Abstract
Highly anabolic diets and excessive body fat accumulation have been shown to negatively impact sperm biology in humans and murine biomedical models. Current research indicates that obesity is associated with decreased semen quality and represents a major contributor to male subfertility in humans. Male overnutrition is commonly observed in the beef cattle industry and the use of high-energy diets during bull development has been shown to negatively impact semen quality. Most research efforts in bovine reproductive physiology have focused on understanding and optimizing female fertility. This emphasis is even more evident in research investigating the relationship between nutritional interventions and reproductive performance, which has limited the development of nutritional strategies that optimize fertility in bulls. Increasing our understanding of the genetic and environmental factors that influence bull fertility will contribute to future increases in cattle reproductive and productive efficiency. Moreover, exploring the impact of overnutrition in bulls may offer valuable insight and help address diet-induced male subfertility in humans. Herein, we summarize the currently available literature evaluating the impact of highly anabolic diets on male fertility, with an emphasis in the bovine species. The literature summarized in the present review evaluates the impact of overnutrition on sperm biology, early embryonic development and explores its potential to impact postnatal performance of the offspring.
Lay summary
Research indicates that obesity has detrimental effects to semen quality and is a major contributor to male subfertility. Diet-induced subfertility is a concern not only in humans but also in livestock species. Male overnutrition is observed in the beef cattle industry, where bulls are often fed high-energy diets to achieve high rates of body weight gain and fat accumulation. This review provides a summary of the current scientific literature showing that bull overnutrition negatively impacts sperm biology and has negative consequences to subsequent embryo development after fertilization occurs. Moreover, this review shows that paternal diet-induced obesity in rodent models can program the postnatal life of the offspring that is sired by obese males. Further research is required to determine if the same occurs in cattle.
Introduction
Reproductive efficiency stands as the primary driver of profitability in cattle operations, with reproductive failure incurring annual costs exceeding 2 billion dollars for the United States beef and dairy industries (Lamb et al. 2016). Assisted reproductive technologies (ART) have the potential to significantly bolster reproductive efficiency while elevating the genetic quality and economic value of a calf crop (Rodgers et al. 2012, Bisinotto et al. 2014). Furthermore, the broader adoption of ART and improvements in cattle reproductive efficiency represent one of the most effective means to reduce the environmental footprint and enhance the sustainability of cattle production systems (White et al. 2015). Regardless of whether cattle producers are utilizing ART or natural service breeding, the sire is a major contributor to herd fertility and reproductive performance. Nonetheless, most research efforts in bovine reproductive physiology have focused on understanding and optimizing female fertility. This is likely explained by the fact that most herd reproductive performance indicators in cattle production settings (pregnancy rates, calving interval, age at first calving and others) are assessed when examining females. The fact that most genetic selection traits for fertility in dairy cattle and all genetic traits for fertility in beef cattle are related to female fertility further highlights the emphasis placed on optimizing female instead of male fertility. Therefore, increasing our understanding of the genetic and environmental factors that influence bull fertility can have substantial contributions to future increases in cattle reproductive performance. This review attempts to summarize the currently available literature exploring the impact of highly anabolic diets on male fertility, with an emphasis in the ruminant species. Literature in murine models and humans was also explored in order to describe the impact of paternal obesity on fertility across different species.
Consequences of high-energy diets to sperm biology and its relevance to the beef production industry
Overconditioning of bulls is common in the beef industry. A variety of extension programs and bull development stations have reported the general preference of beef cattle producers for bulls with high rates of average daily gain (ADG) during growth and development. In fact, when selecting herd sires, cattle producers often prioritize growth performance and growth-related genetic traits versus feed efficiency traits such as feed-to-gain ratio (F:G) or residual feed intake; (McDonald et al. 2010, Oosthuizen et al. 2018). This preference encourages seedstock producers to develop bulls with diets that induce rapid growth and fat deposition to achieve the desired phenotype. In fact, these diets induce rates of body weight gain, which resemble what is observed in feedlot steers (Marques et al. 2017, Colombo et al. 2019, Pancini et al. 2020).
Another factor that encourages seedstock producers to increase energy intake during sire development is the neuroendocrine regulatory effect of these dietary strategies on pubertal development. Similar to what has been thoroughly shown in heifers, young sires that are exposed to high-energy diets achieve puberty earlier (Dance et al. 2015, 2016, Byrne et al. 2018 a ). Although the neuroendocrine changes associated with puberty are less understood in young bulls compared with replacement heifers (reviewed by Cardoso et al. (2018), Kenny & Byrne (2018)), enhancing early life plane of nutrition in bulls stimulates metabolic and neuroendocrine signaling pathways that culminates in earlier onset of sexual maturation (Byrne et al. 2018a , b ). It is worth noting that the timing of nutritional intervention appears to dictate the impact of high-energy diets on puberty achievement (Harstine et al. 2015, Byrne et al. 2018a , b ). High planes of nutrition before six months of age decreased age at puberty; however, a high plane of nutrition after six months of age had no effects on puberty achievement. Moreover, bulls exposed to higher planes of nutrition before six months of age produced a greater amount of semen by 12–15 months of age compared with bulls exposed to higher planes of nutrition after six months of age (Byrne et al. 2018a ). This is important considering the current industry effort to decrease generation interval and produce offspring from young sires.
