Julienne N. Rutherford

Early origins of inflammation: microbial exposures in infancy predict lower levels of C-reactive protein in adulthood

Ecological factors are important determinants of the development and function of anti-pathogen defences. Inflammation is a central part of innate immunity, but the developmental factors that shape the regulation of inflammation are not known. We test the hypothesis that microbial exposures in infancy are associated with high sensitivity C-reactive protein (CRP) in adulthood using prospective data from a birth cohort in the Philippines (n = 1461). Lower birth weight was associated with increased CRP, consistent with a role for inflammation in the widely documented inverse relationship between birth weight and adult cardiovascular diseases. In addition, higher levels of microbial exposure in infancy were associated with lower CRP. These associations were independent of socioeconomic status, measures of current body fat and other health behaviours. We conclude that measures of microbial exposure and nutrition during the pre-natal and early post-natal periods are important predictors of CRP concentration in young adulthood. We speculate that the development of anti-inflammatory regulatory networks in response to early microbial exposure represents plasticity in the development of anti-pathogen defences, and that this process may help explain the low CRP concentrations in this population.

Survey of Academic Field Experiences (SAFE): Trainees Report Harassment and Assault

Little is known about the climate of the scientific fieldwork setting as it relates to gendered experiences, sexual harassment, and sexual assault. We conducted an internet-based survey of field scientists (N = 666) to characterize these experiences. Codes of conduct and sexual harassment policies were not regularly encountered by respondents, while harassment and assault were commonly experienced by respondents during trainee career stages. Women trainees were the primary targets; their perpetrators were predominantly senior to them professionally within the research team. Male trainees were more often targeted by their peers at the research site. Few respondents were aware of mechanisms to report incidents; most who did report were unsatisfied with the outcome. These findings suggest that policies emphasizing safety, inclusivity, and collegiality have the potential to improve field experiences of a diversity of researchers, especially during early career stages. These include better awareness of mechanisms for direct and oblique reporting of harassment and assault and, the implementation of productive response mechanisms when such behaviors are reported. Principal investigators are particularly well positioned to influence workplace culture at their field sites.

Building babies: Primate development in proximate and ultimate perspective

Preface.- I. CONCEPTION & PREGNANCY.- 1. Inflammation, reproduction, and the Goldilocks Principle.- 2. The primate placenta as an agent of developmental and health trajectories across the lifecourse.- 3. Placental development, evolution, and epigenetics of primate pregnancies.- 4. Nutritional ecology and reproductive output in female chimpanzees (Pan troglodytes): variation among and within populations.- II. FROM PRE- TO POST-NATAL LIFE.- 5. Prenatal androgens affect development and behavior in primates.- 6. Navigating transitions in HPA function from pregnancy through lactation: implications for maternal health and infant brain development.- 7. Genome-environment coordination in neurobehavioral development.- 8. Building Marmoset Babies: Trade-offs and Cutting Bait.- III. MILK: COMPLETE NUTRITION FOR THE INFANT.- 9. Lactational programming: mothers milk predicts infant behavior and temperament.- 10. Do bigger brains mean better milk? .- 11. Infant gut microbiota: developmental influences and health outcomes.- IV. MOTHERS AND INFANTS: THE FIRST SOCIAL RELATIONSHIP.- 12. Maternal influences on social and neural development in rhesus monkeys.- 13. Behavioral Response of Mothers and Infants to Variation in Maternal Condition: Adaptation, Compensation and Resilience.- 14. The role of mothers in the development of tool-use in chimpanzees.- V. THE EXPANDING SOCIAL NETWORK.- 15. Reproductive strategies and infant care in the Malagasy primates.- 16. When dads help: male behavioral care during primate infant development.- 17. Ontogeny of social behavior in the genus Cebus and the application of an integrative framework for examining plasticity and complexity in evolution.- VI. TRANSITIONS TO JUVENILITY AND REPRODUCTIVE MATURITY.- 18. Identifying proximate and ultimate causation in the development of primate sex-typed social behavior.- 19. Future adults or old children? Integrating life history frameworks for understanding primate positional patterns.- 20. Quantitative genetic perspectives female macaque life histories: heritability, plasticity, and trade-offs.- 21. Cultural evolution and human reproductive behavior.- CONCLUSION 22. The ontogeny of investigating primate ontogeny.

