•Humans, rodents, and wild mammals share biological generalities in maternal programming.•Maternal androgens, photoperiod, microbiome and immunity influence offspring phenotype.•Milk is a rich source ...of maternal hormones, microbiota, immune factors and exosomes.•Milk exosomes transfer microRNA into offspring cells and may induce biological changes.•The extent of maternal programming cannot be fully understood by examining a single cue.
The perinatal period is a sensitive time in mammalian development that can have long-lasting consequences on offspring phenotype via maternal effects. Maternal effects have been most intensively studied with respect to two major conditions: maternal diet and maternal stress. In this review, we shift the focus by discussing five major additional maternal cues and their influence on offspring phenotype: maternal androgen levels, photoperiod (melatonin), microbiome, immune regulation, and milk composition. We present the key findings for each of these topics in mammals, their mechanisms of action, and how they interact with each other and with the maternal influences of diet and stress. We explore their impacts in the contexts of both predictive adaptive responses and the developmental origins of disease, identify knowledge gaps and research opportunities in the field, and place a particular emphasis on the application and consideration of these effects in non-model species and natural ecological systems.
The boreal forest is one of the world’s ecosystems most affected by global climate warming. The snowshoe hare, its predators, and their population dynamics dominate the mammalian component of the ...North American boreal forest. Our past research has shown the 9–11-year hare cycle to be predator driven, both directly as virtually all hares that die are killed by their predators, and indirectly through sublethal risk effects on hare stress physiology, behavior, and reproduction. We replicated this research over the entire cycle by measuring changes in predation risk expected to drive changes in chronic stress. We examined changes in hare condition and stress axis function using a hormonal challenge protocol in the late winter of 7 years—spanning all phases of the cycle from the increase through to the low (2014–2020). We simultaneously monitored changes in hare abundance as well as those of their primary predators, lynx and coyotes. Despite observing the expected changes in hare–predator numbers over the cycle, we did not see the predicted changes in chronic stress metrics in the peak and decline phases. Thus, the comprehensive physiological signature indicative of chronic predator-induced stress seen from our previous work was not present in this current cycle. We postulate that hares may now be increasingly showing behavior-mediated rather than stress-mediated responses to their predators. We present evidence that increases in primary productivity have affected boreal community structure and function. We speculate that climate change has caused this major shift in the indirect effects of predation on hares.
Predation is a key organizing force in ecosystems. The threat of predation may act to programme the endocrine hypothalamic-pituitary-adrenal axis during development to prepare offspring for the ...environment they are likely to encounter. Such effects are typically investigated through the measurement of corticosteroids (Cort). Corticosteroid-binding globulin (CBG) plays a key role in regulating the bioavailability of Cort, with only free unbound Cort being biologically active. We investigated the effects of prenatal predator odour exposure (POE) in mice on offspring CBG and its impact on Cort dynamics before, during and after restraint stress in adulthood. POE males, but not females, had significantly higher serum CBG at baseline and during restraint and lower circulating levels of Free Cort. Restraint stress was associated with reduced liver transcript abundance of
(CBG-encoding gene) only in control males. POE did not affect
promoter DNA methylation. Our results indicate that prenatal exposure to a natural stressor led to increased CBG levels, decreased per cent of Free Cort relative to total and inhibited restraint stress-induced downregulation of CBG transcription. These changes suggest an adaptive response to a high predator risk environment in males but not females that could buffer male offspring from chronic Cort exposure.
Maternal stress can prenatally influence offspring phenotypes and there are an increasing number of ecological studies that are bringing to bear biomedical findings to natural systems. This is ...resulting in a shift from the perspective that maternal stress is unanimously costly, to one in which maternal stress may be beneficial to offspring. However, this adaptive perspective is in its infancy with much progress to still be made in understanding the role of maternal stress in natural systems. Our aim is to emphasize the importance of the ecological and evolutionary context within which adaptive hypotheses of maternal stress can be evaluated. We present five primary research areas where we think future research can make substantial progress: (1) understanding maternal and offspring control mechanisms that modulate exposure between maternal stress and subsequent offspring phenotype response; (2) understanding the dynamic nature of the interaction between mothers and their environment; (3) integrating offspring phenotypic responses and measuring both maternal and offspring fitness outcomes under real-life (either free-living or semi-natural) conditions; (4) empirically testing these fitness outcomes across relevant spatial and temporal environmental contexts (both pre- and post-natal environments); (5) examining the role of maternal stress effects in human-altered environments—i.e., do they limit or enhance fitness. To make progress, it is critical to understand the role of maternal stress in an ecological context and to do that, we must integrate across physiology, behavior, genetics, and evolution.