Postpubertal overnutrition in bulls increases body adiposity and results in insulin resistance (Coulter et al. 1987, Seekford et al. 2023, de Sousa et al. 2022). In addition, prolonged exposure to high-energy diets negatively impact bull fertility based on standard spermiogram parameters utilized in breeding soundness examinations (Coulter et al. 1987, 1997, Mwansa & Makarechian 1991). Sires fed a high-energy diet for 168 days had increased scrotal circumference, reduced progressive sperm motility and reduced percentage of morphologically normal sperm (Coulter & Kozub 1984, Coulter et al. 1987) (Fig. 1A, B, C). Moreover, using the same experimental approach, Coulter et al. (1997) observed a decrease in scrotal surface temperature gradient in bulls fed a high-energy diet, indicating that increased dietary energy may also influence testicular thermoregulation. In fact, increased body fat deposition in bulls is positively correlated with accumulation of fat around the vascular cone region (Brito et al. 2012) and experimentally insulating the vascular cone region of bulls increased intratesticular temperature and resulted in a greater percentage of morphologically abnormal sperm cells in the ejaculate. Impaired testicular thermoregulation decreases progressive sperm motility, percentage of live sperm in the ejaculate, increases morphologically abnormal sperm, deteriorates acrosome integrity and increases sperm oxidative stress (Barth & Bowman 1994, Kastelic et al. 2018, Ferrer et al. 2020). A more recent study evaluated the effects of plane of nutrition on sperm quality of mature beef bulls (Dahlen et al. 2020). Sires that were fed to have a negative energy balance for 112 days had greater post-thaw sperm motility compared with bulls in a positive energy balance. The same study showed an increase in sperm reactive oxygen species in bulls that were in a positive energy balance compared with bulls in a negative energy balance. Redox equilibrium is important for various aspects of sperm functionality and excessive reactive oxygen species in sperm has been associated with impaired sperm quality and increased sperm DNA damage, which can have implications to postfertilization conceptus development (Mitchell et al. 2011, Ayad et al. 2022). Epidemiological data collected in bull development programs also corroborate the abovementioned experimental findings and indicate that excessive subcutaneous fat accumulation is associated with decreased semen quality. Smith et al. (2024) investigated the relationship between subcutaneous backfat thickness and sperm morphology in growing beef bulls that were exposed to the same diet and environmental conditions. Bulls were retrospectively ranked based on subcutaneous backfat thickness and bulls in the top 10 and 20% of the population for subcutaneous backfat thickness had greater morphological defects in sperm and were more likely to fail an industry-standard breeding soundness examination compared with bulls with less subcutaneous backfat (Fig. 2).
Bulls were fed their respective diet for 168 days at which time scrotal circumference (A), sperm motility (B) or secondary sperm defects (C) were evaluated. Control: moderate-gain diet. HG, high-gain diet. SC, Scrotal circumference. a, b superscript differ: P < 0.05 for all panels. Adapted from Coulter et al.(1997).
Citation: Reproduction and Fertility 6, 1; 10.1530/RAF-24-0082
Relationship between subcutaneous backfat thickness and sperm morphology in growing beef bulls that were exposed to the same diet. Bulls were retrospectively ranked based on subcutaneous backfat thickness as top, medium or bottom 10 or 20% of the population for subcutaneous backfat thickness. a, b superscript differ: P ≤ 0.05 for all panels. BSE, breeding soundness examination. Bulls were considered to have failed the BSE when morphologically normal cells were <70% according to the Society of Theriogenology. Adapted from Smith et al. (2024).
Citation: Reproduction and Fertility 6, 1; 10.1530/RAF-24-0082
Negative effects of high rates of body weight gain and excessive fat deposition on semen quality in the bull are also observed in other species such as humans and rodents (Kort et al. 2006, Barbagallo et al. 2021). Obese men are more likely to experience infertility and have an increased percentage of sperm, with low-mitochondrial membrane potential, increased DNA fragmentation and increased abnormal sperm morphology (Campbell et al. 2015). These observations are repeatable in murine experimental models, where diet-induced obesity results in increased systemic inflammation, sperm oxidative stress, chromatin damage and causes epigenetic modifications, which collectively impair sperm function and reduce male fertility (reviewed by Houfflyn et al. (2018), Barbagallo et al. (2021)). While sire overconditioning clearly changes semen quality, the magnitude of these changes does not necessarily limit the ability of sires to meet industry quality standards for semen or sire commercialization. Yet, the contribution of such changes in sperm biology to sire fertility and postfertilization developmental events in a commercial setting remains poorly described in the literature.