Evolutionary genetics and implications of small size and twinning in callitrichine primates

Significance New World monkeys (NWMs) are characterized by an extensive size range, and clawed NWMs (callitrichines) such as marmosets manifest diminutive size and unique reproductive adaptations such as twinning. Evolutionary explanations have been proposed for these traits, and with the common marmoset genome assembly the genetic underpinnings of these traits can now be explored. Callitrichine-specific nonsynonymous substitutions were identified in GDF9, BMP15, BMP4, and WFIKKN1. We postulate that positive selection affected NWM growth patterns, with callitrichine miniaturization coevolving with a series of reproductive adaptations that bear benefit when gestating multiples. Given the high rate of morbidity and mortality with human twins, future studies into callitrichine genomic adaptations will undoubtedly lead to unique insights of benefit to their human counterparts. New World monkeys (NWMs) are characterized by an extensive size range, with clawed NWMs (subfamily Callitrichinae, or callitrichines) such as the common marmoset manifesting diminutive size and unique reproductive adaptations. Perhaps the most notable of these adaptations is their propensity toward multiple gestations (i.e., dichorionic twins and trichorionic triplets). Indeed, with the exception of Goeldi’s monkey (Callimico), callitrichine singleton pregnancies rarely occur. Multiple gestations seem to have coevolved with a suite of reproductive adaptations, including hematopoetic chimerism of siblings, suppression of reproduction in nondominant females, and cooperative alloparenting. The sequencing of the common marmoset (Callithrix jacchus) genome offers the opportunity to explore the genetic basis of these unusual traits within this primate lineage. In this study, we hypothesized that genetic changes arising during callitrichine evolution resulted in multiple ovulated ova with each cycle, and that these changes triggered adaptations that minimized complications common to multiple gestations in other primates, including humans. Callitrichine-specific nonsynonymous substitutions were identified in GDF9, BMP15, BMP4, and WFIKKN1. WFIKKN1, a multidomain protease inhibitor that binds growth factors and bone morphogenetic proteins, has nonsynonymous changes found exclusively in common marmosets and other tested callitrichine species that twin. In the one callitrichine species that does not produce twins (Callimico), this change has reverted back to the ancestral (nontwinning) primate sequence. Polymorphisms in GDF9 occur among human cohorts with a propensity for dizygotic twins, and polymorphisms in GDF9 and BMP15 are associated with twinning in sheep. We postulate that positive selection affected NWM growth patterns, with callitrichine miniaturization coevolving with a series of reproductive adaptations.

Framing Postpartum Hemorrhage as a Consequence of Human Placental Biology: An Evolutionary and Comparative Perspective

Postpartum hemorrhage (PPH), the leading cause of maternal mortality worldwide, is responsible for 35 percent of maternal deaths. Proximately, PPH results from the failure of the placenta to separate from the uterine wall properly, most often because of impairment of uterine muscle contraction. Despite its prevalence and its well-described clinical manifestations, the ultimate causes of PPH are not known and have not been investigated through an evolutionary lens. We argue that vulnerability to PPH stems from the intensely invasive nature of human placentation. The human placenta causes uterine vessels to undergo transformation to provide the developing fetus with a high plane of maternal resources; the degree of this transformation in humans is extensive. We argue that the particularly invasive nature of the human placenta increases the possibility of increased blood loss at parturition. We review evidence suggesting PPH and other placental disorders represent an evolutionarily novel condition in hominins.

Hormones and Reproductive Cycles in Primates

Publisher Summary This chapter summarizes the current perspectives and understanding of reproductive function in human and nonhuman primates, including the hypothalamic-pituitary-gonadal (HPG) axis function across the lifespan; pregnancy and lactation; sexual behavior and its hormonal underpinnings; and seasonal, social, and energetic influences on reproduction. Descriptive data on reproductive patterns are available for several hundred primate species and subspecies studied in the wild and/or in captivity. Primates are morphologically generalized mammals that are distinguished by their large brains, advanced cognitive abilities, flexible behavior, sophisticated social systems, and long lives. Although primate species exhibit marked diversity in morphology, ecology, life-history parameters, and social organization, they share a reproductive profile characterized by low fecundity and extensive investment in each infant, associated with delayed reproductive maturation, long gestations, small litters, large neonates, long lactational periods, and slow postnatal growth.

Change in waist circumference over 11 years and current waist circumference independently predict elevated CRP in Filipino women.

C‐reactive protein, a marker of chronic, low‐grade inflammation, is strongly associated with current central adiposity, and has been linked to elevated risk of cardiovascular disease. Less is known about the contribution of longitudinal change in waist circumference to current inflammation. We evaluated the extent to which current waist circumference and change over an 11‐year interval contribute independently to low‐grade systemic inflammation measured in a group of 1,294 women, 35–69 years, participating in the Cebu Longitudinal Nutrition and Health Survey in the Philippines. Waist circumference was measured at the time of blood draw for CRP analysis in 2005 and during an earlier survey in 1994. A waist circumference delta variable was constructed by subtracting current circumference from past circumference. We used logistic regression models to predict having an elevated plasma CRP concentration (3 mg L−1 < CRP < 10 mg L−1). Waist circumference in 2005 was a strong predictor of elevated CRP (OR 1.10, 95% CI = 1.08, 1.12, P < 0.001). In combined models, increase in circumference over 11 years was a significant and independent predictor of elevated CRP risk (OR = 1.023, 95% CI = 1.00, 1.05, P < 0.05). Considering the average increase over time, the cumulative risk of elevated CRP due to increased central adiposity was 25.7%. However, women who reduced their waist circumference between 1994 and 2005 had greatly reduced risk (6.2%), suggesting that even long‐term inflammatory burden can be reversed by weight loss. Although current waist circumference is an important contributor to risk of elevated systemic inflammation in this as in other populations, history of central adiposity may be an independent phenomenon. Am. J. Hum. Biol. 2010.

