paternal obesity, interventions, and mechanistic pathways to impaired health in offspring
TRANSCRIPT
E-Mail [email protected]
Ann Nutr Metab 2014;64:231–238 DOI: 10.1159/000365026
Paternal Obesity, Interventions,and Mechanistic Pathways to Impaired Health in Offspring
Nicole O. McPherson a, d Tod Fullston a R. John Aitken b Michelle Lane a, c
a Robinson Institute, Research Centre for Reproductive Health, School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, S.A. , b School of Environmental and Life Sciences, University of Newcastle, Callaghan, N.S.W. , c Repromed, Dulwich, S.A. , and d Freemasons Foundation Centre for Mens Health, University of Adelaide, Adelaide, S.A., Australia
cise interventions have shown improvements in sperm func-tion and molecular composition, resulting in restorations of both embryo and fetal health and subsequent male off-spring fertility. The direct mode for paternal inheritance is likely mediated via spermatozoa. We propose two main the-ories for the origin of male obesity-induced paternal pro-gramming: (1) accumulation of sperm DNA damage result-ing in de novo mutations in the embryo and (2) changes in sperm epigenetic marks (microRNA, methylation, or acetyla-tion) altering the access, transcription, and translation of pa-ternally derived genes during early embryogenesis. Conclu-
sions: Paternal overweight/obesity induces paternal pro-gramming of offspring phenotypes likely mediated through genetic and epigenetic changes in spermatozoa. These pro-grammed changes to offspring health appear to be partially restored via diet/exercise interventions in obese fathers pre-conception, which have been shown to improve aspects of sperm DNA integrity. However, the majority of data sur-rounding paternal obesity and offspring phenotypes have come from rodent models; therefore, we contend that it will be increasingly important to study population-based data to determine the likely mode of inheritance in humans.
© 2014 S. Karger AG, Basel
Key Words
Sperm · Fertility · Infertility · Embryos · Epigenetics · DNA damage · Mutation · Male obesity
Abstract
Background: The global rates of male overweight/obesity are rising, approaching 70% of the total adult population in Western nations. Overweight/obesity increases the risk of chronic diseases; however, there is increasing awareness that male obesity negatively impacts fertility, subsequent pregnancy, and the offspring health burden. Developmental programming is well defined in mothers; however, it is be-coming increasingly evident that developmental program-ming can be paternally initiated and mediated through pa-ternal obesity. Key Messages: Both human and rodentmodels have established that paternal obesity impairs sex hormones, basic sperm function, and molecular composi-tion. This results in perturbed embryo development and health and an increased subsequent offspring disease bur-den in both sexes. The reversibility of obesity-induced pa-rental programming has only recently received attention. Promising results in animal models utilizing diet and exer-
Published online: October 2, 2014
Nicole McPherson School of Paediatrics and Reproductive HealthDiscipline of Obstetrics and Gynaecology, University of Adelaide Level 2 Medical School South, Adelaide, SA 5005 (Australia) E-Mail nicole.mcpherson @ adelaide.edu.au
© 2014 S. Karger AG, Basel0250–6807/14/0644–0231$39.50/0
www.karger.com/anm
Dow
nloa
ded
by:
Kel
logg
Hea
lth S
cien
ces
Libr
.
12
9.17
3.72
.87
- 11
/10/
2014
1:5
4:23
PM
McPherson /Fullston /Aitken /Lane
Ann Nutr Metab 2014;64:231–238 DOI: 10.1159/000365026
232
Introduction
Globally, 1.46 billion adults and over 170 million children aged less than 18 years are overweight or obese, with the incidence of overweight and obesity in males in developed nations approaching 70% and rising. The impacts of obesity on an individual are well document-ed and involve increased risks of cardiovascular disease, diabetes, and stroke; however, there is increasing aware-ness that parental obesity can negatively impact fertility and subsequent pregnancy as well as the offspring. This concept of developmental programming is a phenom-enon whereby perturbations of the environment before birth can alter the offspring phenotype through a range of mechanisms. This is most well defined in mothers in whom postnatal environmental exposures such as obe-sity impact the incidence of childhood obesity. While developmental programming of offspring health by the mother is widely accepted, it is increasingly evident that developmental programming can be paternally initiat-ed. For example, paternal smoking, age, and occupa-tional chemical exposure are associated with an in-creased risk of cancer and mental health disorders in children. This review will focus on the line of evidence for the impacts of paternal obesity on fertility, pregnan-cy, and offspring health and whether these can be re-versed.
