Consequences of maternal heat stress at different stages of embryonic and fetal development on dairy cows’ progeny

Maternal response to late-gestation heat stress alters developmental programming in lactating dairy cattle. There is currently limited knowledge on the effects of maternal heat stress occurring during the first months of gestation on postnatal phenotypes in dairy cows. Recent evidence indicates that differential DNA methylation arising in utero and intrauterine growth restriction are in part responsible for the long-term altered phenotypes. Further research is needed to determine if heat stress exposure during in utero development has direct effects on the germ cells of the developing fetus, leading to phenotype alteration of the granddaughters. Heat is one of the most important physiological stressors in livestock. Maternal heat stress, defined as an environmentally induced increase in core body temperature above euthermic levels, triggers a series of physiological and behavioral responses (Figure 1) all aimed at decreasing core heat production and/or increasing heat dissipation to the environment (West, 2003). These homeorhetic processes hinder the pregnant dam’s performance (Figure 1) and prenatally expose the offspring to an environment that can trigger lasting epigenetic alterations (Laporta et al., 2020). Prenatal heat stress significantly contributes to global production losses in pigs as it was reported to decrease swine birth weight, increase teratogenicity and core body temperature set point, and alter postnatal body composition (Johnson et al., 2015). Whereas the impacts of prenatal heat stress are well defined in pigs, the effects of a heat insult occurring at critical prenatal stages of development are just becoming apparent in dairy cows. Summary of heat stress-related effects on some physiological parameters and on the performance of dairy cows when heat stress occurs during lactation and the dry period which is defined as the last 6 to 8 wk before calving. The red arrow indicates a decrease, while the blue arrow indicates an increase. Summary of heat stress-related effects on some physiological parameters and on the performance of dairy cows when heat stress occurs during lactation and the dry period which is defined as the last 6 to 8 wk before calving. The red arrow indicates a decrease, while the blue arrow indicates an increase. Dairy cows are gestating during most of their lactation cycle, including the periconceptional period, which includes the period before conception to early gestation, and the dry period, which is commonly defined as a 6- to 8-wk nonlactating phase before calving. While the first months of gestation, coinciding with lactation, are characterized by embryogenesis, placentation, and organ development, the last 2 mo of gestation are concurrent with the dry period and are hallmarked by rapid fetal growth. It is now well established that the maternal intrauterine environment during conception and gestation is determinant for the phenotype of the offspring at adulthood (Bach et al., 2012). In light of this, in utero heat stress (IUHT), defined as prenatal exposure of the fetus to maternal body temperatures above euthermic levels, can lead to permanent changes in tissue structure and function, and have detrimental impacts on the subsequent offspring of dairy cows (Brown et al., 2015, 2016; Dado-Senn et al., 2020a). For instance, aberrant mammary gland morphology and the methylation profile of mammary gland DNA have recently been described in late-gestation IUHT heifers, which indicates that epigenetic changes during fetal development may contribute to altered postnatal phenotypes (Skibiel et al., 2018a, 2018b). Along with potential direct epigenetic changes, prenatal heat stress may indirectly impact the developing fetus through intrauterine growth restriction, which can impair the development of the fetus during gestation and have lifelong negative impacts on animal growth and development (Ji et al., 2017). Regardless of the mechanism, maternal heat stress exerts lifelong negative impacts on the resulting offspring that cannot be rescued by postnatal management (Laporta et al., 2020). This review describes the consequences of maternal heat stress at different stages of embryonic and fetal development on the prenatal development, intrauterine and postnatal growth, thermotolerance, metabolism, immune response, and production outcomes of the dairy cows’ progeny. We also discuss underlying physiological mechanisms and identify gaps in current knowledge relevant to epigenetics effects of maternal heat stress. Maternal heat stress occurring during the periconceptional period and early stages of gestation can alter embryogenesis as preimplantation embryos are highly sensitive to elevated