Body mass growth in common marmosets: toward a model of pediatric obesity.

While much is known about adult obesity in nonhuman primates, very little is known regarding development of childhood adiposity. As small monkeys that are easy to handle and have a relatively fast life history, common marmoset monkeys (Callithrix jacchus) offer interesting opportunities to examine the question of fat versus lean mass growth in a nonhuman primate. This article provides an overview of our understanding of early life growth in mass in marmoset monkeys, based primarily upon our past 20 years of research, culminating in our recent findings on early life obesity in this species. Common marmosets display variance in early life growth patterns that is related to both pre- and postnatal factors and the marmoset uterine environment is exquisitely designed to reflect resources available for the gestation of multiple offspring, making them an interesting model of developmental programming. We have demonstrated that obesity can be generated in very early life in captive marmosets, with excess adiposity evident by one month of age, making this species a potentially valuable model in which to study pediatric obesity and its sequelae. Birth weight is associated with adiposity in animals vulnerable to obesity. Early life exposure to higher fat diets enhances the chances of postweaning obesity development. However, overall higher food consumption is also associated with obesity development at later ages. One unexpected finding in our studies has been the relatively high body fat percentage of neonatal (12-18%) marmosets suggesting that hypotheses regarding the uniqueness of high human neonatal adiposity merit further examination.

The Primate Placenta as an Agent of Developmental and Health Trajectories Across the Life Course

The significance of the intrauterine environment extends beyond the fetal and postnatal phases of growth into adulthood and across generations, as addressed by the developmental programming research paradigm. Much of this paradigm hinges on interpretations of birth weight as a proxy of this dynamic environment. However, the key player in this environment and more direct driver of birth weight is often overlooked and poorly understood in this context. The placenta is an incredible organ, existing in obscurity for a relatively short time, but performing myriad functions at the complex genomic intersection of three individuals: mother, father, and fetus. Regulation of placental function and structure is complex; just as fetal growth is a variable and plastic phenomenon depending on maternal condition, so does placental function respond sensitively to external ecological inputs. The goal of this chapter is to introduce the reader to the placenta as an extrasomatic fetal organ that interacts directly with maternal ecology, describe some of the mechanisms that underlie fetal development, explore the morphological and functional plasticity of the placenta in relation to fetal growth variation particularly in humans, and relate these observations to programming of adult function. Further, I present lessons about placental plasticity in a litter-bearing anthropoid primate, the common marmoset monkey, with special attention paid to life history and reproductive programming to suggest that placental function may serve as a driver of evolutionary change. Finally, I argue that including the placenta in primate research will lead to important evolutionary and clinically-relevant discoveries.

Toward a nonhuman primate model of fetal programming: phenotypic plasticity of the common marmoset fetoplacental complex.

Nonhuman primates offer unique opportunities as animal models in the study of developmental programming and the role of the placenta in developmental processes. All primates share fundamental similarities in life history and reproductive biology. Thus, insights gleaned from studies of nonhuman primates have a higher degree of biological salience to human biology than do studies of rodents or agricultural animals. The common marmoset monkey is a small-bodied primate from South America that produces litters of dizygotic fetuses that share a single placental mass. This natural variation allows us to model different intrauterine conditions and associated fetoplacental phenotypes. The marmoset placenta is phenotypically plastic according to litter size. Triplet litters are characterized by low individual fetal weights and significantly more efficient placentas and attendant alterations to the microscopic architecture and endocrine function, thus modeling a nutrient restricted intrauterine environment. Consistent with this model, triplet neonates experience a higher risk of perinatal mortality and an increased likelihood of elevated adult weight. Recent evidence has shown that the intrauterine experience of females has an impact on their own pregnancy outcomes in adulthood: triplet females experience significantly greater pregnancy loss than do twin females. The marmoset monkey thus represents a potential powerful nonhuman primate model of multiple pregnancies, restrictive prenatal experiences, and differential reproductive outcomes in adulthood, which may have important implications for studying the impact of in vitro fertilization on adult reproductive health. It is still too early to determine exactly what developmental pathways lead to this disparity or what specific role the placenta plays; future work on this front will be critical to establish the marmoset as an important model of fetal programming of reproductive function in adulthood and across generations.