Paternal contributions to preimplantation conceptus development
Early embryonic development and placentation in cattle have unique characteristics. The bovine embryo arrives in the uterus approximately 5.5 days after fertilization, where the blastocyst subsequently hatches from the zona pellucida and the free-floating conceptus undergoes dramatic morphological and functional changes before implantation. After hatching, the bovine spherical blastocyst elongates along the uterine lumen, increasing its surface area for apposition before adhering to the uterine luminal epithelium. As the conceptus elongates from an ovoid (1–4 mm) and tubular (5–19 mm) structure to a filamentous shape (20–60 mm), it undergoes remarkable transcriptome change, which are associated with changes in endometrial transcriptome and composition of the uterine histotroph (Betteridge & Flechon 1988, Santos et al. 2016). These series of events precede conceptus attachment to the endometrium and represent an orchestrated paracrine crosstalk between the preimplantation conceptus and the uterus that is required for successful pregnancy establishment and has been comprehensively reviewed by others (Spencer et al. 2015, Bazer et al. 2018).
Although fertilization rates are thought to be relatively high (>80%) in cattle (Santos et al. 2004), pregnancy rates in beef females that are exposed to a single artificial insemination or embryo transfer generally range between 40 and 60% at 30 days after breeding (Lamb et al. 2010), indicating that pregnancy loss between fertilization and the first pregnancy diagnosis occurs in a high proportion of cows and heifers (Reese et al. 2020, Fontes & Oosthuizen 2022). Therefore, the first 30 days of gestation represent a pivotal period for pregnancy establishment in cattle (Wiltbank et al. 2016, Reese et al. 2020) and has considerable implications to fertility and cattle production efficiency. Recent research from other species has shown that sperm play an important role in early embryonic development and postfertilization infertility (Daigneault 2021). In addition to its genetic contributions, sperm-derived factors are involved in many postfertilization events, such as syngamy, cleavage and epigenetic regulation of the developing embryo. In fact, a growing body of evidence indicates that sperm epigenetic abnormalities may be major contributors to embryo developmental failures and pregnancy loss (Emery & Carrell 2006).
Contributions of paternal diet to early embryonic development
Maternal nutritional status has been thoroughly described as an important driver of early embryonic development and successful pregnancy establishment in cattle. These research efforts resulted in the development of several nutritional interventions in the cow diet that optimize embryo development, minimize pregnancy loss and optimize reproductive performance. Such interventions range from altering energy and protein levels in the diet (Kruse et al. 2017, Fontes et al. 2019, 2021) to manipulating specific nutrients that optimize the uterine environment and favor preimplantation conceptus development. Examples include, but are not limited to, altering trace minerals source (Perry et al. 2021, Crites et al. 2022, Mion et al. 2023), increasing dietary amounts of omega-3 (Staples et al. 1998, Sinedino et al. 2017) and omega-6 polyunsaturated fatty acids (Lopes et al. 2009, Brandão et al. 2018, Pickett et al. 2023), methyl donor supplementation (Toledo et al. 2017, Estrada-Cortés et al. 2021) and others. Alternatively, less research emphasis has been placed on the impact of nutritional interventions on bull fertility and limited information is available for the cattle industry to improve bull fertility through dietary interventions.