Obesity, Male Fertility, Pregnancy, and Offspring:
Human Studies
Overall, there is a consensus that male obesity alters sex hormones and the molecular composition and func-tion of spermatozoa. Male obesity is known to reduce sex hormone-binding globulin and testosterone levels while increasing estrogen levels, directly impairing spermatogenesis [1] . Furthermore, multiple studies have determined the impacts of excess weight and obe-sity on sperm motility, morphology, and count, param-eters that are routinely tested by primary care physi-cians in the analysis of male fertility. While there are conflicting results regarding the effect of male obesity on simple sperm parameters, a recent meta-analysis de-termined that male obesity reduced sperm counts, in-creasing the incidence of oligospermia and azoospermia [1] ( fig. 1 ).
Besides simple spermatozoon parameters, there is mounting evidence that male obesity perturbs the mo-lecular composition of spermatozoa, increasing reactive oxygen species (ROS) generation which subsequently leads to an associative increase in oxidative sperm DNA damage and reduced sperm mitochondrial function [2] ( fig. 1 ). These molecular perturbations in spermatozoa are independently associated with reduced pregnancy rates and an increased risk of miscarriage [3] . A small
Sperm Embryo Offspring
Male obesity
Fig. 1. Summary of the effects of paternal overweight/obesity on sperm function, subsequent early embryo development, and impairment of offspring health. Male obesity alters both the structure and the molecular composition of spermatozoa, impairing subsequent embryo develop-ment and health and reducing pregnancy outcomes and live birth rates (animal mod-els and human), and in animal models the resulting offspring have an increased risk of noncommunicable diseases with an in-creased risk of metabolic syndrome and subfertility extending through 2 genera-tions.
Colo
r ver
sion
ava
ilabl
e on
line
Dow
nloa
ded
by:
Kel
logg
Hea
lth S
cien
ces
Libr
.
12
9.17
3.72
.87
- 11
/10/
2014
1:5
4:23
PM
Paternal Obesity and Developmental Programming
Ann Nutr Metab 2014;64:231–238 DOI: 10.1159/000365026
233
number of clinical studies have also implicated male obesity as a negative factor for pregnancy success, with decreased pregnancy rates and an increase in pregnancy loss in couples undergoing assisted reproductive tech-nologies (ART) [4] . In part, this effect appears to be due to reduced spermatozoa-egg binding and a resultant de-crease in fertilization rates during in vitro fertilization (IVF/ICSI). Studies including ART patients have estab-lished that male obesity at the time of conception im-pairs embryo development to the blastocyst stage, there-fore reducing implantation and live-birth rates [4] ( fig. 1 ). In addition to the disruption of embryonic de-velopment and the progress of early pregnancy, epide-miological studies have also concluded that obese fa-thers are more likely to father obese children [5] . How-ever, it is noted that the extent of individual contributions from genetic, epigenetic, and environment sources can-not be delineated due to the common environment shared by both the father and the child.
Obesity, Male Fertility, Pregnancy, and Offspring:
Animal Studies
Given the many confounding factors associated with human studies, much of the information collected to date on obesity-induced paternal programming comes from animal models. The seminal paper in this field, published by Morris and colleagues, demonstrated for the first time that paternal nutritional cues, including obesity and glucose intolerance, could directly impact the metabolic syndrome susceptibility of the offspring [6] . These observations have been extended to other pa-ternal programming exposures, including a paternal low-protein diet which increases the cardiovascular and metabolic disease risk of the offspring [7] . Several ro-dent models have established that diet-induced male obesity negatively impacts sperm function and molecu-lar composition, decreasing the spermatozoon motility, count, normal morphology, ability to capacitate and bind to an oocyte, while increasing sperm ROS-associ-ated DNA damage and mitochondrial dysfunction [4] ( fig. 1 ). When these diet-induced obese rodents were mated with normal-weight female rodents, embryo de-velopment was delayed, with extended first, second, and third cleavage times, reduced rates of compaction, and decreased development to the blastocyst stage, mirror-ing findings in humans [8] . Further, blastocysts that did develop had an altered metabolism and reduced num-bers of both inner cell mass and trophectoderm cells,
causing functional reductions in outgrowth when the embryos were plated onto a fibronectin cell layer, sug-gesting an impaired capacity for implantation [8] ( fig. 1 ). This was confirmed by embryo transfer experiments which determined that implantation rates were reduced and fetal growth delayed at embryonic day 15, embry-onic day 18, and birth, with delays in eye and limb de-velopment [6, 8, 9] . By neonatal day 5, the offspring had accelerated, catch-up growth, becoming heavier than control diet-sired pups and maintaining the difference until weaning [10] ( fig. 1 ).