temperatures. In fact, many embryos do not survive heat-stress exposure, especially in the first week postfertilization (Sakatani et al., 2008). Further, exposure of Holstein heifers to heat stress during the first 7 d after estrus increased the proportion of abnormally and slowly developing embryos (Putney et al., 1989). This was more recently confirmed in vitro as exposure of culture of bovine zygotes to 40–40.5 °C reduced the percentage of zygotes that reached the blastocyst stage (Ortega et al., 2016). Abnormal development in bovine preimplantation embryos under hyperthermia is multifactorial. Maternal heat stress was reported to induce cytoplasmic changes such as reductions in mitochondrial membrane potential, a marker for developmental control in oocytes and preimplantation embryos, and in calcium ions levels, which has been associated with the impairment of cellular functions (Kamano et al., 2014). In addition, heat stress is associated with nuclear changes such as DNA fragmentation, a characteristic of apoptosis (Paula-Lopes and Hansen, 2002a). Part of the deleterious effects of elevated temperature on preimplantation embryos is also mediated by the increased production of reactive oxygen species, leading to a variety of cellular damages (de Barros and Paula-Lopes, 2018). Moreover, it is also possible that heat stress exposure at the zygote stage affects paternally imprinted genes, because paternal genome is the first one to be actively demethylated after fertilization (Oswald et al., 2000). Such susceptibility of the paternally imprinted genome to heat stress at this early stage could have immediate effects on embryo development, and errors in DNA methylation could be inherited by subsequent generations (de Barros and Paula-Lopes, 2018). However, this hypothesis warrants further investigation in dairy cows. Embryos become more resistant to temperature as they advance in development. This thermotolerance was suggested to be related to the higher cell number as compared with the preimplantation embryo. It is also possible that the embryo acquires biochemical mechanisms of thermotolerance such as an increased protection by heat shock proteins as development progresses (Sakatani et al., 2013). Moreover, periconceptional heat stress could act as a means of natural selection causing only the best embryos to survive, thereby improving their thermotolerance (Rhoads, 2020). However, this hypothesis requires further research. Maternal heat stress exposure during late gestation also impacts the developing fetus. Fetal temperature is maternally dependent until birth. Thus, alterations in maternal core temperature can impact fetal temperature. Maternal heat is transferred to the fetus via the placenta and the uterus. Conversely, heat generated by fetal metabolism is dissipated by the amniotic fluid to the uterine wall or via umbilical cord and placenta to maternal blood. The majority of heat is transferred through the placenta via the fetal–placental circulation, with only 10 to 20% dissipated via amniotic fluid (Kasiteropolou et al., 2020). Thus, prenatal fetal thermoregulation is facilitated by the maternal–fetal temperature gradient, fetal–maternal blood flow, and placental function and morphology. During heat stress, maternal blood flow is diverted from the gravid uterus to the periphery in an effort to maximize maternal radiant heat loss thereby limiting the fetal temperature increment (Reynolds, 1990). Heat stress also decreases maternal dry matter intake in lactating pregnant cows, and in late-gestation dry cows, but to a lesser extent (Ouellet et al., 2020). Nutrition during pregnancy is a key determinant of placental growth. In addition, heat stress reduces blood concentrations of circulating placental hormones such as estrone sulfate, placental lactogen, and pregnancy-specific protein B reflecting an impairment of placental function, and development (Collier et al., 1982; Bell et al., 1989; Thompson et al., 2013). As the placenta is the organ for communication between mother and fetus, placental malfunctions invariably affect embryonic development and phenotypes in later life. Recent work revealed that a total of 169 genes were differentially expressed in placentae of pigs exposed to cyclic heat stress from day 40 to day 60 of gestation compared to placentae of pigs exposed to thermoneutral conditions (Zhao et al., 2021). Several of these genes were revealed to be involved in transport activity, glycoprotein biosynthetic processes, carbohydrate metabolic processes, solute carrier-mediated transmembrane transport, and glycosaminoglycan biosynthesis, which modulates placental stroma synthesis. Therefore, these authors identified altered placental nutrient transport capacity and metabolism as a possible mechanism for heat stress-induced