Skip to main content Accessibility help
×
Home
Hostname: page-component-7f7b94f6bd-w6m4b Total loading time: 0.688 Render date: 2022-06-28T19:46:47.428Z Has data issue: true Feature Flags: { "shouldUseShareProductTool": true, "shouldUseHypothesis": true, "isUnsiloEnabled": true, "useRatesEcommerce": false, "useNewApi": true } hasContentIssue true

Paternal periconception metabolic health and offspring programming

Published online by Cambridge University Press:  27 October 2021

Nader Eid
Affiliation:
Academic Unit of Population and Lifespan Sciences, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK
Hannah L. Morgan
Affiliation:
Academic Unit of Population and Lifespan Sciences, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK
Adam J. Watkins*
Affiliation:
Academic Unit of Population and Lifespan Sciences, School of Medicine, Queen's Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK
*
*Corresponding author: Adam J. Watkins, email adam.watkins@nottingham.ac.uk
Rights & Permissions[Opens in a new window]

Abstract

The association between maternal metabolic status at the time of conception and subsequent embryogenesis and offspring development has been studied in detail. However, less attention has been given to the significance of paternal nutrition and metabolism in directing offspring health. Despite this disparity, emerging evidence has begun to highlight an important connection between paternal metabolic well-being, semen quality, embryonic development and ultimately adult offspring health. This has established a new component within the Developmental Origins of Health and Disease hypothesis. Building on the decades of understanding and insight derived from the numerous models of maternal programming, attention is now becoming focused on defining the mechanisms underlying the links between paternal well-being, post-fertilisation development and offspring health. Understanding how the health and fitness of the father impact on semen quality is of fundamental importance for providing better information to intending fathers. Furthermore, assisted reproductive practices such as in vitro fertilisation rely on our ability to select the best quality sperm from a diverse and heterogeneous population. With considerable advances in sequencing capabilities, our understanding of the molecular and epigenetic composition of the sperm and seminal plasma, and their association with male metabolic health, has developed dramatically over recent years. This review will summarise our current understanding of how a father's metabolic status at the time of conception can affect sperm quality, post-fertilisation embryonic and fetal development and offspring health.

Type
Conference on Nutrition in a changing world
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

Introduction

Over recent decades, human and animal model studies have highlighted the significance of the in utero period in shaping patterns of fetal development and offspring long-term health(Reference Hanson and Gluckman1). Investigations into maternal exposure to different environmental factors during pregnancy have shown that the offspring can display an increased propensity for developing a range of non-communicable conditions such as CVD(Reference Drake and Reynolds2), insulin resistance and obesity(Reference Boerschmann, Pfluger and Henneberger3) and certain behavioural disorders(Reference Rodriguez, Miettunen and Henriksen4). The Developmental Origins of Health and Disease (DOHaD) field has expanded to investigate a range of environmental and lifestyle challenges, as well as defining the sensitivity of specific ‘windows’ before, during and even after pregnancy(Reference Barouki, Gluckman and Grandjean5). One such window that appears to display specific sensitivity is the time about conception and early embryonic development. This preconception period, as defined in Fleming et al.(Reference Fleming, Watkins and Velazquez6), typically represents a time encompassing parental gamete maturation, fertilisation of the oocyte and development of the preimplantation embryo. The importance of the periconception period is highlighted by the fact that it encompasses a transition in developmental regulation, driven initially by the quality of the parental gametes before being directed by the embryonic genome. Underlying these fundamental developmental processes are dramatic reorganisations of the epigenetic status of the parental genomes, allowing a new embryonic pattern to be established which then determines subsequent fetal and postnatal development(Reference Marcho, Cui and Mager7). Due to the dramatic epigenetic remodelling that takes place within the preimplantation embryo, understanding the consequences of programmed changes in offspring epigenetic status (DNA/RNA methylation, histone modifications, non-coding RNA populations) as a result of periconception environmental insults has become a significant focus in the DOHaD field(Reference Ross and Canovas8).

The fact that the periconception period represents a time of both critical developmental importance for future offspring well-being, as well as heightened sensitivity to environmental perturbations, has significant implications for our current lifestyle and fertility. The global population is burdened by an increase in the number of people experiencing either over- or under-nutrition(Reference Onyango, Jean-Baptiste and Samburu9). In addition, an increase in the number of people actively delaying parenthood(Reference Carslake, Tynelius and van den Berg10) has resulted in a general decline in fertility, highlighting the interplay between our modern lifestyle and its influence on our gametes and general reproductive health(Reference Skakkebaek, Jorgensen and Andersson11). Infertility now affects about 15 % of couples in their reproductive age and its global rate has increased significantly in the period between 1990 and 2017(Reference Sun, Gong and Jiang12). Furthermore, the demand for infertility treatment using assisted reproductive technologies (ARTs) such as in-vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) has increased also(Reference Te Velde, Habbema and Nieschlag13). While the relationship between maternal diet, gamete quality and fertility has been studied in detail, the significance of male nutritional status and post-fertilisation embryo development has received less attention. Paternal obesity has been shown to negatively impact male endocrine function, sperm quality and genomic/epigenetic integrity, fertilisation capacity, embryonic development and offspring health(Reference Raad, Hazzouri and Bottini14). Similarly, studies have also shown that paternal undernutrition affects sperm quality and post-fertilisation development and offspring well-being(Reference Watkins and Sinclair15). Therefore, a greater understanding of the paternal contribution to offspring development is needed if new parental strategies are to be developed to combat the rise in rates of global non-communicable disease.

