suggesting that there may be other substances that transmit epigenetic information. While many studies have focused on the differential expression of microRNAs in sperm, Peng et al found that microRNAs account for only a small proportion of non-coding small RNAs in sperm, and tsRNAs account for the majority of non-coding small RNAs in sperm. More recently, Chen et al further showed that by injecting tsRNAs-rich RNA fragments from the sperm of the father mice on a long-term HFD into normal fertilized eggs, the offspring inherited a phenotype of glucose intolerance (but not insulin resistance) from the father obese mice. At the same time, changes in genes related to metabolic pathways were found in early embryos and islets after the injection of RNA fragments rich in tsRNAs, suggesting that tsRNAs may be able to alter the phenotype in offspring mice by influencing gene expression levels. This study revealed that tsRNAs may be a new kind of epigenetic information element. A study in humans reported that 28 microRNAs were expressed differently in the sperm of men who do and do not smoke, and their expression patterns may be maintained through multiple generations. These results indicate that the alteration of sperm RNA expression may be involved in the mechanism of intergenerational inheritance.
A growing number of experimental animal studies have shown that paternal diet can program offspring health, potentially by mediating epigenetic modifications in sperm. However, few epidemiological studies have investigated the effects of epigenetic modifications in obese father sperm upon offspring health in humans. Furthermore, epigenetic modification is a dynamic process, suggesting that epigenetic effects may be reversible. Therefore, given the growing obesity burden worldwide, it will ultimately be beneficial to human health if we improve epidemiological research on human sperm and offspring health to propose further interventions.
In addition, the underlying epigenetic mechanisms remain unclear. Compared with traditional genetic research, the current studies on epigenetic inheritance of acquired phenotype still cannot fully explain the causal link between the epigenetic information carried by the gametes and offspring phenotype. It also spawned several scientific problems to be solved: how does the paternal environmental exposure such as dietary changes directly/indirectly lead to epigenetic changes in gametes? In what form does the epigenetic information in these gametes achieve accurate storage (DNA methylation, chromatin structure and histone modifications, non-coding RNAs)? What is the causal/synergy relationship between these potential “molecular carriers”? Most importantly, how does the epigenetic information inherited by gametes reproduce the acquired traits of the previous generation through gene expression regulation in the next generation? These important scientific issues will become the main direction of future research.
HH conceived this review. YZ and HW wrote the manuscript. All authors read and approved the final manuscript.
Conflicts of interest
The authors declare that they have no conflicts of interest.
1. Haslam DW, James WP. Obesity Lancet
2. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. 1992. Int J Epidemiol
3. Wadhwa PD, Buss C, Entringer S, et al. Developmental origins of health and disease: brief history of the approach and current focus on epigenetic mechanisms. Semin Reprod Med
4. Samuelsson AM, Matthews PA, Argenton M, et al. Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming. Hypertension
5. Stothard KJ, Tennant PW, Bell R, et al. Maternal overweight and obesity and the risk of congenital anomalies: a systematic review and meta-analysis. JAMA
6. Boerschmann H, Pfluger M, Henneberger L, et al. Prevalence and predictors of overweight and insulin resistance in offspring of mothers with gestational diabetes mellitus. Diabetes Care
7. Drake AJ, Reynolds RM. Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Reproduction
8. Rodriguez A, Miettunen J, Henriksen TB, et al. Maternal adiposity prior to pregnancy is associated with ADHD symptoms in offspring: evidence from three prospective pregnancy cohorts. Int J Obes (Lond)
9. Jensen TK, Andersson AM, Jørgensen N, et al. Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men. Fertil Steril