placental inefficiency. Moreover, compensatory placental adaptations were reported in ewes exposed to hyperthermia during early pregnancy as the ratio of fetal to placental weight 15 to 20 d after the heat insult was approximately 40% higher compared to control ewes even though fetal weight was not different from that of control ewes. Increased expression of insulin-like growth factors (IGF-1), placental growth factor, and vascular endothelial growth factor in the placenta at day 55 of gestation suggests mechanisms for initial compensatory mechanisms (De Vrijer et al., 2006). Heat stress was also reported to reduce placental weight which is related to a decrease in tissue size rather than the number of placentomes (Early et al., 1991). Compared with those from sheep under thermoneutrality, the placenta from the hyperthermic animals had decreased total DNA, RNA, and protein content but concentrations were similar, which indicates that the reduced placenta mass is due to smaller cell number rather than cell size (Early et al., 1991). However, this remains to be demonstrated in dairy cows. Although nutrition is a key determinant of placental growth most studies suggest the negative effects of heat stress on placental and fetal growth are independent of nutrient intake (Bell et al., 1989; Alexander and Williams, 1971). To the best of our knowledge, there is currently a lack of investigations tracking the effects of periconceptional heat stress on placental function and morphology. Such investigations are important as the development of cotyledons, which transmit fetal blood and allow exchange of oxygen and nutrients with the maternal blood, starts early on in gestation (Van Eetvelde et al., 2016). Novel work conducted in dairy cows indicated that late-gestation maternal heat stress can impact placental gross morphology with the potential to affect placental function. Late-gestation cows exposed to heat stress were reported to have an increased number of cotyledons, cotyledonary weights, and cotyledonary surface area and volume (Potadle et al., 2019). This could potentially indicate that the placenta responds to hyperthermia and nutrient restriction by a compensatory expansion of the cotyledonary surface. Interestingly, the increased cotyledonary surface associated with maternal heat-stress in dairy cattle does not seem to equate to higher nutrient and oxygen delivery to the fetus as IUHT calves are on average lighter at birth and have lower hematocrit relative to calves born to cooled dams (Monteiro et al., 2016a). However, conflicting results exist in the literature regarding the effects of late-gestation maternal heat stress on placental morphology in cattle. Recent work conducted at the University of Florida has demonstrated that placentae collected from late gestation heat-stressed dairy cows had lower cotyledons number and tended to have lower cotyledons surface relative to cows that were cooled during the last 2 mo of gestation (Casarotto et al., 2021). However, only a small subset of placentas was evaluated in the analysis. Placenta-related studies are challenging in the bovine, given that placentae are expelled within 2 to 12 h after parturition. The bovine placenta contains high levels of RNases (Burton et al., 2014). Hence, the length of the interval between separation from uterine wall, delivery, and tissue collection is a critical parameter to be considered when estimating gene expression (Burton et al., 2014). Taken together, diverted blood flow, reduced nutrient intake, and alterations in placental morphology and function can create a nutrient-restricted hyperthermic intrauterine environment that limits fetal growth and eventually results in permanent adaptations (Ji et al., 2017). Moreover, maternal nutrition can have long-term metabolic consequences without necessarily affecting intrauterine growth (Bach et al., 2012). Birthweight of calves can act as a proxy of intrauterine growth. As far as we know, no controlled studies investigated the direct effects of periconceptional heat stress on calves’ birthweight and growth. However, a series of studies conducted in Holstein cows (Table 1) have demonstrated that late-gestation IUHT calves are born lighter relative to calves born to cooled dams (in utero with a of (Figure In the majority of pregnant dams were in or exposed to heat stress In to between the direct effects of hyperthermia and effects of reduced maternal intake on intrauterine growth, are all of the studies in only the one conducted by et a These authors reported that late-gestation IUHT calves were lighter at birth compared with calves born to cooled dams that intrauterine growth restriction under IUHT is independent of maternal of studies in the to in gestation and growth between late-gestation in utero heat-stressed