In line with our increased interest in the role, nutrition plays in the regulation of our reproductive fitness, our understanding of the interplay between our microbiome and the function of multiple physiological systems has grown also(Reference Valdes, Walter and Segal16). Our microbiota, the populations of micro-organisms that live within and on our bodies, and the role they play in regulating multiple aspects of our health and well-being are of increasing interest. Within the gut, the microbiota regulates numerous aspects of metabolism; secreting hormones and metabolites which regulate processes such as appetite, glucose tolerance, insulin sensitivity and fat storage(Reference Martin, Sun and Rogers17), all of which are connected to reproductive health. During pregnancy, the maternal microbiota shows significant changes in composition(Reference Gupta, Singh and Goyal18) and the female reproductive microbiota has been associated with a variety of gynaecological cancers(Reference Lee, Lee and Lee19). In addition, the maternal-offspring microbiome exchange at birth is critical in establishing the neonate's microbiome in postnatal life(Reference Mueller, Bakacs and Combellick20). Interestingly, in males, the seminal plasma has been shown to have its own microbiota, which is modifiable by diet(Reference Baud, Pattaroni and Vulliemoz21). While the significance of the seminal plasma microbiota has yet to be defined, the role of the seminal plasma in modulating the maternal reproductive tract during preimplantation embryo development is becoming evident(Reference Morgan and Watkins22). As our metabolic health, microbiota and our reproductive fitness appear directly interconnected, the role of the microbiome in regulating fertility is one we will explore within this review.

Here, we review the growing body of data surrounding the paternal nutritional status and the association with sperm quality, preimplantation embryo development and adult offspring health. Throughout this review, we aim to present and highlight evidence reported from both animal models and human studies discussing, where possible, the potential relationship(s) between them. Similar to studies exploring maternal programming, animal model studies have been fundamental in understanding the mechanistic relationships between paternal health, reproductive fitness and offspring development. This has allowed for in-depth analysis of male gametogenesis, epigenetic status and regulation, in addition to customised experimental models designed to simulate real-world nutritional profiles and lifestyle conditions. These models have aided the characterisation of the mechanisms underlying the paternal programming of offspring health.

Paternal nutrition and reproductive fitness

Obesity, defined in human subjects as a BMI >30 kg/m2, is associated with adverse metabolic effects and higher CVD risk(Reference Lavie, Milani and Ventura23). Obesity has also been linked to reproductive dysfunction and an association with male infertility(Reference Cabler, Agarwal and Flint24). However, while conflicting effects of obesity on semen quality and fertility have been reported in men, multiple studies in animal (mostly rodent) models have shown negative effects of obesity of a high-fat diet (HFD) on male reproductive fitness. Hammoud et al. demonstrated that with increasing BMI in men, the incidence of oligozoospermia increased also, with obese men having a 15⋅62 % incidence compared to 5⋅32 % for normal-weight men(Reference Hammoud, Wilde and Gibson25). Disturbances in endocrine homoeostasis underpinning spermatogenesis indicate one mechanism by which obesity-mediated alterations in hormonal profiles may alter male fertility. For example, obese men have been found to have decreased testosterone, inhibin B and increased oestrogen levels, all associated with impaired spermatogenesis(Reference Du Plessis, Cabler and McAlister26). Furthermore, alterations in the balance of gonadotropin-releasing hormone and luteinising hormone/follicle-stimulating hormone (GnRH-LH/FSH) may further contribute to an obesity-related impairment of spermatogenesis by disrupting Leydig and Sertoli cell function in bulls(Reference Thundathil, Dance and Kastelic27). Additionally, fat accumulation in male obesity can increase the scrotal temperature which impairs spermatogenesis, contributing to decreased sperm quality(Reference Kasturi, Tannir and Brannigan28). In men, obesity has also been associated with an increased risk of sperm DNA damage(Reference Dupont, Faure and Sermondade29), while in mice, increased reactive oxygen species (ROS) production and higher levels of DNA damage in sperm of HFD fed males have been reported(Reference Bakos, Mitchell and Setchell30). Elevated levels of testicular ROS, and the subsequent increase in oxidative stress, have been shown to have detrimental effects on mammalian sperm integrity through the impairment of the sperm plasma membrane(Reference Aitken, Smith and Jobling31). Furthermore, the elevation of ROS in men and the resultant increase in sperm cytotoxicity and DNA fragmentation(Reference Mahfouz, Sharma and Thiyagarajan32), have been shown to reduce sperm vitality and motility(Reference Shi, Chen and Huang33), lower levels of sperm capacitation(Reference Morielli and O'Flaherty34) and diminish sperm-oocyte binding capacity(Reference Aitken, Gordon and Harkiss35).