10. Belloc S, Cohen-Bacrie M, Amar E, et al. High body mass index has a deleterious effect on semen parameters except morphology: results from a large cohort study. Fertil Steril
11. MacDonald AA, Herbison GP, Showell M, et al. The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis. Hum Reprod Update
12. Campbell JM, Lane M, Owens JA, et al. Paternal obesity
negatively affects male fertility and assisted reproduction outcomes: a systematic review and meta-analysis. Reprod Biomed Online
13. Kumar K, Deka D, Singh A, et al. Predictive value of DNA integrity analysis in idiopathic recurrent pregnancy loss following spontaneous conception. J Assist Reprod Genet
14. Brahem S, Mehdi M, Landolsi H, et al. Semen parameters and sperm DNA fragmentation as causes of recurrent pregnancy loss. Urology
15. Chavarro JE, Toth TL, Wright DL, et al. Body mass index in relation to semen quality, sperm DNA integrity, and serum reproductive hormone levels among men attending an infertility clinic. Fertil Steril
16. Kort HI, Massey JB, Elsner CW, et al. Impact of body mass index values on sperm quantity and quality. J Androl
17. Kriegel TM, Heidenreich F, Kettner K, et al. Identification of diabetes- and obesity-associated proteomic changes in human spermatozoa by difference gel electrophoresis. Reprod Biomed Online
18. La Vignera S, Condorelli RA, Vicari E, et al. Negative effect of increased body weight on sperm conventional and nonconventional flow cytometric sperm parameters. J Androl
19. Fariello RM, Pariz JR, Spaine DM, et al. Association between obesity and alteration of sperm DNA integrity and mitochondrial activity. BJU Int
20. Aitken RJ, Baker MA. Oxidative stress, sperm survival and fertility control. Mol Cell Endocrinol
21. Aziz N, Saleh RA, Sharma RK, et al. Novel association between sperm reactive oxygen species production, sperm morphological defects, and the sperm deformity index. Fertil Steril
22. Zorn B, Vidmar G, Meden-Vrtovec H. Seminal reactive oxygen species as predictors of fertilization, embryo quality and pregnancy rates after conventional in vitro fertilization and intracytoplasmic sperm injection. Int J Androl
23. Tunc O, Bakos HW, Tremellen K. Impact of body mass index on seminal oxidative stress. Andrologia
24. Bakos HW, Mitchell M, Setchell BP, et al. The effect of paternal diet-induced obesity on sperm function and fertilization in a mouse model. Int J Androl
25. Figueroa-Colon R, Arani RB, Goran MI, et al. Paternal body fat is a longitudinal predictor of changes in body fat in premenarcheal girls. Am J Clin Nutr
26. Danielzik S, Langnäse K, Mast M, et al. Impact of parental BMI on the manifestation of overweight 5–7 year old children. Eur J Nutr
27. Li L, Law C, Lo Conte R, et al. Intergenerational influences on childhood body mass index: the effect of parental body mass index trajectories. Am J Clin Nutr
28. Loomba R, Hwang SJ, O’Donnell CJ, et al. Parental obesity and offspring serum alanine and aspartate aminotransferase levels: the Framingham heart study. Gastroenterology
29. Bygren LO, Kaati G, Edvinsson S. Longevity determined by paternal ancestors’ nutrition during their slow growth period. Acta Biotheor
30. Kaati G, Bygren LO, Pembrey M, et al. Transgenerational response to nutrition, early life circumstances and longevity. Eur J Hum Genet
31. Kaati G, Bygren LO, Edvinsson S. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet
32. Soubry A, Schildkraut JM, Murtha A, et al. Paternal obesity
is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med
33. Soubry A, Murphy SK, Wang F, et al. Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int J Obes (Lond)
34. Ng SF, Lin RC, Laybutt DR, et al. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature
35. Ng SF, Lin RC, Maloney CA, et al. Paternal high-fat diet consumption induces common changes in the transcriptomes of retroperitoneal adipose and pancreatic islet tissues in female rat offspring. FASEB J
36. de Castro Barbosa T, Ingerslev LR, Alm PS, et al. High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring. Mol Metab
37. Fullston T, Ohlsson Teague EM, Palmer NO, 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
38. Terashima M, Barbour S, Ren J, et al. Effect of high fat diet on paternal sperm histone distribution and male offspring liver gene expression. Epigenetics
39. Ornellas F, Souza-Mello V, Mandarim-de-Lacerda CA, et al. Programming of obesity and comorbidities in the progeny: lessons from a model of diet-induced obese parents. PLoS One
