Calen P. Ryan

Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood

Significance Environments in infancy and childhood influence levels of inflammation in adulthood—an important risk factor for multiple diseases of aging—but the underlying biological mechanisms remain uncertain. Using data from a unique cohort study in the Philippines with a lifetime of information on each participant, we provide evidence that nutritional, microbial, and psychosocial exposures in infancy and childhood predict adult levels of DNA methylation—biochemical marks on the genome that affect gene expression—in genes that regulate inflammation. We also show that DNA methylation in these genes relates to levels of inflammatory biomarkers implicated in cardiovascular and other diseases. These results suggest that epigenetic mechanisms may partially explain how early environments have enduring effects on inflammation and inflammation-related diseases. Chronic inflammation contributes to a wide range of human diseases, and environments in infancy and childhood are important determinants of inflammatory phenotypes. The underlying biological mechanisms connecting early environments with the regulation of inflammation in adulthood are not known, but epigenetic processes are plausible candidates. We tested the hypothesis that patterns of DNA methylation (DNAm) in inflammatory genes in young adulthood would be predicted by early life nutritional, microbial, and psychosocial exposures previously associated with levels of inflammation. Data come from a population-based longitudinal birth cohort study in metropolitan Cebu, the Philippines, and DNAm was characterized in whole blood samples from 494 participants (age 20–22 y). Analyses focused on probes in 114 target genes involved in the regulation of inflammation, and we identified 10 sites across nine genes where the level of DNAm was significantly predicted by the following variables: household socioeconomic status in childhood, extended absence of a parent in childhood, exposure to animal feces in infancy, birth in the dry season, or duration of exclusive breastfeeding. To evaluate the biological significance of these sites, we tested for associations with a panel of inflammatory biomarkers measured in plasma obtained at the same age as DNAm assessment. Three sites predicted elevated inflammation, and one site predicted lower inflammation, consistent with the interpretation that levels of DNAm at these sites are functionally relevant. This pattern of results points toward DNAm as a potentially important biological mechanism through which developmental environments shape inflammatory phenotypes across the life course.

The role of testosterone in coordinating male life history strategies: The moderating effects of the androgen receptor CAG repeat polymorphism

&NA; Partnered fathers often have lower testosterone than single non‐parents, which is theorized to relate to elevated testosterone (T) facilitating competitive behaviors and lower T contributing to nurturing. Cultural‐ and individual‐factors moderate the expression of such psychobiological profiles. Less is known about genetic variations role in individual psychobiological responses to partnering and fathering, particularly as related to T. We examined the exon 1 CAG (polyglutamine) repeat (CAGn) within the androgen receptor (AR) gene. AR CAGn shapes Ts effects after it binds to AR by affecting AR transcriptional activity. Thus, this polymorphism is a strong candidate to influence individual‐level profiles of “androgenicity.” While males with a highly androgenic profile are expected to engage in a more competitive‐oriented life history strategy, low androgenic men are at increased risk of depression, which could lead to similar outcomes for certain familial dynamics, such as marriage stability and parenting. Here, in a large longitudinal study of Filipino men (n = 683), we found that men who had high androgenicity (elevated T and shorter CAGn) or low androgenicity (lower T and longer CAGn) showed elevated likelihood of relationship instability over the 4.5‐year study period and were also more likely be relatively uninvolved with childcare as fathers. We did not find that CAGn moderated mens T responses to the fatherhood transition. In total, our results provide evidence for invested fathering and relationship stability at intermediate levels of androgenicity and help inform our understanding of variation in male reproductive strategies and the individual hormonal and genetic differences that underlie it. HighlightsTestosterone (T) mediates trade‐offs between mating‐ and parenting‐ behaviors.Little is known about the role of genetic contributions to T‐related psychobiology.We examine the CAG (polyglutamine) repeat (CAGn) within the androgen receptor (AR).Men with high or low androgenicity were prone to relationship instability.Men with high or low androgenicity engaged in low levels of direct caregiving.

Hsp90 and Physiological Stress Are Linked to Autonomous Transposon Mobility and Heritable Genetic Change in Nematodes

Abstract Transposable elements (TEs) have been recognized as potentially powerful drivers of genomic evolutionary change, but factors affecting their mobility and regulation remain poorly understood. Chaperones such as Hsp90 buffer environmental perturbations by regulating protein conformation, but are also part of the PIWI-interacting RNA pathway, which regulates genomic instability arising from mobile TEs in the germline. Stress-induced mutagenesis from TE movement could thus arise from functional trade-offs in the dual roles of Hsp90. We examined the functional constraints of Hsp90 and its role as a regulator of TE mobility by exposing nematodes (Caenorhabditis elegans and Caenorhabditis briggsae) to environmental stress, with and without RNAi-induced silencing of Hsp90. TE excision frequency increased with environmental stress intensity at multiple loci in several strains of each species. These effects were compounded by RNAi-induced knockdown of Hsp90. Mutation frequencies at the unc-22 marker gene in the offspring of animals exposed to environmental stress and Hsp90 RNAi mirrored excision frequency in response to these treatments. Our results support a role for Hsp90 in the suppression of TE mobility, and demonstrate that that the Hsp90 regulatory pathway can be overwhelmed with moderate environmental stress. By compromising genomic stability in germline cells, environmentally induced mutations arising from TE mobility and insertion can have permanent and heritable effects on both the phenotype and the genotype of subsequent generations.