The impact of paternal nutrition has on a male's reproductive health extends beyond the pre-conception period and into the peri-conception period. An association between elevated paternal BMI and impaired embryo development has been identified in men and animal models. In men undergoing ART interventions, an increasing BMI was significantly associated with a decreased rate of embryo blastulation on day 5 of culture(Reference Bakos, Henshaw and Mitchell36). Furthermore, the same study reported rates of pregnancy, embryo implantation and live birth decreased from 41⋅3 % for men of a BMI <25 kg/m2 to 22⋅6 % for obese men(Reference Bakos, Henshaw and Mitchell36). In rats, similar observations were reported for embryos derived from obese males, with HFD-induced obesity reducing the cleavage rates of preimplantation embryos. Furthermore, these embryos demonstrated an impaired ability to achieve developmental milestones in vitro and ultimately failed to achieve blastocyst expansion at an appropriate time-point(Reference Mitchell, Bakos and Lane37). Early embryo cleavage dynamics have been associated with rates of ongoing development and live birth within clinical ART settings(Reference Bartolacci, Dal Canto and Guglielmo38). Recently, the association between being overweight in men and a reduction in fertility has been supported further through a large-scale meta-analysis of 115 158 study participants, revealing obese men had an increased likelihood of infertility(Reference Campbell, Lane and Owens39). Similar to the metabolic insult of high fat and obesogenic diets, paternal undernutrition and nutrient-deficient diets have also demonstrated an impact on sperm quality and early embryo development. In mice, pre-implantation embryos from low-protein fed stud males were found to have a reduction in genes associated with metabolic homoeostasis, particularly a decreased expression of genes involved in the AMPK pathway(Reference Watkins, Sirovica and Stokes40). Separately, paternal global dietary restriction found undernutrition in male mice resulted in a faster cleavage time in preimplantation embryos, yet reduced rates of blastocyst expansion were observed(Reference McPherson, Fullston and Kang41).

Paternal nutrition and offspring health

The influence of paternal nutritional status extends beyond alterations in early embryonic development and a number of studies in animal models have highlighted the deleterious effects paternal over- and under-nutrition have on the health of a male's offspring. In mice, perturbed patterns of fetal growth and skeletal formation have been reported in response to both paternal low protein and low folate diets(Reference Watkins, Sirovica and Stokes40,Reference Lambrot, Xu and Saint-Phar42) . Interestingly, in both studies, altered placental development was highlighted as one central regulator of the changes in fetal growth, mirroring observations from many maternal programming studies(Reference Sferruzzi-Perri and Camm43). Changes in expression of several hepatic genes for lipid metabolism have also been observed in response to paternal low protein diet (LPD)(Reference Carone, Fauquier and Habib44). These differential growths and metabolic profiles seen during fetal development are then mirrored in postnatal life. In mice, a paternal 70 % caloric restriction model, designed to reflect the nutritional availability in of developing countries, increased levels of adiposity in male offspring adiposity as well as inducing dyslipidaemia(Reference McPherson, Fullston and Kang41). Similarly, a paternal reduction in caloric intake (reduced by 25 %) in the rat resulted in an increase in displays of anxiety-such as behaviours in the adult offspring in addition to inducing a reduction in food intake, weight gain and serum leptin levels(Reference Govic, Penman and Tammer45). Data from the Overkalix epidemiological data sets also connect patterns of paternal and grand-paternal nutrition with significant changes in offspring development(Reference Bygren, Kaati and Edvinsson46). Here, periods of low availability of food between the ages of 9 and 12 in males, defined as a ‘slow growth period’ decreased the mortality risk from CVD in their offspring(Reference Kaati, Bygren and Edvinsson47,Reference Pembrey, Bygren and Kaati48) . In contrast, paternal and grand-paternal over-nutrition during this same period was associated with an increased predisposition to diabetes-related mortality(Reference Kaati, Bygren and Edvinsson47,Reference Pembrey, Bygren and Kaati48) . Intergenerational paternal programming has also been reported within experimental animal models. Paternal HFD-induced obesity in male rats results in increased adiposity, impaired glucose tolerance and insulin sensitivity within a second (F2) generation(Reference Fullston, Ohlsson Teague and Palmer49). Underlying these changes was a significant decrease in DNA methylation in the paternal testicular germ cells associated with the differential expression of 414 genes and 11 miRNAs(Reference Fullston, Ohlsson Teague and Palmer49). More recently, we have shown that offspring cardiovascular dysfunction and impaired renin-angiotensin system homoeostasis were programmed into a second generation in response to a paternal LPD in mice(Reference Morgan, Paganopoulou and Akhtar50).