The population dynamics of snowshoe hares (Lepus americanus) are fundamental to the ecosystem dynamics of Canada’s boreal forest. During the 8- to 11-year population cycle, hare densities can ...fluctuate up to 40-fold. Predators in this system (lynx, coyotes, great-horned owls) affect population numbers not only through direct mortality but also through sublethal effects. The chronic stress hypothesis posits that high predation risk during the decline severely stresses hares, leading to greater stress responses, heightened ability to mobilize cortisol and energy, and a poorer body condition. These effects may result in, or be mediated by, differential gene expression. We used an oligonucleotide microarray designed for a closely-related species, the European rabbit (Oryctolagus cuniculus), to characterize differences in genome-wide hippocampal RNA transcript abundance in wild hares from the Yukon during peak and decline phases of a single cycle. A total of 106 genes were differentially regulated between phases. Array results were validated with quantitative real-time PCR, and mammalian protein sequence similarity was used to infer gene function. In comparison to hares from the peak, decline phase hares showed increased expression of genes involved in metabolic processes and hormone response, and decreased expression of immune response and blood cell formation genes. We found evidence for predation risk effects on the expression of genes whose putative functions correspond with physiological impacts known to be induced by predation risk in snowshoe hares. This study shows, for the first time, a link between changes in demography and alterations in neural RNA transcript abundance in a natural population.
•Hair cortisol concentrations (HCC) positively correlated across body regions.•Individual variation explains highest proportion (44%) of variance in HCC.•HCC captures prey’s seasonal and cyclical ...physiological responses to predation risk.•HCC is an integrative index of long-term adrenocortical activity in wild mammal.
Hair cortisol concentration is increasingly used as a convenient, non-invasive, and integrative measure of physiology and health in natural populations of mammals. However, the use of this index is potentially confounded by individual variation in body region-specific differences in cortisol deposition rates. Here we examine correlations in cortisol concentrations in hair collected from the ear, shoulder, and thigh of wild snowshoe hares, Lepus americanus, as well as the influence of sex on cortisol measurements. We further evaluated this technique’s ability to capture seasonal and cyclical patterns of snowshoe hare glucocorticoid secretion from 2013 to 2015 in the southwestern Yukon (Canada). We found positive correlations (R2 = 0.20–0.32) in all pairwise comparisons among body regions, and differences among individuals accounted for the greatest proportion of variance (47.3%) in measurements. From 2013 to 2015 the hares’ primary predator – Canada lynx – approximately doubled in population abundance. We found a significant increase in hare hair cortisol concentrations across this time period. Cortisol indices were higher in summer than winter pelage, reflecting predicted physiological responses to seasonal variation in food availability and individual risk. Variation in hair cortisol concentrations was more similar to long-term (weeks-months) integrative indices of adrenal capacity than point samples of fecal glucocorticoid metabolite concentrations. Overall, we find that hair cortisol analysis is a simple and useful tool for estimations of population-level stress physiology in wild mammals, and sampling of core body regions with consistent moulting patterns produced the most robust results in this species.
Technological miniaturization is driving a biologging revolution that is producing detailed and sophisticated techniques of assessing individual behavioral responses to environmental conditions. ...Among the many advancements this revolution has brought is an ability to record behavioral responses of nocturnal, free-ranging species. Here, we combine captive validations of acceleration signatures with acoustic recordings from free-ranging individuals to classify behavior at two resolutions. Combining these classifications with ~2 month-long recordings, we describe winter time budgets, and responses of free-ranging snowshoe hares to changing moonlight. We successfully classified snowshoe hare behavior into four categories (not moving, foraging, hopping, and sprinting) using low frequency accelerometry, with an overall model accuracy of 88%, and acoustic recordings to three categories (silence, hopping, and chewing) with an accuracy of 94%. Broad-scale accelerometer-classified categories were composed of multiple fine-scale behavioral states with the composition varying between individuals and across the day. Time budgets revealed that hares spent ~50% of their time foraging and ~50% not moving, with most foraging and feeding occurring at night. We found that hares adjusted timing of activity in response to moon phase, with a 6% reduction in foraging and 30% reduction in traveling during the night when the moon was full. Hares compensated for this lost foraging time by extending foraging into the morning hours of the following day. Using two biologging technologies to identify behavior, we demonstrate the possibility of combining multiple devices when documenting behavior of cryptic species.