As described previously, bull nutritional overconditioning is a common phenotype in the beef cattle industry. In murine models, diet-induced obesity increases oxidative stress and DNA damage in spermatozoa (Bakos et al. 2011), resulting in decreased pregnancy rates (Ghanayem et al. 2010). Moreover, embryos sired from diet-induced obese sires had reduced cleavage and blastocyst rates compared with embryos from control sires (Mitchell et al. 2011). Similar results were observed in models of paternal diabetes (Kim & Moley 2008), scrotal heat stress (Zhu et al. 2004) and paternal age (Luna et al. 2009), which are known mechanisms to induce oxidative stress, increase DNA fragmentation and promote epigenetic changes in sperm. In addition to decreased blastocyst development rates when sired by obese males, embryos that successfully develop to the blastocyst stage were shown to have a reduced number of inner cell mass (ICM) and trophectoderm (TE) cells, indicating that reaching the blastocyst stage does not rule out the negative contributions of paternal high-energy diets to embryo development (Mitchell et al. 2011). Interestingly, paternal high-energy diets also result in decreased implantation rates and placental development in mice (Binder et al. 2012, 2014). Epidemiological data in human fertility clinics support the rationale that paternal obesity negatively impacts postfertilization embryonic development. Zhang et al. (2024) investigated the impact of male obesity in couples undergoing in vitro fertilization and reported decreased fertilization rates in couples, where the male was classified as obese based on body mass index (BMI). A negative association between BMI and the percentage of transferable embryos was also reported (Zhang et al. 2024). Fertilization rates and the percentage of transferable embryos produced in vitro were also decreased in couples, in which the male was classified as overweight (Yang et al. 2016, Hoek et al. 2022). Similar results were observed for clinical pregnancies, where couples with overweight males had decreased post-transfer clinical pregnancies compared with couples in which the male partner was not classified as overweight (Yang et al. 2016). Collectively, these results indicate that the negative effects of sire obesity are not limited to changes in semen quality, highlighting that paternal diet also impacts blastocyst development and subsequent percentage of clinical pregnancies after the use of ART.
Many large-scale field fertility studies have shown differences between bulls’ ability to sire successful pregnancies (Markusfeld-Nir 1997, López-Gatius et al. 2002, Pegorer et al. 2007). However, fewer studies have investigated the paternal contributions to early embryonic development in cattle. Ortega et al. (2018) classified bulls as high or low fertility based on sire conception rates (SCRs) obtained from large-scale artificial insemination records. These bulls with divergent SCR values were then utilized to evaluate in vivo and in vitro embryo production. Low SCR sires produced fewer day 8 blastocysts in vitro and resulted in a greater percentage of unfertilized oocytes when utilized to breed superovulated cows in vivo. Moreover, high SCR sires resulted in blastocysts with greater numbers of trophectoderm cells compared to low SCR sires (Ortega et al. 2018). In a subsequent study, Lockhart et al. (2019) characterized embryo developmental kinetics in bulls with varying capacities to produce blastocysts in vitro. Low embryo producing sires had an increased proportion of embryos undergoing developmental arrest at the 5–6-cell stage, increased expression of autophagy markers at the same stage of development and transcriptome analyses suggested disturbed mitochondrial clearance, histone retention and DNA damage compared with high embryo-producing sires (Lockhart et al. 2023).
Seminal plasma has also been proposed as a factor influencing paternal contributions to early embryonic development and pregnancy establishment. It is well-establish that seminal plasma plays a key role in sperm transport, protection and nutrient availability at the time of ejaculation (Bromfield 2014). Moreover, endometrial exposure to seminal plasma alters gene expression of inflammatory mediators, potentially contributing to uterine receptivity and pregnancy establishment (Ibrahim et al. 2018, Bromfield 2016). In fact, exposing females to seminal plasma has been shown to improve embryo development in mice, humans, pigs and more recently, in cattle (O’Leary et al. 2004, Crawford et al. 2015, Mateo-Otero et al. 2020). Exposing embryo recipient heifers to vasectomized bulls during estrus resulted in increased conceptus development and altered conceptus gene expression compared with non-mated controls (Mateo-Otero et al. 2020), indicating that seminal plasma might also play a role in pregnancy establishment in the bovine. However, there is no clear evidence that seminal plasma exposure increases pregnancy rates in cattle (Pfeiffer et al. 2012, Ortiz et al. 2019). Interestingly, bull plane of nutrition appears to alter seminal plasma cytokine profile (Harrison et al. 2023). Yet, further research is required to determine the contributions of diet-induced changes in seminal plasma to sperm biology and pregnancy establishment in cattle.
