Robin M. Bernstein

Hair cortisol levels track phylogenetic and age related differences in hypothalamic-pituitary-adrenal (HPA) axis activity in non-human primates.

Hair has been shown to archive a uniquely time averaged signal of endocrine activity, and holds attractive advantages for both laboratory and field research. Prior research has explored the potential of hair hormone analysis to examine hormone-behavior relationships. To date, no research has focused on the potential of the technique to investigate age-related changes or taxon differences in endocrine function. It is known that non-human primate infants of many taxa exhibit high cortisol levels after parturition, which rapidly decline with age. It has also been shown that hypercortisolism generally characterizes platyrrhine (New World monkey) endocrine function. These endocrine trends have been characterized using cortisol levels determined from serum, plasma, and feces. Here we test whether cortisol levels determined from hair recover similar phylogenetic and age related patterns in endocrine function in non-human primates. In order to test whether hair cortisol reflect infant hypercortisolism with significant age-related decline, hair cortisol levels are measured in samples from wild vervet monkeys (Chlorocebus aethiops) and captive Guinea baboons (Papio hamadryas papio), ranging in age from infants through juveniles. Further, in order to test whether platyrrhines exhibit significantly higher hair cortisol levels compared to strepsirrhines and catarrhines, and therefore faithfully recover similar signals as more traditionally used substrates (e.g. serum), hair cortisol levels are quantified in adult female hair samples collected from a broad range of non-human primate taxa. Results confirm that hair cortisol levels accurately reflect known phylogenetic and age related patterns of circulating cortisol levels. Therefore, these results suggest that hair may be an ideal hormone bearing substrate for research focused on the examination of population endocrine profiles, cross-sectional studies of endocrine function and taxon variation in hormone levels, as well as stable behavioral trends.

Adrenal androgen production in catarrhine primates and the evolution of adrenarche

Adrenarche is a developmental event involving differentiation of the adrenal gland and production of adrenal androgens, and has been hypothesized to play a role in the extension of the preadolescent phase of human ontogeny. It remains unclear whether any nonhuman primate species shows a similar suite of endocrine, biochemical, and morphological changes as are encompassed by human adrenarche. Here, we report serum concentrations of the adrenal androgens dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) measured in 698 cross-sectional and mixed longitudinal serum samples from catarrhine primates ranging from 0.6 to 47 years of age. DHEAS in Pan is most similar to that of humans in both age-related pattern and absolute levels, and a transient early increase appears to be present in Gorilla. DHEA levels are highest in Cercocebus, Cercopithecus, and Macaca. We also tested for evidence of adaptive evolution in six genes that code for proteins involved in DHEA/S synthesis. Our genetic analyses demonstrate the protein-coding regions of these genes are highly conserved among sampled primates. We describe a tandem gene duplication event probably mediated by a retrotransposon that resulted in two 3-β-hydroxysteroid dehydrogenase/Delta 5-Delta 4 genes (HSD3B1 and HSD3B2) with tissue specific functions in catarrhines. In humans, HSD3B2 is expressed primarily in the adrenals, ovary, and testis, while HSD3B1 is expressed in the placenta. Taken together, our findings suggest that while adrenarche has been suggested to be unique to hominoids, the evolutionary roots for this developmental stage are more ancient.

Adrenarche in nonhuman primates: the evidence for it and the need to redefine it

Adrenarche is most commonly defined as a prepubertal increase in circulating adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfo-conjugate (DHEAS). This event is thought to have evolved in humans and some great apes but not in Old World monkeys, perhaps to promote brain development. Whether adrenarche represents a shared, derived developmental event in humans and our closest relatives, adrenal androgen secretion (and its regulation) is of considerable clinical interest. Specifically, adrenal androgens play a significant role in the pathophysiology of polycystic ovarian disease and breast and prostate cancers. Understanding the development of androgen secretion by the human adrenal cortex and identifying a suitable model for its study are therefore of central importance for clinical and evolutionary concerns. This review will examine the evidence for adrenarche in nonhuman primates (NHP) and suggest that a broader definition of this developmental event is needed, including morphological, biochemical, and endocrine criteria. Using such a definition, evidence from recent studies suggests that adrenarche evolved in Old World primates but spans a relatively brief period early in development compared with humans and some great apes. This emphasizes the need for frequent longitudinal sampling in evaluating developmental changes in adrenal androgen secretion as well as the tenuous nature of existing evidence of adrenarche in some species among the great apes. Central to an understanding of the regulation of adrenal androgen production in humans is the recognition of the complex nature of adrenarche and the need for more carefully conducted comparative studies and a broader definition in order to promote investigation among NHP in particular.