Identifying the mechanisms of paternal programming

The observation that paternal programming can operate over multiple generations implicates epigenetic transmission of paternal traits as one potential mediator. Epigenetic alterations to the sperm (DNA and histone modifications, RNA populations) have been proposed as one mechanism for transmission of paternal programming effects in the offspring. In mice, global sperm DNA hypomethylation, coupled with a reduced testicular expression of the key regulatory methyltransferase genes Dnmt1 and Dnmt3L, have been reported in response to a paternal LPD(Reference Watkins, Dias and Tsuro51). Aberrant patterns of sperm DNA methylation have also been observed in response to caloric restriction(Reference McPherson, Fullston and Kang41) and dietary insufficiency of key vitamins and minerals such as folate(Reference Lambrot, Xu and Saint-Phar42). Similarly, obesity has been shown to induce alterations to DNA methylation profiles as well as miRNA populations in sperm of male mice(Reference Fullston, Ohlsson Teague and Palmer49). In men, differential sperm DNA methylation profiles and ncRNA profiles have also been observed between obese and lean men(Reference Donkin, Versteyhe and Ingerslev52). With regard to paternal obesity in men, studies have shown hypomethylation of the IGF2 differentially methylated region in offspring leucocytes at birth(Reference Soubry, Murphy and Wang53). Furthermore, significant hypomethylation of other imprinted genes including MEST, PEG3 and NNAT were found in offspring of obese fathers(Reference Soubry, Murphy and Wang53). Due to the involvement of these genes in growth and metabolic regulation, their differential DNA methylation could be one mechanism linking paternal obesity with altered offspring growth and metabolism. Separately, infertility has been associated with differential sperm DNA methylation(Reference Lujan, Caroppo and Niederberger54), histone distribution(Reference Wang, Gao and Li55) and RNA content(Reference Bianchi, Boekelheide and Sigman56). Interestingly, mature sperm contain several different populations of RNA, both within the nucleus and the mitochondria(Reference Miller and Ostermeier57). Sperm RNAs are detectible within the fertilised oocyte and can contribute to early embryonic development(Reference Krawetz58). The significance of sperm RNAs in programming offspring development is exemplified through the observation that the injection of sperm tsRNA fragments isolated from dietary-induced obese mice into control zygotes is able to programme the long-term metabolic ill health in the offspring(Reference Chen, Yan and Cao59).

Changes to a dietary status not only induce change to the composition of the sperm, it can also impact the non-sperm fraction of the semen, the seminal plasma. The role of the seminal plasma in modulating the maternal inflammatory and immune status during the periconception period has been reviewed in detail recently(Reference Morgan and Watkins22,Reference Schjenken and Robertson60) . However, a relatively unexplored connection is between the seminal plasma microbiome and paternal reproductive fitness. The mammalian microbiome consists of anywhere between 10 and 100 trillion microorganisms and functions in a symbiotic relationship with its host(Reference Turnbaugh, Ley and Hamady61). Until recently, our view of our microbes has centred on their role in pathogenic processes. However, it is now widely accepted that our body's microbiota is central in many developmental, physiological, metabolic and even psychological areas of everyday life. Our bodies possess many different and diverse bacterial populations including our skin, gut and oral microbiomes. Due to modern advances in sequencing capabilities, we are beginning to understand the association between our microbiota and complex conditions such as inflammatory bowel disease(Reference Frank, St Amand and Feldman62) and even obesity(Reference Ley, Turnbaugh and Klein63). The interplay between our microbiota and reproductive health has come to the forefront over the past few years with the discussion regarding the sterility of the intra-uterine environment(Reference Stinson, Boyce and Payne64). Gaining a better insight into the parental interplay between the maternal reproductive tract and the developing fetus is critical for developing new biomarkers for gestational well-being and both maternal and offspring long-term health. Initial studies into the seminal microbiome focused on the detection of pathogenic bacterial species, using comparatively simple techniques such as microscopy and RT-qPCR. In some of the earlier studies, negative associations between the levels of Anaerococcus and semen quality were reported(Reference Hou, Zhou and Zhong65). In a separate study, semen samples identified as ‘normal’ within a clinical setting were populated predominantly with Lactobacillus, while samples of ‘low quality’ displayed a predominance of Prevotella (Reference Weng, Chiu and Lin66). One influence of bacteria on male reproduction stems from the toxic effects of inflammatory cytokines or ROS produced by them within the male reproductive tract(Reference Alahmar67). In addition, bacteria may also bind directly to the sperm, influencing motility or inducing apoptosis(Reference Calogero, Duca and Condorelli68). Prebiotics supplementation in both human and animal models has been shown to influence seminal plasma composition and sperm quality. In obese mice, supplementation with Lactobacillus rhamnosus PB01 (DSM 14870) improved sperm kinetics(Reference Dardmeh, Alipour and Gazerani69). The authors observed increased testosterone levels and sperm with higher velocity and motility in supplemented obese males than non-supplemented obese males(Reference Dardmeh, Alipour and Gazerani69). In men, increased sperm motility, reduced sperm DNA fragmentation and intracellular H202 levels have also been reported following L. rhamnosus CECT8361 and Bifidobacterium longum CECT7347 supplementation in asthenozoospermic males(Reference Valcarce, Genoves and Riesco70).

Not only can the seminal microbiome influence male reproductive health, unprotected sexual intercourse can result in the exchange of microbes between partners, suggesting that each partner's reproductive microbiota can affect that of the other. Factors such as frequency of sexual intercourse and number of partners can all be related to the vaginal microbiota and incidences of bacterial vaginosis(Reference Brotman, Ravel and Cone71,Reference Plummer, Vodstrcil and Danielewski72) . Therefore, it is conceivable that the male's metabolic status at the time of conception could influence his seminal microbiome, which in turn influence the female reproductive microbiota. As the female reproductive microbiota is directly related to that of the neonate(Reference Mueller, Bakacs and Combellick20), this offers a novel mode of paternal programming of offspring metabolic health. However, such direct demonstration of seminal microbiota paternal programming has yet to be demonstrated.