The population dynamics of snowshoe hares (Lepus americanus) are fundamental to the ecosystem dynamics of Canada’s boreal forest. During their 8-11 year population cycle, hare densities can fluctuate ...up to 40-fold. Predators in this system (lynx, coyotes, great-horned owls) affect hare demography not only through direct mortality but also through non-consumptive effects on reproduction that are mediated by chronic stress. There is strong evidence for the acute physiological sensitivity of snowshoe hares to fluctuating predator pressure, characterized by major shifts in glucocorticoid profiles, energy mobilization, immunity and body condition under situations of extreme risk. This thesis aimed first to determine whether the predator-induced variation in hare stress physiology seen across the cycle is associated with predictable neurobiological changes in transcriptional activity and the expression of corticosteroid receptors in key limbic regulatory regions of the hypothalamic-pituitary-adrenal (HPA) axis, and second, whether predation risk has intergenerational impacts on offspring phenotype that may act to prolong the lag in population recovery that follows the decline phase of the cycle, even though food resources are plentiful and predators have all but disappeared. I found changes in the expression of gene networks that mediate hormone responses and hematological condition, and in the expression of glucocorticoid-sensitive receptors that regulate the HPA axis as a function of increasing predation risk in the natural population. During the increase and peak phases of the cycle, predator-induced maternal stress programmed for a neuroresilient offspring phenotype characterized by key transcriptional changes that allow for sensitive physiological responses to environmental stress through activation of the amygdala, balanced by gene activity that confers neuroendocrine resilience and maintains basal HPA function in the hippocampus. Offspring stress physiology was associated with a number of anti-predator behaviours that could confer an initial survival advantage in risky environments, but become maladaptive when conditions change. Taken together, these results provide support for predator-induced maternal stress effects on offspring phenotype that could become important mediators of the lag in population recovery under conditions of chronic maternal stress.
Vitamin D deficiency is common in the United States and leads to altered immune function, including T cell and macrophage activity that may impact responses to SARS-CoV-2 infection. This study ...investigated 131 adults with a history of a positive SARS-CoV-2 nasopharyngeal PCR and 18 adults with no COVID-19 diagnosis that were recruited from the community or hospital into the Northern Colorado Coronavirus Biorepository (NoCo-COBIO). Participants consented to enrollment for a period of 6 months and provided biospecimens at multiple visits for longitudinal analysis. Plasma 25-hydroxyvitamin D levels were quantified by LC-MS/MS at the initial visit (n = 149) and after 4 months (n = 89). Adults were classified as deficient (<30 nM or <12 ng/mL), insufficient (<30−50 nM or 12−20 ng/mL), or optimal (50−75 nM or >20 ng/mL) for 25-hydroxyvitamin D status. Fisher’s exact test demonstrated an association between disease severity, gender, and body mass index (BMI) at baseline. Mixed model analyses with Tukey-Kramer were used for longitudinal analysis according to BMI. Sixty-nine percent (n = 103) of the entire cohort had optimal levels of total 25(OH)D, 22% (n = 32) had insufficient levels, and 9% (n = 14) had deficent levels. Participants with severe disease (n = 37) had significantly lower 25-hydroxyvitamin D (total 25(OH)D) when compared to adults with mild disease (p = 0.006) or no COVID-19 diagnosis (p = 0.007). There was 44% of the cohort with post-acute sequalae of COVID-19 (PASC) as defined by experiencing at least one of the following symptoms after 60 days’ post-infection: fatigue, dyspnea, joint pain, chest pain, forgetfulness or absent-mindedness, confusion, or difficulty breathing. While significant differences were detected in 25-hydroxyvitamin D status by sex and BMI, there were no correlations between 25-hydroxyvitamin D for those without and without PASC. This longitudinal study of COVID-19 survivors demonstrates an important association between sex, BMI, and disease severity for 25-hydroxyvitamin D deficiency during acute stages of infection, yet it is not clear whether supplementation efforts would influence long term outcomes such as developing PASC.
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