While several studies have investigated the impact of experimental exposure to highly anabolic diets on traditional estimates of semen quality, such as motility and morphology, research investigating the impact of paternal diets on sperm biology and postfertilization events is limited in the bovine. A recent study exposed mature beef bulls to either a diet to maintain body weight or a high-gain diet that elicited an ADG of 1.97 kg per day for 67 days (Seekford et al. 2023), which resembles rates of body weight gain observed in bull development programs (McDonald et al. 2010, Oosthuizen et al. 2018). Bulls were then exposed to serial semen collection at the end of the feeding period and semen was used to investigate potential contributions of paternal diet to postfertilization outcomes using in vitro embryo production. Bulls exposed to the high-gain diet had subtle changes in semen quality, including an increased post-thaw acrosome damage and a greater percentage of sperm classified as early necrotic (Fig. 3). Furthermore, while cleavage rates were not different between treatments, bulls exposed to the high-gain diet tended to have decreased embryo production and had decreased blastocyst rates relative to the number of cleaved structures (Fig. 4). As opposed to research in murine models (Bakos et al. 2011, Mitchell et al. 2011), there were no differences in the allocation of either ICM or trophectoderm cells (Seekford et al. 2023). Similar decreases in early embryonic development were observed in the bovine when bulls were exposed to other environmental stressors. For example, scrotal insulation is a common experimental approach to impair testicular thermoregulation, disrupt spermatogenesis and decrease sperm motility and morphology (Kastelic et al. 2018). Using a scrotal insulation model, Walters et al. (2005) observed a decrease in fertilization and blastocyst rates between semen samples collected before and after scrotal insulation. Fernandes et al. (2008) exposed bulls to a 5-day scrotal insulation period and observed similar results. Testicular insulation increased the percentage of sperm with head defects, nuclear vacuoles and abnormal chromatin. Moreover, cleavage rates and blastocyst rates were decreased after testicular insulation (Fernandes et al. 2008). The sperm cell has a limited antioxidant system and is highly sensitive to elevated levels of reactive oxygen species (Ayad et al. 2022). Both testicular insulation and diet-induced obesity increase sperm oxidative stress, DNA fragmentation and impair chromatin integrity (Ferrer et al. 2020, Ayad et al. 2022). Experimental exposure of sperm to low levels of hydrogen peroxide results in substantial sperm DNA damage and sperm oxidative stress has been shown to reduce blastocyst rates (Silva et al. 2007, de Assis et al. 2015, de Castro et al. 2016), indicating that the impaired embryo development associated with diet-induced obesity might be partially explained by changes in sperm biology driven by oxidative damage. While the specific mechanism that explains the consequences of diet-induced obesity are not completely understood, results described here support the hypothesis that sperm is a major contributor to early embryonic development in cattle. Moreover, environmental factors, such as prolonged exposure to high-energy diets and impaired testicular thermoregulation, can alter sperm biology and result in impaired embryo development.
Fresh and frozen-thawed semen from bulls fed either a maintenance (ADG = 0.02 kg/day) or a high-gain diet (ADG = 1.97 kg/day) were analyzed using flow cytometry for acrosomal integrity (A), early necrosis (B) and viability (C). Different superscripts indicate statistical differences (P ≤ 0.05) and symbols indicate a tendency (P < 0.10; Seekford et al. 2023).
Citation: Reproduction and Fertility 6, 1; 10.1530/RAF-24-0082
Oocytes were fertilized using semen from bulls fed either a maintenance (ADG = 0.02 kg/day) or a high-gain diet (ADG = 1.97 kg/day). Zygote cleavage was assessed at day 3 postfertilization (A). The percentage of oocytes (B) and cleaved oocytes (C) that formed blastocysts were analyzed 7.5 days after fertilization (Seekford et al. 2023).
Citation: Reproduction and Fertility 6, 1; 10.1530/RAF-24-0082
Paternal contributions to pregnancy establishment, placental development and fetal growth
Maternal nutrition can influence pre- (Thatcher et al. 2011, Kruse et al. 2017) and post-hatching conceptus development (Brandão et al. 2018), placental (Vonnahme et al. 2007, Lemley et al. 2018) and fetal growth (Long et al. 2010) and offspring postnatal growth performance and carcass composition in cattle (Stalker et al. 2006, Larson et al. 2009). Alternatively, the relationship between sire nutrition and postimplantation development of the offspring is poorly understood in the bovine. In mice, uniparental experimental models provide significant insight into the paternal contribution to embryo development. Androgenetic embryos that are generated through the replacement of the female pronuclei by a second male pronuclei results in relatively normal placental development. Alternatively, when uniparental embryos were generated using only female pronuclei (parthenogenetic embryos), the embryo proper experienced relatively normal development; however, placental development was dramatically limited (Surani et al. 1986), suggesting that the paternal genome and epigenome play an important role in trophectoderm cell differentiation and development. Based on the significant influence that the male plays in placental development, evaluating the relationships between sire-related factors and placental formation could provide valuable insights into male fertility and fetal development in cattle. Moreover, identifying factors that influence paternal programming of placental development might provide important insights into the male contributions to pregnancy loss, fetal development and postnatal offspring performance.
In the bovine, as the attachment of the conceptus trophoblast to the uterine luminal epithelium progresses (3–4 weeks of gestation), binucleated giant cells (BNCs) migrate to the uterine luminal epithelium for syncytialization with epithelial cells. Pregnancy-associated glycoproteins (PAGs) located within secretory granules of BNCs are released into the uterine stroma and some of these proteins make their way into maternal peripheral blood circulation (Green et al. 2005, Seo et al. 2024). Although the roles of these proteins are not completely understood, they can be successfully utilized as biomarkers of pregnancy in ruminants (Wallace et al. 2015). Moreover, lower concentrations of PAG in maternal circulation are associated with impaired placental function and high rates of late embryonic mortality (Pohler et al. 2016, Holton et al. 2022 a , b ).