Conclusions and future perspectives

It is now widely recognised that a connection between sub-optimal in utero development and long-term offspring ill-health exists. Despite this wealth of knowledge, much less attention has been given to the influence of the father's lifestyle on the health of his offspring. However, it is becoming increasingly apparent that a father's nutritional status at the time of conception can influence post-fertilisation development through a range of mechanisms (see Fig. 1). Sperm quality and functionality can be influenced by factors such as obesity and the associated hormonal imbalances. New sequencing approaches have revealed the epigenetic complexity of the sperm, revealing how sperm can regulate the first few cell cycles of the preimplantation embryo(Reference Schulz and Harrison73). Separately, studies have revealed the role of the seminal plasma in modulating the maternal reproductive tract vascular and immune systems, preparing the uterus for the implanting embryo(Reference Schjenken and Robertson60). With new analyses indicating the seminal microbiome may also influence post-fertilisation development, our understating of this male reproductive component is extending from just a simple supportive medium for the sperm during their transit through the female reproductive tract, to a central mediator in paternal programming. As our understanding of the interplay between our physiology and our microbiomes increases, modification of our reproductive fitness through changes in our microbiota may open up a new area of personalised reproductive medicine.

Fig. 1. Outline of key mechanisms linking paternal metabolic status at the time of conception to post-fertilisation development and offspring health. The seminal microbiome has been associated with semen quality and may influence the post-fertilisation maternal uterine microbiome. Seminal plasma cytokines and signalling molecules, such as transforming growth factor-β, interact with the maternal reproductive tract, priming the immune system and preparing the uterine tissue for the implanting embryo. Changes in epigenetic status of the sperm provide one mechanism capable to propagating paternal influences over multiple generations. Histones have been shown to be located at key pluripotency genes within the paternal genome and have been shown to contribute to the zygotic histone pool after fertilisation. More recently, sperm-borne RNAs (e.g. ncRNA, miRNA, tsRNA) have been shown to be capable of programming offspring metabolic health separate to the genomic content of the sperm. Sperm, as fully differentiated cells, possess high levels of DNA methylation. Changes in sperm DNA methylation can be indicative of a perturbed testicular environment and reduced male fertility.

Looking forward, there is a clear need to define the associations between other aspects of paternal lifestyle with his nutrition and fertility. Sperm quality is a fundamental component for a successful outcome in ART practices. However, there is still a heavy reliance on factors such as sperm morphology and motility in guiding practitioners to select single sperm in procedures such as ICSI. As such, a more detailed understanding of what cellular constituents make a ‘good quality sperm’ are clearly needed. Furthermore, many ART practices are conducted within a seminal plasma-free environment, precluding the normal interaction that occurs between the seminal plasma and the female reproductive tract during natural conception. The impact of removing such interactions for ongoing pregnancy and child health remain to be defined(Reference Schjenken and Robertson60). Finally, factors such as advancing paternal age, and the changes in metabolic status that accompany male ageing, have received limited attention until recently. However, connections between paternal age and offspring well-being are becoming more evident(Reference Khandwala, Baker and Shaw74). We believe that gaining a fuller understanding of how modern lifestyle factors influence paternal metabolic status, sperm quality, embryo development and offspring health is of fundamental significance for ensuring the life-long health and well-being of his offspring.

Financial Support

A.J.W. and his research are supported by the Biotechnology and Biological Sciences Research Council (BBSRC) under grant number BB/R003556/1.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Authorship

All authors were involved in the conception, design, preparation and proofing of the present paper.