Diet-Induced Male Obesity Initiates Metabolic
Syndrome in Offspring
Two rodent studies have now been published that establish a direct effect of a paternal high-fat diet (HFD) on the metabolic health of the next generation in the absence [10] and presence of altered glucose homeosta-sis [6] in founder males ( fig. 1 ). Founder males fed an HFD and mated with normal-weight females produced F 1 female offspring that were heavier and had reduced glucose tolerance, increased insulin resistance, and in-creased adiposity as they aged despite being fed stan-dard chow. These changes in metabolic health in F 1 fe-male offspring were concomitant with altered pancre-atic and adipose function, with an increased insulin section, a reduced pancreatic islet cell size, and altera-tions to methylation and gene profiles [6, 11] . Addi-tionally, F 1 males born to founders fed an HFD dis-played an altered glucose and insulin sensitivity; how-ever, this was not evident until later in life. Several of these metabolic effects seen in the F 1 generation were shown to persist in the F 2 generation, with F 1 females (who had increased adiposity) themselves producing F 2 males with increased adiposity [10] . Similarly, F 2 fe-male and male offspring from F 1 females had compro-mised metabolic health (reduced glucose tolerance/clearance and insulin sensitivity) as they aged com-pared to those born from a control-diet grandfather [10] . While the transmission effects were less evident down the F 1 male linage, F 2 females resulting from F 1 males of grandfathers exposed to HFD also had im-paired insulin tolerance [10] . Taken together, these data suggest that paternal obesity at the time of conception has a marked effect on offspring metabolic health, which seems to be exacerbated in female offspring and can extend to 2 generations, albeit with different de-grees of penetration and presentation.
Dow
nloa
ded
by:
Kel
logg
Hea
lth S
cien
ces
Libr
.
12
9.17
3.72
.87
- 11
/10/
2014
1:5
4:23
PM
McPherson /Fullston /Aitken /Lane
Ann Nutr Metab 2014;64:231–238 DOI: 10.1159/000365026
234
Diet-Induced Male Obesity Programs Offspring
Subfertility
In addition to the reported changes in metabolic health in offspring from an obese father, one study to date in a rodent model of male obesity has also reported a negative effect to the reproductive health of male off-spring extending to 2 generations [12] ( fig. 1 ). HFD-fed founders produced F 1 males with reduced sperm func-tion, including reduced motility and increases in sperm ROS generation and DNA damage. These F 1 males went on to produce F 2 male offspring with similarly impaired reproductive health involving reduced sperm motility and altered mitochondrial function. F 1 daughters of founders fed an HFD displayed altered oocyte health, with reduced meiotic progression and altered mitochon-drial membrane potential. Their F 2 male offspring, how-ever, showed severe subfertility phenotypes, with re-duced testis weights and serum testosterone, reduced sperm motility, and increased sperm ROS. However, it should be noted that F 1 females born to HFD-fed found-ers had increased adiposity at mating and were glucose intolerant and insulin insensitive, which likely contrib-uted to the F 2 phenotypes from this lineage [12] . Wheth-er paternal obesity in humans also affects the reproduc-tive health of their children and grandchildren remains to be established. However, the increasing reliance on ART methods to achieve pregnancy in Western societies suggests a likely role for environmental factors, among which obesity is a prime candidate.
Reversibility of Male Obesity-Programmed
Perturbed Fetal and Offspring Growth
While it is becoming clear that male obesity has neg-ative impacts on fertility, spermatozoon function, and potentially the long-term disease burden of the off-spring, there is emerging evidence that these effects might be reversible. Weight loss in obese men via bar-iatric surgery has been shown to improve hormone pro-files (testosterone, inhibin B, sex hormone-binding globulin, and estrogens) and erectile dysfunction and it has been proven not to interfere with sperm function [13] . There have been two case studies showing that aro-matase inhibitors (i.e. anastrozole) in obese men can re-store testosterone, LH, FSH, and estrogen levels as well as sperm function (count, motility, and morphology) [14] . Animal models of male obesity have shown im-provements of both metabolic health (glucose, insulin,
and cholesterol levels) and fertility measures (increased sperm count, increased sperm motility, and decreased sperm ROS and DNA damage) with the intake of seleni-um-enriched probiotics, olive oil, and metformin (dia-betes medication) [15–17] .