Large-scale studies have indirectly investigated the paternal contributions to placental function and pregnancy establishment in beef cattle herds managed in different production scenarios representative of North and South American beef production systems (Pohler et al. 2013, Franco et al. 2018, Fontes et al. 2019). Franco et al. (2018) evaluated the effect of sire on PAG concentrations in maternal circulation on day 30 of gestation. Cows that were diagnosed as pregnant via ultrasonography on day 30, but were open on day 100 of gestation, were considered to have experienced late embryonic/early fetal mortality (LEM). Cows that were classified as LEM had lower PAG concentrations on day 30 compared to cows that successfully maintained pregnancy (Fig. 5A). In the same study, sires were retrospectively classified as either high pregnancy loss (HPL; mean of 7.25% late embryonic mortality was observed) or low pregnancy loss (LPL; mean of 3.93% late embryonic mortality observed) according to the percentage of pregnancy loss observed in the cows that received their semen. Intriguingly, cows that maintained pregnancy from HPL sires had decreased PAG concentrations on day 30 of gestation compared with cows that maintained pregnancy from LPL sires (Fig. 5B).
(A) Plasma concentrations of PAGs in cows that had a viable pregnancy on day 30 of gestation, but experienced pregnancy loss by day 100 of gestation. (B) Plasma PAG on day 30 of gestation in cows that maintained pregnancy and were sired by bulls that induce high (HPL) or low rates of pregnancy loss (LPL). (C) Plasma PAGs from cows receiving parthenogenome (PA; no male pronuclei) or control embryos (treatment × time; P ≤ 0.05). a,b superscript differ (P ≤ 0.05). Adapted from Franco et al. (2018) and Singleton et al. (2023).
Citation: Reproduction and Fertility 6, 1; 10.1530/RAF-24-0082
Recent research has explored the use of a uniparental embryo transfer model to investigate the paternal contributions to placenta formation in beef cattle. This model relied on the production of embryos lacking the paternal pronuclei (parthenogenetic; PA) and control biparental embryos that were then transferred to recipient cows and assessments of conceptus and placental development were performed (Singleton et al. 2023, Pohler & Oliveira Filho 2024). Embryo morphology was abnormal in PA embryos; however, some embryos were detectable via transrectal ultrasound until day 40 of gestation. Remarkably, circulating concentrations of PAG were not detected in the maternal circulation of cows that received PA embryos, whereas control embryos resulted in a normal increase in circulating PAG concentrations (Fig. 5C). In addition, all PA pregnancies were spontaneously terminated before day 45 of gestation. The timing of pregnancy loss (between days 28 and 45) observed in this study coincides with a period of active placental development and remodeling of the uterine–placental interface (Seo et al. 2024). Taken together, the lack of circulating PAG in PA pregnancies and the lower concentrations of PAG in HPL sires provide clear evidence that sires have a substantial contribution to placental formation in cattle. While placental development is paramount for fetal development and consequently postnatal performance of the offspring, paternal-related factors associated with placental development are poorly understood. Moreover, a knowledge gap exists with regards to the relationship between sire management factors (e.g., sire diets) and placental development.
Paternal environmental factors and paternal programming of postnatal metabolism
The contributions of the pregnant female body composition, diet and lifestyle to the health of the offspring have been thoroughly investigated in the context of fetal programming. In the 1980s, Barker and colleagues began publishing epidemiological findings of associations between birth weight and lifetime risk of coronary heart disease in humans (Barker & Osmond 1986, Barker et al. 1989, Barker 1995). Additional associations have since been made between birth weight and risk for type 2 diabetes, hypertension and stroke (Barker et al. 2002, 2010). It is now well-accepted that birth weight is not a prerequisite for these problems but rather represents one of several scenarios of slowed fetal development that predisposes various physiological disorders in adult life. The sheep is a recognized biomedical model for human fetal programming events, since several models of intrauterine growth restriction (IUGR) have been developed in this species. Fetal growth restriction can be induced during early gestation in ewes by heat stress exposure, surgical blood flow restriction and maternal over- or undernutrition (Wallace et al. 2005, Barry & Anthony 2008, Yates et al. 2012). These events impair placental function, decrease nutrient availability to the fetus and create hypoglycemic states in utero that predispose offspring to postnatal metabolic disorders. For example, maternal nutrient restriction during gestation negatively impacts placentome development and vascularization leading to changes in fetal growth rates in utero (Vonnahme et al. 2007). Moreover, lambs born from nutrient-restricted ewes have more kidney and pelvic area adipose tissue, reduced longissimus and semitendinosus muscle weight, reduced hot carcass weight and increased insulin resistance as adults (Wallace et al. 2005, Ford & Long 2012). Elevated fetal growth is also commonly observed in models of maternal obesity and gestational diabetes and is also associated with postnatal metabolic disorders in the offspring (Dabelea & Crume 2011). Thus, disproportionate fetal growth, whether slowed or elevated, can have significant impacts on long-term health outcomes.