References

Hanson, MA & Gluckman, PD (2014) Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol Rev 94, 10271076.CrossRefGoogle ScholarPubMed
Drake, AJ & Reynolds, RM (2010) Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Reproduction 140, 387398.CrossRefGoogle ScholarPubMed
Boerschmann, H, Pfluger, M, Henneberger, L et al. (2010) Prevalence and predictors of overweight and insulin resistance in offspring of mothers with gestational diabetes mellitus. Diabetes Care 33, 18451849.CrossRefGoogle ScholarPubMed
Rodriguez, A, Miettunen, J, Henriksen, TB et al. (2008) Maternal adiposity prior to pregnancy is associated with ADHD symptoms in offspring: evidence from three prospective pregnancy cohorts. Int J Obes (Lond) 32, 550557.CrossRefGoogle ScholarPubMed
Barouki, R, Gluckman, PD, Grandjean, P et al. (2012) Developmental origins of non-communicable disease: implications for research and public health. Environ Health 11, 42.CrossRefGoogle ScholarPubMed
Fleming, TP, Watkins, AJ, Velazquez, MA et al. (2018) Origins of lifetime health around the time of conception: causes and consequences. Lancet 391, 18421852.CrossRefGoogle ScholarPubMed
Marcho, C, Cui, W & Mager, J (2015) Epigenetic dynamics during preimplantation development. Reproduction 150, R109R120.CrossRefGoogle ScholarPubMed
Ross, PJ & Canovas, S (2016) Mechanisms of epigenetic remodelling during preimplantation development. Reprod Fertil Dev 28, 2540.CrossRefGoogle ScholarPubMed
Onyango, AW, Jean-Baptiste, J, Samburu, B et al. (2019) Regional overview on the double burden of malnutrition and examples of program and policy responses: African region. Ann Nutr Metab 75, 127130.CrossRefGoogle ScholarPubMed
Carslake, D, Tynelius, P, van den Berg, GJ et al. (2019) Associations of parental age with offspring all-cause and cause-specific adult mortality. Sci Rep 9, 17097.CrossRefGoogle ScholarPubMed
Skakkebaek, NE, Jorgensen, N, Andersson, AM et al. (2019) Populations, decreasing fertility, and reproductive health. Lancet 393, 15001501.CrossRefGoogle ScholarPubMed
Sun, H, Gong, TT, Jiang, YT et al. (2019) Global, regional, and national prevalence and disability-adjusted life-years for infertility in 195 countries and territories, 1990–2017: results from a global burden of disease study, 2017. Aging (Albany NY) 11, 1095210991.CrossRefGoogle ScholarPubMed
Te Velde, E, Habbema, D, Nieschlag, E et al. (2017) Ever growing demand for in vitro fertilization despite stable biological fertility-a European paradox. Eur J Obstet Gynecol Reprod Biol 214, 204208.CrossRefGoogle ScholarPubMed
Raad, G, Hazzouri, M, Bottini, S et al. (2017) Paternal obesity: how bad is it for sperm quality and progeny health? Basic Clin Androl 27, 20.CrossRefGoogle ScholarPubMed
Watkins, AJ & Sinclair, KD (2014) Paternal low protein diet affects adult offspring cardiovascular and metabolic function in mice. Am J Physiol Heart Circ 306, H1444H1452.CrossRefGoogle ScholarPubMed
Valdes, AM, Walter, J, Segal, E et al. (2018) Role of the gut microbiota in nutrition and health. Br Med J 361, k2179.CrossRefGoogle ScholarPubMed
Martin, AM, Sun, EW, Rogers, GB et al. (2019) The influence of the gut microbiome on host metabolism through the regulation of gut hormone release. Front Physiol 10, 428.CrossRefGoogle ScholarPubMed
Gupta, P, Singh, MP & Goyal, K (2020) Diversity of vaginal microbiome in pregnancy: deciphering the obscurity. Front Public Health 8, 326.CrossRefGoogle ScholarPubMed
Lee, JE, Lee, S, Lee, H et al. (2013) Association of the vaginal microbiota with human papillomavirus infection in a Korean twin cohort. PLoS One 8, e63514.CrossRefGoogle Scholar
Mueller, NT, Bakacs, E, Combellick, J et al. (2015) The infant microbiome development: mom matters. Trends Mol Med 21, 109117.CrossRefGoogle ScholarPubMed
Baud, D, Pattaroni, C, Vulliemoz, N et al. (2019) Sperm microbiota and its impact on semen parameters. Front Microbiol 10, 234.CrossRefGoogle ScholarPubMed
Morgan, HL & Watkins, AJ (2020) The influence of seminal plasma on offspring development and health. Semin Cell Dev Biol 97, 131137.CrossRefGoogle ScholarPubMed
Lavie, CJ, Milani, RV & Ventura, HO (2009) Obesity and cardiovascular disease: risk factor, paradox, and impact of weight loss. J Am Coll Cardiol 53, 19251932.CrossRefGoogle ScholarPubMed
Cabler, S, Agarwal, A, Flint, M et al. (2010) Obesity: modern man's fertility nemesis. Asian J Androl 12, 480489.CrossRefGoogle ScholarPubMed
Hammoud, AO, Wilde, N, Gibson, M et al. (2008) Male obesity and alteration in sperm parameters. Fertil Steril 90, 22222225.CrossRefGoogle ScholarPubMed
Du Plessis, SS, Cabler, S, McAlister, DA et al. (2010) The effect of obesity on sperm disorders and male infertility. Nat Rev Urol 7, 153161.CrossRefGoogle ScholarPubMed
Thundathil, JC, Dance, AL & Kastelic, JP (2016) Fertility management of bulls to improve beef cattle productivity. Theriogenology 86, 397405.CrossRefGoogle ScholarPubMed
Kasturi, SS, Tannir, J & Brannigan, RE (2008) The metabolic syndrome and male infertility. J Androl 29, 251259.CrossRefGoogle ScholarPubMed
Dupont, C, Faure, C, Sermondade, N et al. (2013) Obesity leads to higher risk of sperm DNA damage in infertile patients. Asian J Androl 15, 622625.CrossRefGoogle ScholarPubMed
Bakos, HW, Mitchell, M, Setchell, BP et al. (2011) The effect of paternal diet-induced obesity on sperm function and fertilization in a mouse model. Int J Androl 34(5 Pt 1), 402410.CrossRefGoogle ScholarPubMed
Aitken, RJ, Smith, TB, Jobling, MS et al. (2014) Oxidative stress and male reproductive health. Asian J Androl 16, 3138.CrossRefGoogle ScholarPubMed
Mahfouz, R, Sharma, R, Thiyagarajan, A et al. (2010) Semen characteristics and sperm DNA fragmentation in infertile men with low and high levels of seminal reactive oxygen species. Fertil Steril 94, 21412146.CrossRefGoogle ScholarPubMed
Shi, TY, Chen, G, Huang, X et al. (2012) Effects of reactive oxygen species from activated leucocytes on human sperm motility, viability and morphology. Andrologia 44(Suppl 1), 696703.CrossRefGoogle ScholarPubMed
Morielli, T & O'Flaherty, C (2015) Oxidative stress impairs function and increases redox protein modifications in human spermatozoa. Reproduction 149, 113123.CrossRefGoogle ScholarPubMed
Aitken, RJ, Gordon, E, Harkiss, D et al. (1998) Relative impact of oxidative stress on the functional competence and genomic integrity of human spermatozoa. Biol Reprod 59, 10371046.CrossRefGoogle ScholarPubMed
Bakos, HW, Henshaw, RC, Mitchell, M et al. (2011) Paternal body mass index is associated with decreased blastocyst development and reduced live birth rates following assisted reproductive technology. Fertil Steril 95, 17001704.CrossRefGoogle ScholarPubMed
Mitchell, M, Bakos, HW & Lane, M (2011) Paternal diet-induced obesity impairs embryo development and implantation in the mouse. Fertil Steril 95, 13491353.CrossRefGoogle ScholarPubMed