Diet and Exercise Interventions in Obese Fathers Restore Sperm Function and Early Embryo and Fetal Health To date, only one study in humans has assessed the
impact of diet and exercise lifestyle interventions on obese males, demonstrating improvements in sperm function as measured by motility, morphology, count, and DNA integrity in those men who lost the greatest amount of weight [18] . A rodent model of diet and ex-ercise interventions in obese males also demonstrated similar findings, with diet and/or exercise interventions improving sperm motility, morphology, capacitation and sperm-egg binding, and sperm mitochondrial func-tion while decreasing ROS generation and DNA dam-age [19] . Furthermore, when these obese rodents were mated with normal-weight females, diet and/or exercise interventions restored blastocyst development, blasto-cyst cell numbers, and early fetal development to that of control diet founders [9] . The improvements in markers of embryo health were directly associated with the res-toration of chromatin and sperm function in rodents who underwent a diet and exercise intervention [19] , with improvements in chromatin integrity likely reduc-ing the need for paternal DNA repair at fertilization, eliminating any delay in first and second cleavage events previously reported for paternal obesity. Cell-to-cell contacts, which are indicative of increased cell polariza-tion, junctional communication, and embryo health, were also improved in compacting embryos produced by obese rodents who underwent exercise interventions [9] . These improvements to embryo health resulted in restoration of implantation rates in males who under-went a combined diet and exercise intervention [9] , with all intervention groups (diet and/or exercise) show-ing an increase in fetal weight on embryonic day 18 [9] . This suggests that diet/exercise lifestyle interventions in obese males preconception improve embryo develop-ment and fetal outcomes. The ability to produce off-spring with a reduced susceptibility to developing meta-bolic disorders must be generated via improvements to the molecular composition of the spermatozoa, al-though the precise nature of these changes awaits reso-lution.
Dow
nloa
ded
by:
Kel
logg
Hea
lth S
cien
ces
Libr
.
12
9.17
3.72
.87
- 11
/10/
2014
1:5
4:23
PM
Paternal Obesity and Developmental Programming
Ann Nutr Metab 2014;64:231–238 DOI: 10.1159/000365026
235
Diet and Exercise Interventions in Obese Males Reduce Male Offspring Susceptibility to Subfertility To date, there is only one published study in rodents
assessing the reversibility of altered offspring phenotypes (in this case subfertility) through diet and exercise inter-ventions in diet-induced obese founders [20] . Only inter-ventions involving a change of diet in the obese founder improved perturbed sperm motility and spermatozoa-egg binding in F 1 males, with exercise interventions only resulting in small improvements in F 1 sperm function [20] . Interestingly, it was noted that the improvements in offspring sperm function may be more related to the met-abolic health of their fathers, with the glucose, cholester-ol, and adipose state of the fathers correlating with repro-ductive measures in their sons [20] . Further studies are required to determine if these findings can be replicated in human longitudinal studies.
DNA Damage and Epigenetic Signals Transmit
Paternal Health Cues to the Next Generation
Given that the effects of male obesity on embryos, preg-nancy, and offspring have been shown to occur with natu-ral conception as well as in an ART setting, where interac-tions with the female reproductive tract and seminal fluid are avoided, the transgenerational impact of male obesity is likely mediated through changes in the spermatozoa. There
are two main theories regarding the origin of these changes, i.e. either (1) accumulation of spermatozoon DNA damage or (2) epigenetic changes to the spermatozoa ( fig. 2 ).