Similar to ovine and murine models, the association between maternal diet and long-term health, metabolism and performance of the offspring has been demonstrated in cattle (Stalker et al. 2006, Larson et al. 2009).
While considerable research has been performed to establish maternal factors influencing non-genetic, intergenerational transmission of metabolic sequelae, the contributions of paternal factors to postnatal development of the offspring is a relatively recent research topic in human health. Over the past two decades, a growing body of epidemiological literature indicated that there is a relationship between paternal BMI and postnatal health of the offspring. This concept has been validated with rodent experimental models and it is now well-established that paternal high rates of body weight gain and fat deposition influence growth, metabolism and body composition of the offspring (reviewed by Raad et al. (2017) and Fleming et al. (2018)). Human and murine males with greater BMI have sperm aberrancies at the level of chromatin, excessive semen reactive oxygen species and increased sperm morphological abnormalities (Houfflyn et al. 2018). In addition, men with high BMI had significantly lower sperm concentrations (Chavarro et al. 2010), decreased sperm motility (Hammoud et al. 2008), increased sperm DNA fragmentation and reduced chromatin integrity (Kort et al. 2006). Considering the importance of paternal factors to placenta and fetal development that were described previously, it is not surprising that high paternal adiposity has an intergenerational effect. Paternal overweight results in glucose intolerance and fasting hyperglycemia not only in the exposed individual, but also their offspring and grandoffspring in mice, regardless of the maternal diet. In addition to impaired glucose metabolism, hypertriglyceridemia is also observed in the offspring of obese fathers (Pentinat et al. 2010). When male C57BL/6 mice were fed a high-fat diet for 10 weeks before breeding, an intergenerational transmission of obesity and insulin resistance was initiated in two generations of offspring. This phenotype was transmitted to both male and female F1 offspring, and further transmitted to the F2 generation. During this study, only founder males (F0) were fed a high-gain diet (Ng et al. 2010, Fullston et al. 2013).
Mechanistically, the inheritance of environmentally induced phenotypes through the paternal lineage has been proposed to be associated with epigenetic modifications in the germ line (Jimenez-Chillaron et al. 2016). Changes in sperm DNA methylation, chromatin structure and non-coding RNA profile have been proposed as molecular mechanisms by which paternal diets can influence postnatal metabolism of the offspring. DNA methylation is the chemical addition of a methyl group to the 5 position of cytosine and is generally associated with long-term transcription repression. Although most DNA methylation sites are erased after fertilization through the process of epigenetic reprogramming, specific sequences escape this process. This is also the case for imprinted genes that have methylated regions regulating gene expression in a parent of origin-specific manner. In fact, differences in sperm DNA methylation patterns were observed in several imprinted genes when comparing overweight and normal weight men (Soubry et al. 2016). Moreover, sire dietary interventions in the bovine were also shown to alter sperm epigenome. More specifically, enhanced prepubertal (<7 months of age) nutrition resulted in postpubertal differential sperm methylation when bulls were 16 months of age, with several genes associated with embryonic and fetal development being differentially methylated (Johnson et al. 2022). In addition, sperm methylome has been associated with bull fertility potential and proposed as potential fertility biomarker in bulls (Costes et al. 2022). The impact of bull prolonged exposure to high-energy diets on sperm methylation patterns has not been characterized. Hence, further research is required to determine if paternal overnutrition in the bovine elicit changes in sperm methylome.
Paternal diets were shown to alter not only DNA methylation of gametes, but also alter methylation of somatic cells in the offspring. Rodent sires fed high-fat diets generated female offspring with abnormal insulin secretion and glucose intolerance phenotypes (Ng et al. 2010, Fullston et al. 2013). Moreover, paternal high-fat diets caused histopathological changes to pancreatic islets and changes in pancreatic gene expression that were associated with hypomethylation of these respective genes (Ng et al. 2010), indicating that paternal diets can influence offspring growth and metabolism by inducing tissue-specific changes in DNA methylation of somatic cells.