The big and small of it: How body size evolves

Body size is a biological variable of fundamental importance and plays a central role in analyses of life history, sexual dimorphism, allometry, and natural and sexual selection. Yet, there remains a sizeable gulf in our understanding that lies between what we hypothesize influences change in size, from the point of view of ultimate causation, and what we know about how shifts in body size are regulated from a proximate perspective. I seek here to tie these two perspectives together, and specifically to argue that an understanding of the hormonal regulation of body size is necessary for constructing hypotheses regarding how body size evolves. Recent work using model organisms points to the insulin/insulin-like growth factor pathway as playing a key role in the regulation of growth, size, reproduction, and senescence. I review the role of various components of this pathway in regulating growth and size and illustrate the evidence for different ways in which these might work to generate differences in size in various organisms. Of particular interest are the tradeoffs between size and other life history traits produced by experimental alterations in this pathway. Recent work emphasizing the ways in which body size can be altered based on extrinsic factors provides the opportunity to link advances in uncovering the proximate bases of growth and size and offers an opportunity to frame new hypotheses regarding how variation in size evolves.

Growth and Morbidity of Gambian Infants are Influenced by Maternal Milk Oligosaccharides and Infant Gut Microbiota

Human milk oligosaccharides (HMOs) play an important role in the health of an infant as substrate for beneficial gut bacteria. Little is known about the effects of HMO composition and its changes on the morbidity and growth outcomes of infants living in areas with high infection rates. Mother’s HMO composition and infant gut microbiota from 33 Gambian mother/infant pairs at 4, 16, and 20 weeks postpartum were analyzed for relationships between HMOs, microbiota, and infant morbidity and growth. The data indicate that lacto-N-fucopentaose I was associated with decreased infant morbidity, and 3′-sialyllactose was found to be a good indicator of infant weight-for-age. Because HMOs, gut microbiota, and infant health are interrelated, the relationship between infant health and their microbiome were analyzed. While bifidobacteria were the dominant genus in the infant gut overall, Dialister and Prevotella were negatively correlated with morbidity, and Bacteroides was increased in infants with abnormal calprotectin. Mothers nursing in the wet season (July to October) produced significantly less oligosaccharides compared to those nursing in the dry season (November to June). These results suggest that specific types and structures of HMOs are sensitive to environmental conditions, protective of morbidity, predictive of growth, and correlated with specific microbiota.

Variation in vervet (Chlorocebus aethiops) hair cortisol concentrations reflects ecological disturbance by humans

AbstractVervet monkeys (Chlorocebus aethiops) often live in close proximity to humans. Vervets are known to raid crops, homes and gardens in suburban areas leading to human–vervet conflict. In general, primate groups with access to human foods experience increased population densities and intra-group aggression. This suggests high stress loads for vervets living in environments with high levels of human habitat disturbance and close proximity to humans. We tested the hypothesis that populations characterized by high levels of human impact are more physiologically stressed than low human impact populations, and that this increased stress would be reflected in higher concentrations of hair cortisol. We predicted that because females would be less likely to engage in high risk foraging activities, and hence keep more distance from humans than males, their hair cortisol levels should be lower than those in males. We quantified cortisol in the hair of wild caught individuals from populations that experienced different degrees of human habitat disturbance and differences in access to human food. We found that males in high human impact groups had significantly higher hair cortisol concentrations than those in low human impact groups, although this difference was not observed in female vervets. Human impacts on vervet behavioral ecology appear to be a significant source of stress for male animals in particular.

Mount Pinatubo, Inflammatory Cytokines, and the Immunological Ecology of Aeta Hunter-Gatherers

Abstract Early growth cessation and reproduction are predicted to maximize fitness under conditions of high adult mortality, factors that could explain the pygmy phenotype of many rainforest hunter-gatherers. This life-history hypothesis is elegant but contentious in part because it lacks a clear biological mechanism. One mechanism stems from the field of human immunological ecology and the concept of inflammation “memory” across the life cycle and into subsequent generations. Maternal exposures to disease can infl uence immunological cues present in breast milk; because maternal provisioning via lactation occurs during critical periods of development, it is plausible that these cues can also mediate early growth cessation and small body size. Such epigenetic hypotheses are difficult to test, but the concept of developmental programming is attractive because it could explain how the stature of a population can change over time, in terms of both secular increases and rapid intergenerational decreases. Here we explore this concept by focusing on the Aeta, a population of former hunter-gatherers, and the Ilocano, a population of rice farmers. We predicted that Aeta mothers would produce breast milk with higher concentrations of four bioactive factors due to high infectious burdens. Further, we predicted that the concentrations of these factors would be highest in the cohort of women born in the early 1990s, when exposure to infectious disease was acute following the eruption of Mount Pinatubo in June 1991. We analyzed levels of adiponectin, C-reactive protein, and epidermal growth factor in the milk of 24 Aeta and 31 Ilocano women and found no detectable differences, whereas levels of transforming growth factor-&bgr;2 were elevated among the Aeta, particularly as a function of maternal age. We found no difference between cohorts divided by the volcanic eruption (n = 43 born before, n = 12 born after). We discuss the implications of our findings for the terminal investment hypothesis and we suggest that the historical ecology of the Aeta is a promising model system for testing epigenetic hypotheses focused on the evolution of small body size.