Accumulation of Sperm DNA Damage Results in de
novo Mutations in the Embryo
Spermatozoon protamination is incomplete, resulting in approximately 1% of histones being retained in murine spermatozoa and up to 15% in their human counterparts. Significantly, both spermatozoon nucleosome- and his-tone-bound regions are conserved among mammalian species, and the DNA regions (genes) that are associated with these areas are not randomly distributed and appear to be specifically enriched at loci of developmental impor-tance, including gene promoters for early embryo develop-ment, signal factors, HOX gene clusters, and imprinting regions [21] . It is suggested that the DNA surrounding these histone-bound regions is more susceptible to damage due to its loosened DNA arrangement compared to that of protamine-bound regions. Additionally, during spermato-genesis, spermatozoa shed the majority of their cytoplasm; thus, spermatozoa are highly susceptible to increased oxi-dative damage due to their lack of cytoplasmic scavenging enzymes and the high levels of polyunsaturated fatty acids in their plasma membranes. Therefore, loci associated with retained histones may be vulnerable to attack from oxida-
Obesity
ROS
microRNAHistone-boundDNA
5hMc5hMc
histones
Fig. 2. Hypothesis for the mechanistic path-way of obesity-initiated paternal program-ming of altered offspring health via sperma-tozoa. The mechanistic pathway of obesity-initiated paternal programming is likely multifactorial, with sperm delivering not only chromatin and protamines to the oo-cyte at fertilization but also small noncod-ing RNAs. These changes alter the embryo by: (1) increasing the DNA damage, which increases de novo mutations in the embryo, and (2) altering histone retention and epi-genetic marks, changing the access to pater-nal genes; also (3) changes in microRNAs in sperm alter the degradation of mRNAs in the embryo, impairing the translation of embryonic important proteins.
Colo
r ver
sion
ava
ilabl
e on
line
Dow
nloa
ded
by:
Kel
logg
Hea
lth S
cien
ces
Libr
.
12
9.17
3.72
.87
- 11
/10/
2014
1:5
4:23
PM
McPherson /Fullston /Aitken /Lane
Ann Nutr Metab 2014;64:231–238 DOI: 10.1159/000365026
236
tive agents (i.e. H 2 O2 and O 2 ). In a recent analysis of oxida-tive DNA damage in the GPx5 knockout mouse, it was observed that the major sites of such damage involve his-tone-rich interlinker regions located at the periphery of the spermatozoon nucleus in close association with the nucle-ar matrix, where they interconnect the protamine-domi-nated toroids. Such regions are thought to contain genes that are primed for expression in the early embryo, and as a result their disruption would be expected to have a sig-nificant impact on the normality of development [22] .
A hypothesis for the generation and transmission of paternally mediated pathologies to offspring, involving the aberrant repair of spermatozoon DNA damage, has been suggested by Aitken et al. [23] . The first step in this process involves defective chromatin remodeling during spermiogenesis, with the result that spermatozoa are re-leased into the lumina of the seminiferous tubules in an imperfect state, with poorly protaminated, inadequately compacted chromatin. As a result of such impaired chro-matin remodeling, the spermatozoa are vulnerable to DNA strand breaks most commonly mediated by oxida-tive stress, which increases spermatozoon apoptosis and oxidative DNA damage. At fertilization, the oocyte is equipped with a limited capacity to repair the oxidized DNA damage brought into the zygote by the fertilizing spermatozoon. According to this hypothesis [23] , incom-plete or aberrant repair of paternal DNA damage has the potential to create mutations which, because they precede the S phase in the first mitotic division, will affect every cell in the body ( fig. 2 ). This hypothesis is relevant to both human and rodent models of obesity since increased oxi-dative spermatozoon DNA damage has been reported in both situations [reviewed in 4 ]. However, male obesity is multifactorial, with changes in DNA methylation, mi-croRNAs, and a range of posttranslational modifications affecting chromatin-associated proteins probably accom-panying an increase in oxidative DNA damage. We fur-ther propose additional mechanisms for male obesity transmission to affected offspring involving changes in the fertilizing spermatozoon’s epigenetic state ( fig. 2 ).
Histone Modifications in Sperm in Response
to Obesity Alter the Access to Paternal Genes
Postfertilization
The process of histone-to-protamine transition is reli-ant on histone acetylation regulated by both histone deacetylases and histone acetylases. Histone acetylation presents as an epigenetic mark that is capable of being
transmitted to the oocyte during fertilization. Some class-es of histone deacetylases (class III) are regulated by the metabolic state and, in a mouse model of diet-induced obesity, obese mice had a decreased expression at both the gene and the protein level of histone deacetylase SIRT6 in elongating spermatids which resulted in increased his-tone acetylation during spermiogenesis [24] . This is as-sociated with an increase in DNA damage in transitional spermatids and mature spermatozoa. Thus, changes in the regulation of histone deacetylases via increased adi-posity could perturb or increase the retention of histones. Importantly, histone deacetylase activity can be compro-mised by alkylation reactions involving electrophilic al-dehydes such as 4-hydroxynonenal generated as a result of lipid peroxidation [25] . Therefore, the systemic oxida-tive stress associated with obesity could account for both the oxidative DNA damage seen in spermatozoa and the silencing of histone deacetylases as a secondary conse-quence of aldehydes generated during lipid peroxidation.