Second-to-fourth digit ratio (2D: 4D) is unrelated to measures of somatic reproductive effort among young men from Cebu, the Philippines

OBJECTIVES A low second-to-fourth (2D:4D) digit ratio, a retrospective marker of high prenatal androgens, predicts increased investment in costly sexually dimorphic traits in men in some studies, although results are mixed. Here we test the hypothesis that the association of low 2D:4D ratios with increased muscularity and decreased adiposity depends on current testosterone (T) levels, such that digit ratio will be a particularly strong predictor of outcomes among men exhibiting a mating-effort-oriented endocrinological profile (high T). We also test the association between 2D:4D and somatic traits independently of T. MATERIALS AND METHODS We related 2D:4D digit ratios, and their interaction with T, to handgrip strength, lean mass, arm muscle area, and skinfold thickness in a sample of young, childess men (20-22 y) from Cebu, Philippines (N = 623). RESULTS Digit ratio did not significantly predict mens T-dependent somatic traits. Interactions between 2D:4D and morning T, similarly, did not predict male muscularity or adiposity. Although two of the interactions were significant or marginally significant (p < .1), after adjusting for multiple testing the evidence in support of our hypothesis was weak. DISCUSSION We found no evidence that 2D:4D predicted measures of somatic reproductive effort in this sample of young men from Cebu, who as a group could be considered mostly mating-oriented. These relationships were also not contingent upon, or stronger, when considering the moderating effect of concurrent T levels. In this sample, 2D:4D was therefore either a poor proxy of prenatal androgen exposure or prenatal androgens had limited influence on adult somatic outcomes.

Androgen receptor CAG repeat polymorphism and hypothalamic-pituitary-gonadal function in Filipino young adult males.

Testosterone (T), the primary androgenic hormone in males, is stimulated through pulsatile secretion of LH and regulated through negative feedback inhibition at the hypothalamus and pituitary. The hypothalamic‐pituitary‐gonadal (HPG) axis also controls sperm production through the secretion of follicle‐stimulating hormone (FSH). Negative feedback in the HPG axis is achieved in part through the binding of T to the androgen receptor (AR), which contains a highly variable trinucleotide repeat polymorphism (AR‐CAGn). The number of repeats in the AR‐CAGn inversely correlates with transcriptional activity of the AR. Thus, we predicted longer AR‐CAGn to be associated with higher T, LH, and FSH levels.

Like mother, like daughter: heritability of female Richardson’s ground squirrel Urocitellus richardsonii cortisol stress responses

Abstract Activation of the hypothalamic–pituitary–adrenal (HPA) axis liberates glucocorticoids, which provides an acute indication of an individual’s response to stressors. The heritability of the stress response in wild mammals, however, remains poorly documented. We quantified the cortisol stress response of female Richardson’s ground squirrels (RGSs) to handling and physical restraint, testing for: (1) the effects of individual age, time of day, and sample latency; (2) repeatability within individuals; (3) narrow-sense heritability; and (4) differences among individuals owing to potential genetic and/or environmental effects. We detected a positive linear relationship between baseline plasma cortisol (BL-cortisol) concentration and stress-induced plasma cortisol (SI-cortisol) concentration that defined each individual’s cortisol stress response. BL-cortisol, SI-cortisol, and stress response did not differ according to the time the sample was taken, or by subject age. Cortisol stress response was highly repeatable within individuals, had a mother–offspring heritability of h2 = 0.40 ± 0.24 (mean ± SE), full-sibling heritability of hFS2 = 0.37 ± 0.71, and half-sibling heritability of hHS2= 0.75 ± 1.41. Stress responses of sibling groups, immediate-family groups, and squirrels within a given area did not differ, whereas those of individuals from more distantly related matrilines did. Our results highlight the natural variability in HPA axis reactivity among individuals by quantifying both BL- and SI-cortisol levels, demonstrate partial heritability of the stress response that is not attributable to environmental variation, and suggest that at least part of an individual’s stress response can be accounted for by differences in matrilineal history.

Reproduction predicts shorter telomeres and epigenetic age acceleration among young adult women

Evolutionary theory predicts that reproduction entails costs that detract from somatic maintenance, accelerating biological aging. Despite support from studies in human and non-human animals, mechanisms linking ‘costs of reproduction’ (CoR) to aging are poorly understood. Human pregnancy is characterized by major alterations in metabolic regulation, oxidative stress, and immune cell proliferation. We hypothesized that these adaptations could accelerate blood-derived cellular aging. To test this hypothesis, we examined gravidity in relation to telomere length (TL, n = 821) and DNA-methylation age (DNAmAge, n = 397) in a cohort of young (20–22 year-old) Filipino women. Age-corrected TL and accelerated DNAmAge both predict age-related morbidity and mortality, and provide markers of mitotic and non-mitotic cellular aging, respectively. Consistent with theoretical predictions, TL decreased (p = 0.031) and DNAmAge increased (p = 0.007) with gravidity, a relationship that was not contingent upon resource availability. Neither biomarker was associated with subsequent fertility (both p > 0.3), broadly consistent with a causal effect of gravidity on cellular aging. Our findings provide evidence that reproduction in women carries costs in the form of accelerated aging through two independent cellular pathways.

Is early postnatal growth velocity, a proxy of minipubertal androgen action, related to adult second‐to‐fourth digit (2D:4D) ratios in men? A test in Cebu, Philippines

The ratio of the length of the second to the fourth digit (2D:4D) of the hand is often used as an index of prenatal androgen exposure but it might also be affected by androgens during “minipuberty,” a period of temporarily high testosterone (T) production in the first few months of life. To examine this, we tested the prediction that men with lower 2D:4D ratios had greater weight growth velocities during the first months of life—a metric recently shown to correlate with concurrent T levels.