Bartolacci, A, Dal Canto, M, Guglielmo, MC et al. (2021) Early embryo morphokinetics is a better predictor of post-ICSI live birth than embryo morphology: speed is more important than beauty at the cleavage stage. Zygote 29, 495502, doi: 10.1017/S0967199421000253.CrossRefGoogle Scholar
Campbell, JM, Lane, M, Owens, JA et al. (2015) Paternal obesity negatively affects male fertility and assisted reproduction outcomes: a systematic review and meta-analysis. Reprod Biomed Online 31, 593604.CrossRefGoogle ScholarPubMed
Watkins, AJ, Sirovica, S, Stokes, B et al. (2017) Paternal low protein diet programs preimplantation embryo gene expression, fetal growth and skeletal development in mice. Biochim Biophys Acta 1863, 13711381.CrossRefGoogle ScholarPubMed
McPherson, NO, Fullston, T, Kang, WX et al. (2016) Paternal under-nutrition programs metabolic syndrome in offspring which can be reversed by antioxidant/vitamin food fortification in fathers. Sci Rep 6, 27010.CrossRefGoogle ScholarPubMed
Lambrot, R, Xu, C, Saint-Phar, S et al. (2013) Low paternal dietary folate alters the mouse sperm epigenome and is associated with negative pregnancy outcomes. Nat Commun 4, 2889.CrossRefGoogle ScholarPubMed
Sferruzzi-Perri, AN & Camm, EJ (2016) The programming power of the placenta. Front Physiol 7, 33.CrossRefGoogle ScholarPubMed
Carone, BR, Fauquier, L, Habib, N et al. (2010) Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell 143, 10841096.CrossRefGoogle ScholarPubMed
Govic, A, Penman, J, Tammer, AH et al. (2016) Paternal calorie restriction prior to conception alters anxiety-like behavior of the adult rat progeny. Psychoneuroendocrinology 64, 111.CrossRefGoogle ScholarPubMed
Bygren, LO, Kaati, G & Edvinsson, S (2001) Longevity determined by paternal ancestors' nutrition during their slow growth period. Acta Biotheor 49, 5359.CrossRefGoogle ScholarPubMed
Kaati, G, Bygren, LO & Edvinsson, S (2002) Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period. Eur J Hum Genet 10, 682688.CrossRefGoogle ScholarPubMed
Pembrey, ME, Bygren, LO, Kaati, G et al. (2006) Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 14, 159166.CrossRefGoogle ScholarPubMed
Fullston, T, Ohlsson Teague, EM, Palmer, NO et al. (2013) 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, 42264243.CrossRefGoogle Scholar
Morgan, HL, Paganopoulou, P, Akhtar, S et al. (2020) Paternal diet impairs F1 and F2 offspring vascular function through sperm and seminal plasma specific mechanisms in mice. J Physiol 598, 699715.CrossRefGoogle ScholarPubMed
Watkins, AJ, Dias, I, Tsuro, H et al. (2018) Paternal diet programs offspring health through sperm- and seminal plasma-specific pathways in mice. Proc Natl Acad Sci U S A 115, 1006410069.CrossRefGoogle ScholarPubMed
Donkin, I, Versteyhe, S, Ingerslev, LR et al. (2016) Obesity and bariatric surgery drive epigenetic variation of spermatozoa in humans. Cell Metab 23, 369378.CrossRefGoogle ScholarPubMed
Soubry, A, Murphy, SK, Wang, F et al. (2015) Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int J Obes (Lond) 39, 650657.CrossRefGoogle ScholarPubMed
Lujan, S, Caroppo, E, Niederberger, C et al. (2019) Sperm DNA methylation epimutation biomarkers for male infertility and FSH therapeutic responsiveness. Sci Rep 9, 16786.CrossRefGoogle ScholarPubMed
Wang, T, Gao, H, Li, W et al. (2019) Essential role of histone replacement and modifications in male fertility. Front Genet 10, 962.CrossRefGoogle ScholarPubMed
Bianchi, E, Boekelheide, K, Sigman, M et al. (2019) Spermatozoal large RNA content is associated with semen characteristics, sociodemographic and lifestyle factors. PLoS One 14, e0216584.CrossRefGoogle Scholar
Miller, D & Ostermeier, GC (2006) Towards a better understanding of RNA carriage by ejaculate spermatozoa. Hum Reprod Update 12, 757767.CrossRefGoogle ScholarPubMed
Krawetz, SA (2005) Paternal contribution: new insights and future challenges. Nat Rev Genet 6, 633642.CrossRefGoogle ScholarPubMed
Chen, Q, Yan, M, Cao, Z et al. (2016) Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397400.CrossRefGoogle ScholarPubMed
Schjenken, JE & Robertson, SA (2020) The female response to seminal fluid. Physiol Rev 100, 10771117.CrossRefGoogle ScholarPubMed
Turnbaugh, PJ, Ley, RE, Hamady, M et al. (2007) The human microbiome project. Nature 449, 804810.CrossRefGoogle ScholarPubMed
Frank, DN, St Amand, AL, Feldman, RA et al. (2007) Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A 104, 1378013785.CrossRefGoogle ScholarPubMed
Ley, RE, Turnbaugh, PJ, Klein, S et al. (2006) Microbial ecology: human gut microbes associated with obesity. Nature 444, 10221023.CrossRefGoogle ScholarPubMed
Stinson, LF, Boyce, MC, Payne, MS et al. (2019) The not-so-sterile womb: evidence that the human fetus is exposed to bacteria prior to birth. Front Microbiol 10, 1124.CrossRefGoogle Scholar
Hou, D, Zhou, X, Zhong, X et al. (2013) Microbiota of the seminal fluid from healthy and infertile men. Fertil Steril 100, 12611269.CrossRefGoogle ScholarPubMed
Weng, SL, Chiu, CM, Lin, FM et al. (2014) Bacterial communities in semen from men of infertile couples: metagenomic sequencing reveals relationships of seminal microbiota to semen quality. PLoS One 9, e110152.CrossRefGoogle ScholarPubMed
Alahmar, AT (2019) Role of oxidative stress in male infertility: an updated review. J Hum Reprod Sci 12, 418.CrossRefGoogle ScholarPubMed
Calogero, AE, Duca, Y, Condorelli, RA et al. (2017) Male accessory gland inflammation, infertility, and sexual dysfunctions: a practical approach to diagnosis and therapy. Andrology 5, 10641072.CrossRefGoogle ScholarPubMed
Dardmeh, F, Alipour, H, Gazerani, P et al. (2017) Lactobacillus rhamnosus PB01 (DSM 14870) supplementation affects markers of sperm kinematic parameters in a diet-induced obesity mice model. PLoS One 12, e0185964.CrossRefGoogle Scholar
Valcarce, DG, Genoves, S, Riesco, MF et al. (2017) Probiotic administration improves sperm quality in asthenozoospermic human donors. Benef Microbes 8, 193206.CrossRefGoogle ScholarPubMed
Brotman, RM, Ravel, J, Cone, RA et al. (2010) Rapid fluctuation of the vaginal microbiota measured by Gram stain analysis. Sex Transm Infect 86, 297302.CrossRefGoogle ScholarPubMed
Plummer, EL, Vodstrcil, LA, Danielewski, JA et al. (2018) Combined oral and topical antimicrobial therapy for male partners of women with bacterial vaginosis: acceptability, tolerability and impact on the genital microbiota of couples – a pilot study. PLoS One 13, e0190199.CrossRefGoogle ScholarPubMed
Schulz, KN & Harrison, MM (2019) Mechanisms regulating zygotic genome activation. Nat Rev Genet 20, 221234.CrossRefGoogle ScholarPubMed
Khandwala, YS, Baker, VL, Shaw, GM et al. (2018) Association of paternal age with perinatal outcomes between 2007 and 2016 in the United States: population based cohort study. Br Med J 363, k4372.CrossRefGoogle ScholarPubMed
Figure 0