The histone-bound regions so affected have been shown to be vital for paternal DNA replication following fertilization as well as the activation of paternal genome transcription during early embryogenesis [26] . While, spermatozoon protamines are replaced by maternal his-tones [26] , paternally bound histone segments are not ini-tially replaced by the oocyte and thus any modifications to either these histones or the DNA within these regions are likely inherited by the embryo [26] . Therefore, we hy-pothesize that damage to spermatozoa in histone-bound DNA regions in male obese patients will likely persist in the early embryo, altering the accessibility for transcrip-tion of paternally derived developmental genes and changing the transcriptome of the developing embryo ( fig. 2 ).
Obesity-Induced Sperm Hypomethylation
There is now clear evidence that the paternal epi-genome influences early embryonic development, with chemically induced site-specific changes in spermatozo-on DNA methylation within the male pronucleus, associ-ated with increased postimplantation pregnancy loss [27] . Male obesity is associated with the DNA hypometh-ylation profiles of spermatozoa in both rodents [10] and humans, with hypomethylation [28] of imprinting genes and repeat elements in spermatozoa linked to reduced pregnancy success [26] . It has been reported that oxida-tive stress in human spermatozoa as seen in male obesity is also associated with spermatozoon hypomethylation
Dow
nloa
ded
by:
Kel
logg
Hea
lth S
cien
ces
Libr
.
12
9.17
3.72
.87
- 11
/10/
2014
1:5
4:23
PM
Paternal Obesity and Developmental Programming
Ann Nutr Metab 2014;64:231–238 DOI: 10.1159/000365026
237
and reduced pregnancy rates [26] . Evidence of how changes in the methylation profiles of spermatozoa result in a phenotypic change in the developing embryo is ur-gently needed.
Sperm-Born microRNAs Influence Gene
Expression in the Early Embryo, Programming
Offspring Phenotypes
A further proposed mechanism for paternal program-ming is via noncoding RNAs. Mature spermatozoa con-tain significant amounts of RNA and noncoding RNAs, including microRNAs, with human spermatozoa con-taining ∼ 1,700 microRNAs [29] . microRNAs are short ( ∼ 22 nt), endogenous, single-stranded noncoding RNAs that act to degrade gene transcripts (mRNA) and/or sup-press protein translation by specific binding to target mRNAs. microRNAs predominantly function via mRNA decay, and during fertilization this spermatozoon RNA pool is transferred to the oocyte [29] . Microinjection of a single microRNA (or its predicted target mRNA) into the pronuclei of mouse embryos has been shown to alter the resultant offspring phenotypes, including loss of pigmen-tation, cardiac hypertrophy, and increased growth trajec-tories (early embryo to adulthood) [26] . The microinject-ed microRNAs were detected until the 2-cell stage, trig-gering an altered signaling cascade within the 1- to 2-cell embryo which continued to the blastocyst stage. Further-more, these paramutations appear to be inherited as they were detected in the next 2–3 generations. microRNAs are dysregulated in the testes and mature spermatozoa [10] of rodent males fed an HFD which alters the levels of mRNA targets that are a part of the molecular networks involved in embryonic development (pluripotency), met-abolic disease (leptin/insulin signaling and carbohydrate/lipid metabolism), transcriptional regulation, RNA post-translational modification, and inflammation [10] . It is conceivable that perturbations of these pathways initially occur in the embryo and persist into the tissues of adult offspring. Altogether, this evidence implicates micro-RNAs as a potential mechanism by which paternal envi-ronmental cues can be passed from father to offspring. Evidence already exists to suggest that the microRNA composition of spermatozoa can respond to environ-mental factors such as stress and via this mechanism make an important epigenetic contribution to the prog-eny that persists into future generations [30] . Therefore, we hypothesize that changes to the endogenous sperma-tozoon microRNAs resulting from male obesity target
mRNA transcripts in the newly fertilized oocyte, altering the activity of key molecular networks and signaling cas-cades that regulate embryonic development, program-ming altered offspring health ( fig. 2 ).