Holstein calves and in utero cooled Holstein calves of studies in the to in gestation and growth between late-gestation in utero heat-stressed Holstein calves and in utero cooled Holstein calves Summary of in gestation length birth weight and weight between calves born to heat-stressed dams during the last stage of gestation and calves born to cooled dams during the last stage of indicates no between the indicates and indicates Summary of in gestation length birth weight and weight between calves born to heat-stressed dams during the last stage of gestation and calves born to cooled dams during the last stage of indicates no between the indicates and indicates reduced gestation length can also contribute to the intrauterine growth restriction and reduced under late-gestation exposed to heat stress during the last d of gestation on average d compared to dams with during the last of gestation (Figure However, studies no in gestation length of late-gestation dams exposed to heat stress or with they reported a in birth weight (Collier et al., 1982; et al., 2015). This indicates that intrauterine growth may also be independent of a gestation et morphology and DNA methylation changes of the in late-gestation IUHT and calves at birth. The authors reported that the of late-gestation IUHT calves more cells relative to and differentially These an epigenetic to postnatal at birth in late-gestation IUHT and However, the authors could not the of epigenetic mechanisms DNA methylation such as and or Late-gestation maternal heat stress exerts effects on growth. many studies reported in weight between IUHT and calves with an average of (Figure Dado-Senn et the impact of prenatal and postnatal heat stress exposure on including average These authors reported that was by prenatal heat stress. a by et reported that the impact of IUHT on body weight through of IUHT heifers to 12 mo of relative to that was by 2 of when the heifers for the first some compensatory Maternal heat stress during critical embryonic and fetal development stages could potentially in the selection of the embryos, thereby improving thermotolerance during postnatal and an to the heat cows during subsequent of heat stress (Rhoads, 2020). While we could not studies the effects of maternal periconceptional heat stress on thermotolerance in dairy cows, et the hypothesis that late-gestation maternal heat stress heat at in dairy cows. to control late-gestation IUHT animals had limited response to heat stress at reflecting a higher This thermotolerance is by an increased blood flow to the in IUHT which body temperature without the Moreover, IUHT animals potentially have a that heat exchange to the the Dado-Senn et reported that late-gestation IUHT dairy calves had temperature and compared to These results are with work conducted in pigs pigs exposed to IUHT had a increase in postnatal core body temperature that elevated of temperature exposure (Johnson et al., 2015). core body temperature thermotolerance under postnatal heat stress as heat loss on a between the animal and the The increase of core body temperature in IUHT pigs under postnatal heat stress is potentially associated with an increase in metabolic heat production and an increase in which can metabolic heat (Johnson et al., 2015). in thermotolerance between late-gestation IUHT calves before and IUHT lactating cows can be to in physiological and to the associated with developmental programming (Rhoads, 2020). This that adaptations are detrimental to the investigation is to the for periconceptional and late-gestation maternal heat stress on thermotolerance in IUHT cows. To the best of our knowledge, no studies the effects of periconceptional heat stress on metabolism and immune In studies that late-gestation IUHT calves have lower concentrations of and insulin-like growth but no in or concentrations within 2 h after birth. In addition, after late-gestation IUHT calves have circulating in the first and of relative to calves (Monteiro et al., et al., 2020). However, this in circulating does not as the (Monteiro et al., investigations conducted on the effects of late-gestation maternal heat stress on metabolism indicate that intrauterine conditions can the metabolism of the fetus as IUHT in but the postnatal and It is also reported that late-gestation maternal heat stress immune function of the offspring maternal IUHT calves have lower at and after h of birth and lower apparent of relative to that IUHT (Monteiro et al., et al., 2017). This was recently confirmed in a conducted in calves born to late gestation heat-stressed heifers apparent of of tended to be lower in late-gestation IUHT calves compared with calves concentrations from birth to day were significantly lower et al., 2021). 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