Variation of hair cortisol concentrations among wild populations of two baboon species ( Papio anubis , P. hamadryas ) and a population of their natural hybrids

Male olive (Papio anubis) and hamadryas (P. hamadryas) baboons have distinctive sociobehavioral and physical characteristics. In the Awash National Park, Ethiopia, a hybrid population at the contact zone between these two species, exhibits heterogeneous sociobehavioral and physical characteristics. The ambiguity of the hybrid social environment and disruption of parental stress genotypes may be sources of physiological stress for hybrids. We examined levels of chronic stress among males of the three populations and tested the prediction that chronic cortisol levels would be higher among the hybrids. Animals were captured, sampled, and released during the wet season, and a hair sample was taken for assay. Cortisol was extracted from 182 hair samples with methanol and quantified by ELISA. We included age, age class, rainfall variation, and species affiliation in models examining variation in hair cortisol levels. Species and age significantly contributed to models explaining variation in hair cortisol. Infant hypercortisolism was observed in all three groups, and a decline in cortisol through juvenile and adolescent stages, with a subsequent rise in adulthood. This rise occurred earliest in hamadryas, corroborating other evidence of the precocious development of hamadryas baboons. As expected, hybrids had significantly elevated hair cortisol compared with olive baboons and hamadryas, irrespective of age, except for very young animals. Infant hypercortisolism was also less pronounced among hybrids. Species differences and age-related differences in cortisol levels suggest a dysregulated cortisol phenotype in hybrids, and possibly reflect some form of hybrid disadvantage. More work will be required to disentangle the effects of genetic factors and the social environment.

Bioactive factors in milk across lactation: Maternal effects and influence on infant growth in rhesus macaques (Macaca mulatta)

Among mammals, numerous bioactive factors in milk vary across mothers and influence offspring outcomes. This emerging area of research has primarily investigated such dynamics within rodent biomedical models, domesticated dairy breeds, and among humans in clinical contexts. Less understood are signaling factors in the milk of non‐human primates. Here, we report on multiple bioactive components in rhesus macaque (Macaca mulatta) milk and their associations with maternal and infant characteristics. Milk samples were collected from 59 macaques at multiple time points across lactation in conjunction with maternal and infant morphometrics and life‐history animal records. Milk was assayed for adiponectin (APN), epidermal growth factor (EGF) and its receptor (EGF‐R), and transforming growth factor beta 2 (TGF‐β2). Regression models were constructed to assess the contributions of maternal factors on variation in milk bioactives, and on the relationship of this variation to infant body mass and growth. Maternal body mass, parity, social rank, and infant sex were all predictive of concentrations of milk bioactives. Primiparous mothers produced milk with higher adiponectin, but lower EGF, than multiparous mothers. Heavier mothers produced milk with lower EGF and EGF‐R, but higher TGF‐β2. Mothers of daughters produced milk with higher TGF‐β2. Mid‐ranking mothers produced milk with higher mean EGF and adiponectin concentrations than low‐ranking mothers. Milk EGF and EGF‐R were positively associated with infant body mass and growth rate. Importantly, these signaling bioactives (APN, EGF, EGF‐R, and TGF‐β2) were significantly correlated with nutritional values of milk. The effects of milk signals remained after controlling for the available energy in milk revealing the added physiological role of non‐nutritive milk bioactives in the developing infant. Integrating analyses of energetic and other bioactive components of milk yields an important perspective for interpreting the magnitude, sources, and consequences of inter‐individual variation in milk synthesis. Am. J. Primatol. 78:838–850, 2016.

Maternal effects and the endocrine regulation of mandrill growth.

Maternal effects can influence offspring growth and development, and thus fitness. However, the physiological factors mediating these effects in nonhuman primates are not well understood. We investigated the impact of maternal effects on variation in three important components of the endocrine regulation of growth in male and female mandrills (Mandrillus sphinx), from birth to 9 years of age. Using a mixed longitudinal set (N = 252) of plasma samples, we measured concentrations of insulin‐like growth factor‐I (IGF‐I), growth hormone binding protein (GHBP), and free testosterone (free T). We evaluated the relationship of ontogenetic patterns of changes in hormone concentration to patterns of growth in body mass and body length, and determined that these endocrine factors play a significant role in growth of both young (infant and juvenile) and adolescent male mandrills, but only in growth of young female mandrills. We also use mixed models analysis to determine the relative contribution of the effects of maternal rank, parity, and age on variation in hormone and binding protein concentrations. Our results suggest that all of these maternal effects account for significant variation in hormone and binding protein concentrations in all male age groups. Of the maternal effects measured, maternal rank was the most frequently identified significant maternal effect on variation in hormone and binding protein concentrations. We suggest that these endocrine factors provide mechanisms that contribute to the maternal effects on offspring growth previously noted in this population. Am. J. Primatol. 74:890‐900, 2012.