Conclusion
Male obesity is clearly a factor that affects the health of subsequent generations in rodent models, an effect that is reversed through diet and exercise interventions in the father. To date, there is limited information re-garding the causal mechanisms by which obesity and its associated comorbidities exert their effects on spermato-zoa and subsequent embryo/fetal and offspring health. However, they appear to be multifactorial, with several implicated pathways including genetic and epigenetic changes precipitated by increased exposure of the male germ line to oxidative stress. Currently, there is little in-formation in humans about the contribution of the male to programming the health of the child. In fact, in many cases the male is used as a control for female exposures. However, data from animal models is increasingly pro-viding evidence that the spermatozoon is not a passive entity in the development of the embryo and that pater-nal exposures preconception do influence the develop-mental trajectory of the developing embryo, affecting fe-tal growth in utero. Therefore, we contend that it will become increasingly important when studying popula-tion-based data to consider male exposures as part of the equation for understanding how parental obesity and al-tered metabolic health impact the health of future gen-erations and how this may be restored through interven-tions.
Disclosure Statement
The authors declare no conflict of interest.
References 1 Sermondade N, Faure C, Fezeu L, Shayeb AG, Bonde JP, Jensen TK, Van Wely M, Cao J, Martini AC, Eskandar M, Chavarro JE, Kolo-szar S, Twigt JM, Ramlau-Hansen CH, Borges E Jr, Lotti F, Steegers-Theunissen RP, Zorn B, Polotsky AJ, La Vignera S, Eskenazi B, Tremellen K, Magnusdottir EV, Fejes I, Herc-berg S, Levy R, Czernichow S: BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum Re-prod Update 2013; 19: 221–231.
Dow
nloa
ded
by:
Kel
logg
Hea
lth S
cien
ces
Libr
.
12
9.17
3.72
.87
- 11
/10/
2014
1:5
4:23
PM
McPherson /Fullston /Aitken /Lane
Ann Nutr Metab 2014;64:231–238 DOI: 10.1159/000365026
238
2 Fariello RM, Pariz JR, Spaine DM, Cedenho AP, Bertolla RP, Fraietta R: Association be-tween obesity and alteration of sperm DNA integrity and mitochondrial activity. BJU Int 2012; 110: 863–867.
3 Ribas-Maynou J, Garcia-Peiro A, Fernandez-Encinas A, Amengual MJ, Prada E, Cortes P, Navarro J, Benet J: Double stranded sperm DNA breaks, measured by comet assay, are associated with unexplained recurrent mis-carriage in couples without a female factor. PLoS One 2012; 7:e44679.
4 Palmer NO, Bakos HW, Fullston T, Lane M: Impact of obesity on male fertility, sperm function and molecular composition. Sper-matogenesis 2012; 2: 253–263.
5 Danielzik S, Langnase K, Mast M, Spethmann C, Muller MJ: Impact of parental BMI on the manifestation of overweight 5–7 year old chil-dren. Eur J Nutr 2002; 41: 132–138.
6 Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ: Chronic high-fat diet in fa-thers programs beta-cell dysfunction in fe-male rat offspring. Nature 2010; 467: 963–966.
7 Watkins AJ, Sinclair KD: Paternal low protein diet affects adult offspring cardiovascular and metabolic function in mice. Am J Physiol Heart Circ Physiol 2014; 306:H1444–H1452.
8 Binder NK, Hannan NJ, Gardner DK: Pater-nal diet-induced obesity retards early mouse embryo development, mitochondrial activity and pregnancy health. PLoS One 2012; 7:e52304.
9 McPherson NOB, H. W., Setchell BP, Owens JA, Lane M: Improving metabolic health in obese male mice via diet and exercise restores embryo development and fetal growth. PLoS One 2013; 8:e71459.
10 Fullston T, Teague EM, Palmer NO, de Blasio MJ, Mitchell M, Print CG, Owens JA, Lane M: Paternal obesity initiates metabolic distur-bances in two generations of mice and alters the transcription profile of tesis and sperm microRNA content. FASEB J 2013; 27: 4226–4243.
11 Ng SF, Lin RC, Maloney CA, Youngson NA, Owens JA, Morris MJ: Paternal high-fat diet consumption induces common changes in the transcriptomes of retroperitoneal adipose and pancreatic islet tissues in female rat off-spring. FASEB J 2014; 28: 1830–1841.
12 Fullston T, Palmer NO, Owens JA, Mitchell M, Bakos HW, Lane M: Diet-induced pater-nal obesity in the absence of diabetes dimin-ishes the reproductive health of two subse-quent generations of mice. Hum Reprod 2012; 27: 1391–1400.
13 Reis LO, Zani EL, Saad RD, Chaim EA, de Oliveira LC, Fregonesi A: Bariatric surgery does not interfere with sperm quality – a pre-liminary long-term study. Reprod Sci 2012; 19: 1057–1062.