40. Ornellas F, Souza-Mello V, Mandarim-de-Lacerda CA, et al. 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
41. Chowdhury SS, Lecomte V, Erlich JH, et al. Paternal high fat diet in rats leads to renal accumulation of lipid and tubular changes in adult offspring. Nutrients
42. Fullston T, Palmer NO, Owens JA, et al. Diet-induced paternal obesity
in the absence of diabetes diminishes the reproductive health of two subsequent generations of mice. Hum Reprod
43. Zhou Y, Zhu H, Wu HY, et al. Diet-induced paternal obesity
impairs cognitive function in offspring by mediating epigenetic modifications
in spermatozoa. Obesity (Silver Spring)
44. Grandjean V, Fourre S, De Abreu DA, et al. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci Rep
45. Chen Q, Yan M, Cao Z, et al. Sperm tsRNAs contribute to intergenerational inheritance
of an acquired metabolic disorder. Science
46. Palmer NO, Bakos HW, Owens JA, et al. Diet and exercise in an obese mouse fed a high-fat diet improve metabolic health and reverse perturbed sperm function. Am J Physiol Endocrinol Metab
47. Håkonsen LB, Thulstrup AM, Aggerholm AS, et al. Does weight loss improve semen quality and reproductive hormones? Results from a cohort of severely obese men. Reprod Health
48. Reis LO, Zani EL, Saad RD, et al. Bariatric surgery does not interfere with sperm quality–a preliminary long-term study. Reprod Sci
49. McPherson NO, Bakos HW, Owens JA, et al. Improving metabolic health in obese male mice via diet and exercise restores embryo development and fetal growth. PLoS One
50. McPherson NO, Owens JA, Fullston T, et al. Preconception diet or exercise intervention in obese fathers normalizes sperm microRNA profile and metabolic syndrome in female offspring. Am J Physiol Endocrinol Metab
51. Denham J, O’Brien BJ, Harvey JT, et al. Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans. Epigenomics
52. Donkin I, Versteyhe S, Ingerslev LR, et al. Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metab
53. Feng S, Jacobsen SE, Reik W. Epigenetic reprogramming in plant and animal development. Science
54. Borgel J, Guibert S, Li Y, et al. Targets and dynamics of promoter DNA methylation during early mouse development. Nat Genet
55. Smallwood SA, Tomizawa S, Krueger F, et al. Dynamic CpG island methylation landscape in oocytes and preimplantation embryos. Nat Genet
56. Jiang L, Zhang J, Wang JJ, et al. Sperm, but not oocyte, DNA methylome is inherited by zebrafish early embryos. Cell
57. Wei Y, Yang CR, Wei YP, et al. Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proc Natl Acad Sci U S A
58. Soubry A, Guo L, Huang Z, et al. Obesity-related DNA methylation at imprinted genes in human sperm: Results from the TIEGER study. Clin Epigenetics
59. Shea JM, Serra RW, Carone BR, et al. Genetic and epigenetic variation, but not diet, shape the sperm methylome. Dev Cell
60. Brykczynska U, Hisano M, Erkek S, et al. Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nat Struct Mol Biol
61. Hammoud SS, Nix DA, Zhang H, et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature
62. Arpanahi A, Brinkworth M, Iles D, et al. Endonuclease-sensitive regions of human spermatozoal chromatin are highly enriched in promoter and CTCF binding sequences. Genome Res
63. Greer EL, Maures TJ, Hauswirth AG, et al. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature
64. Seong KH, Li D, Shimizu H, et al. Inheritance of stress-induced, ATF-2-dependent epigenetic change. Cell
65. Öst A, Lempradl A, Casas E, et al. Paternal diet defines offspring chromatin state and intergenerational obesity. Cell
66. Zhao Y, Li Q, Yao C, et al. Characterization and quantification of mRNA transcripts in ejaculated spermatozoa of fertile men by serial analysis of gene expression. Hum Reprod
67. Rechavi O, Houri-Ze’evi L, Anava S, et al. Starvation-induced transgenerational inheritance of small RNAs in C. elegans. Cell
68. Rassoulzadegan M, Grandjean V, Gounon P, et al. RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature
69. Gapp K, Jawaid A, Sarkies P, et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci
70. Peng H, Shi J, Zhang Y, et al. A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm. Cell Res
71. Marczylo EL, Amoako AA, Konje JC, et al. Smoking induces differential miRNA expression in human spermatozoa: a potential transgenerational epigenetic concern? Epigenetics