Fig. 1. Outline of key mechanisms linking paternal metabolic status at the time of conception to post-fertilisation development and offspring health. The seminal microbiome has been associated with semen quality and may influence the post-fertilisation maternal uterine microbiome. Seminal plasma cytokines and signalling molecules, such as transforming growth factor-β, interact with the maternal reproductive tract, priming the immune system and preparing the uterine tissue for the implanting embryo. Changes in epigenetic status of the sperm provide one mechanism capable to propagating paternal influences over multiple generations. Histones have been shown to be located at key pluripotency genes within the paternal genome and have been shown to contribute to the zygotic histone pool after fertilisation. More recently, sperm-borne RNAs (e.g. ncRNA, miRNA, tsRNA) have been shown to be capable of programming offspring metabolic health separate to the genomic content of the sperm. Sperm, as fully differentiated cells, possess high levels of DNA methylation. Changes in sperm DNA methylation can be indicative of a perturbed testicular environment and reduced male fertility.

You have Access Open access

Save article to Kindle

To save this article to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Paternal periconception metabolic health and offspring programming
Available formats
×

Save article to Dropbox

To save this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about saving content to Dropbox.

Paternal periconception metabolic health and offspring programming
Available formats
×

Save article to Google Drive

To save this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you used this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about saving content to Google Drive.

Paternal periconception metabolic health and offspring programming
Available formats
×
×

Reply to: Submit a response

Please enter your response.

Your details

Please enter a valid email address.

Conflicting interests

Do you have any conflicting interests? *