14 Stephens SM, Polotsky AJ: Big enough for an aromatase inhibitor? How adiposity affects male fertility. Semin Reprod Med 2013; 31: 251–257.
15 Ibrahim HA, Zhu Y, Wu C, Lu C, Ezekwe MO, Liao SF, Haung K: Selenium-enriched probiotics improves murine male fertility compromised by high fat diet. Biol Trace Elem Res 2012; 147: 251–260.
16 Chen XL, Gong LZ, Xu JX: Antioxidative ac-tivity and protective effect of probiotics against high-fat diet-induced sperm damage in rats. Animal 2013; 7: 287–292.
17 Saez Lancellotti TE, Boarelli PV, Romero AA, Funes AK, Cid-Barria M, Cabrillana ME, Monclus MA, Simon L, Vicenti AE, Fornes MW: Semen quality and sperm function loss by hypercholesterolemic diet was recovered by addition of olive oil to diet in rabbit. PLoS One 2013; 8:e52386.
18 Hakonsen LB, Thulstrup AM, Aggerholm AS, Olsen J, Bonde JP, Andersen CY, Bungum M, Ernst EH, Hansen ML, Ramlau-Hansen CH: Does weight loss improve semen quality and reproductive hormones? Results from a co-hort of severely obese men. Reprod Health 2011; 8: 24.
19 Palmer NO, Bakos HW, Owens JA, Setchell BP, Lane M: 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 2012; 302:E768–E780.
20 McPherson NO, Fullston T, Bakos HW, Setchell BP, Lane M: Obese father’s metabolic state, adiposity, and reproductive capacity in-dicate son’s reproductive health. Fertil Steril 2014; 101: 865–873.
21 Hammoud SS, Nix DA, Hammoud AO, Gib-son M, Cairns BR, Carrell DT: Genome-wide analysis identifies changes in histone reten-tion and epigenetic modifications at develop-mental and imprinted gene loci in the sperm of infertile men. Hum Reprod 2011; 26: 2558–2569.
22 Noblanc A, Damon-Soubeyrand C, Karrich B, Henry-Berger J, Cadet R, Saez F, Guiton R, Janny L, Pons-Rejraji H, Alvarez JG, Drevet JR, Kocer A: DNA oxidative damage in mam-malian spermatozoa: where and why is the male nucleus affected? Free Radic Biol Med 2013; 65: 719–723.
23 Aitken RJ, Koopman P, Lewis SE: Seeds of concern. Nature 2004; 432: 48–52.
24 Palmer NO, Fullston T, Mitchell M, Setchell BP, Lane M: SIRT6 in mouse spermatogenesis is modulated by diet-induced obesity. Reprod Fertil Dev 2011; 23: 929–939.
25 Doyle K, Fitzpatrick FA: Redox signaling, al-kylation (carbonylation) of conserved cyste-ines inactivates class I histone deacetylases 1, 2, and 3 and antagonizes their transcriptional repressor function. J Biol Chem 2010; 285: 17417–17424.
26 Gannon JR, Emery BR, Jenkins TG, Carrell DT: The sperm epigenome: implications for the embryo. Adv Exp Med Biol 2014; 791: 53–66.
27 Pathak S, Kedia-Mokashi N, Saxena M, D’Souza R, Maitra A, Parte P, Gill-Sharma M, Balasinor N: Effect of tamoxifen treatment on global and insulin-like growth factor 2-H19 locus-specific DNA methylation in rat sper-matozoa and its association with embryo loss. Fertil Steril 2009; 91: 2253–2263.
28 Tunc O, Tremellen K: Oxidative DNA dam-age impairs global sperm DNA methylation in infertile men. J Assist Reprod Genet 2009; 26: 537–544.
29 Ostermeier GC, Miller D, Huntriss JD, Dia-mond MP, Krawetz SA: Reproductive biolo-gy: delivering spermatozoan RNA to the oo-cyte. Nature 2004; 429: 154.
30 Gapp K, Jawaid A, Sarkies P, Bohacek J, Pelc-zar P, Prados J, Farinelli L, Miska E, Mansuy IM: Implication of sperm RNAs in transgen-erational inheritance of the effects of early trauma in mice. Nat Neurosci 2014; 17: 667–669.
Dow
nloa
ded
by:
Kel
logg
Hea
lth S
cien
ces
Libr
.
12
9.17
3.72
.87
- 11
/10/
2014
1:5
4:23
PM