Changes in sperm chromatin structure and non-coding RNA profile have also been proposed as potential mechanisms regulating paternal programming of offspring performance. Abnormal sperm chromatin structure has been associated with male infertility, and paternal diet-induced obesity alters histone composition at specific genes associated with cell development and differentiation (Raad et al. 2017), suggesting that diet could alter postnatal performance of the offspring through alterations of sperm chromatin. In addition, small non-coding RNAs in sperm have been shown to play a role in early embryonic development and epigenetic inheritance. In an elegant study, Grandjean et al. demonstrated that embryos generated from control-fed parents injected with sperm RNAs obtained from males fed a high-fat diet produced offspring with increased adiposity and a diet-induced diabetes phenotype (Grandjean et al. 2015). In addition, when mouse zygotes were injected with sperm tRNA-derived small RNAs (tsRNA) obtained from males fed a high-fat diet, subsequent offspring had impaired glucose tolerance and insulin secretion (Chen et al. 2016), emphasizing the role of sperm RNAs on subsequent offspring metabolism. In parallel with epigenetic changes to germ and somatic cells, paternal diet-induced obesity can also change placental biology and fetal growth rates in utero. Histoarchitecture changes in the uterine placental interface during early gestation are paramount to increase the surface area and vascularization of the maternal and conceptus systems of the placenta. Moreover, limited placentome development or vascularization can alter fetal growth rates in utero (Vonnahme et al. 2007, Lemley et al. 2018). Utilizing a diet-induced obesity mouse model, Binder et al. (2012) observed a decrease in placental weight, fetal weight, fetal crown-to-rump length and limb morphological grades in pregnancies generated from obese compared with control sires. Hence, changes in placental and fetal plane of development could also be one of the mechanisms in which paternal diets can potentially influence postnatal development of the offspring. It is worth noting that only limited data is currently available on paternal programming of offspring metabolism and performance in livestock species, particularly in cattle. Dietary inclusion of methyl donors in boar diets resulted in leaner carcasses with less subcutaneous backfat in the F2 offspring (Braunschweig et al. 2012). Moreover, paternal methionine supplementation in rams resulted in F1 male offspring reaching puberty at a lighter body weight compared with offspring sired from non-supplemented controls (Gross et al. 2020). Paternal supplementation of rumen-protected methionine before puberty achievement was shown to induce differential methylation patterns in sperm, which were also observed in the male offspring of both F1 and F2 generations, indicating that paternal diet elicits transgenerational inheritance of sperm methylation patterns in small ruminants (Braz et al. 2022). Moreover, Braz et al. (2022) reported that paternal supplementation of methionine altered growth and male fertility phenotypes in subsequent generations, which could have clear commercial implications in livestock production systems. More recently, rams in a negative energy balance sired lambs with greater birth weight, chest circumference and shoulder–hip length compared with lambs sired by rams that were fed a maintenance diet. Yet, these differences in offspring development were no longer present at weaning (Bochantin-Winders et al. 2024a ). Ram plane of nutrition during spermatogenesis has also been recently reported to impact glucose metabolism on female F1 offspring (Bochantin-Winders et al. 2024b ). Collectively, these results indicate that paternal nutrition induces epigenetic changes in sperm, which can be transmitted to subsequent generations through non-Mendelian inheritance and alter offspring growth and physiology.
Conclusions and future directions
In summary (Fig. 6), bull exposure to high-energy diets for an extended period of time negatively impacts sperm biology. These changes in sperm biology have negative consequences to semen quality, postfertilization conceptus development, placental formation and postnatal metabolism of the offspring, which could potentially have major implications to growth, fat deposition and feed efficiency in livestock species. The mechanisms regulating paternal programming of offspring performance might include epigenetic programming of male germ line cells, which cause changes in placental development and/or tissue-specific epigenetic changes to the offspring (Fig. 6). This is particularly intriguing when considering the beef bull population. Beef bulls are often managed to achieve high rates of body weight gain and fat deposition. Moreover, one individual bull can sire thousands of offspring within a single breeding season if utilized in artificial insemination programs. Surprisingly, the effects of paternal high planes of nutrition on conceptus development and offspring physiology are still relatively unexplored in the bovine. Future research is required to better understand the impact of sire overnutrition on postfertilization outcomes, including preimplantation conceptus development beyond the blastocyst stage, placental and fetal development in utero and postnatal performance of the offspring.
Summary of potential consequences of paternal overnutrition to gamete quality, embryo development and paternal programming of the offspring. Bolded items represent the consequences of sire overnutrition that have been reported in the bovine, whereas non-bolded items represent consequences reported in other species. ROS, reactive oxygen species. Figure was generated using BioRender.
Citation: Reproduction and Fertility 6, 1; 10.1530/RAF-24-0082
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.
Funding
This work was supported by the USDA-AFRI Grants program (Animal Nutrition, Growth and Lactation 2022-67015-36649) to PLPF.
Author contribution statement
PLPF summarized the literature and drafted the manuscript. KGP, GCL and JJB interpreted the summarized literature, read, edited and approved the manuscript.
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