Introduction Glucocorticoids (GCs) are synthesised endogenously in mammals by the hypothalamic pituitary adrenal (HPA) axis in response to stress. These hormones can elicit a number of physiological roles by binding to and activating specific receptors (glucocorticoid or mineralocorticoid receptors- GR or MR). GCs are important in tissue development and maturation and commonly used therapeutically. Mammalian animal studies have suggested that over-exposure to GCs, whether pharmacologically or through induction of maternal stress, is associated with increased cardiovascular disease risk in adult life. The underlying mechanisms underpinning this early life programming are poorly understood, however GC exposure during development may have direct and indirect effects on the structure and function of developing tissues and organs which may predispose to disease in later life. Current mammalian models of programming do not lend themselves well to studying organ development during embryogenesis. The zebrafish provides an ideal model to study this phenomenon due to the transparent nature of developing larvae and the availability of transgenic lines expressing fluorescent markers. Methods GC pathways were comprehensively characterised during zebrafish embryo development using qRT-PCR and steroid ELISAs. The physiological roles of GCs were assessed during early zebrafish development (first 120 hours post fertilisation (hpf)) assessing stress response, swim activity and global development following various genetic and pharmacological manipulations of the GC system. The impact that GC manipulation had on the cardiovascular system was also investigated. Embryos which had been exposed to GC manipulation during early development were then allowed to develop to adulthood in order to assess the long term impact. The same parameters were investigated in the adult as in the embryo. Results The key components of the GC system are present and functional in the developing embryo with de novo cortisol biosynthesis evident from 48hpf. A functioning hypothalamic pituitary inter-renal (HPI) axis is demonstrable from 72hpf. Manipulation of specific components of the GC pathway during early embryonic development influences growth-rate, head-trunk angle, chorion hatch-rate and swim behaviour. Manipulation of GCs during embryogenesis resulted in altered body weight, length and girth in adulthood, with altered stress response and swim behaviour also detected. Embryonic heart development was also affected with a reduction in ventricle cardiomyocyte number, cardiac gene abundance (vhmc) and cardiac function during embryogenesis resulting in structural abnormalities such as fewer trabeculae and increased intra-ventricular space. Embryonic GC manipulation also alters the formation and patterning of intersegmental blood vessels by 120hpf. In adulthood this manifests as a reduced angiogenic capacity. Conclusion The zebrafish embryo represents a valid and physiologically relevant model for GC research. Manipulation of GCs during early development results in altered growth, gene abundance and cardiovascular structure. These findings have significant implications for on-going research addressing GC mediated programming and suggest that the zebrafish is a highly suitable model for GC research.

Thesis advisor: Karen Rosen / Thesis advisor: Daniel Bowles / Transgender individuals in the twenty-first century face stigmatization across the globe. Discrimination contributes to the development of early life stress (ELS), and this may lead to depression, anxiety, and social and developmental problems as individuals enter adulthood. Suicide rates in transgender populations in Western countries peak above 41%, compared to 4.6% in the general population (Haas, Rodgers, & Herman, 2014). Though medical and social efforts to treat suicide in the community are being developed, existing measures have been unable to effect significant change regarding these disproportionately-high suicide rates. Some parts of the world are drawing ahead of others in this respect. As one of the most gay-friendly countries in the world (Rand, 2013), for example, Germany is making progress medically and legally, including recently having introduced a third gender option into legal documents and opened new discussions on depathologizing transgender identity in medical care. Germany has been able to build on its early history as the first country to publicly tolerate and provide healthcare to transgender individuals. This has fostered transgender activism from the postwar period to today and may contribute to lowered suicide rates among transgender Germans. This thesis aims to use Germany’s early history of transgender rights to contextualize the state of the transgender population there today. Using an analysis of existing literature, it looks at the effects of stigmatization on suicide rates in the transgender population. Positive and negative aspects of Germany’s LGBTQ+ and transgender culture are evaluated for their impact on neurological development and the perpetuation of suicidal behavior. The thesis concludes with proposals for improved social, legal, and medical practices regarding transgender health in Germany, with a particular focus on the development of cultural understanding of transgender identity. / Thesis (BA) — Boston College, 2018. / Thesis (BA) — Boston College, 2018. / Submitted to: Boston College. College of Arts and Sciences. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Psychology. / Discipline: German Studies.

The poor disproportionately bear the burden of diminished mental health. Despite the pronounced prevalence of these iniquitous disparities, researchers lack a comprehensive understanding of their origins and also the requisite knowledge to reduce or eliminate them. Past studies have largely focused on adult precursors and trajectories of change but have largely neglected the early-life origins, timing, and consequent chains of risk associated with mental health. This dissertation examines these elements and also considers the early-life origins of mental health in a novel way by integrating sociological-based frameworks with biosocial ones. More specifically, this dissertation examines the sensitive periods and chains of risk by which mental health problems develop or persist over time and provides clues as to when and how poverty exerts its noxious effect on mental health. This dissertation employs two national datasets: the Study of Early Child Care and Youth Development and the National Longitudinal Study of Adolescent Health to assess these issues. Viewed in tandem these datasets span from approximately ages 0 to 30 and provide an especially apropos opportunity to examine the early-life origins of mental health. This dissertation found five particularly important results. First poverty experienced in infancy had lasting effects on awakening cortisol – a marker of hypothalamus-pituitary-adrenal axis functioning. HPA dysregualtion, in turn, is thought to be related to a host of mental health disorders. Second poverty experienced in infancy had a pernicious effect on internalizing and externalizing behaviors in adolescence, net of poverty experienced at other points in time. Third, poverty experienced in adolescence was of particular importance compared to poverty exposure at other ages in shaping mental health in young adulthood. Fourth, poverty experienced during sensitive periods acted as a catalyst that set in motion a number of complex chains of risk that proliferated over time. Fifth there were meaningful gender differences in regards to both timing and chains of risk. Overall, these results underscore the need for both theoretical and empirical models that span from infancy to adulthood / text

Current evidence suggests that thyroid hormones (THs) may impact development of the immune system. However, studies that explore the role of THs in immune development are limited, and the mechanisms leading to alterations in immune function are poorly understood. It is important to elucidate the role of THs in immune development given that many environmental contaminants have been shown to disrupt TH homeostasis and may also have negative impacts on the immune system. As such, the main goal of this study was to determine the long-term consequences of early life stage (ELS) hypothyroidism on immune function. To achieve this goal, it was first necessary to further characterize basic immune function in the selected model species, the fathead minnow (FHM, Pimephales promelas). Preliminary studies were conducted to describe the transcriptomic response to Yersinia ruckeri and adapt assays for the assessment of respiratory burst and phagocytic cell activity. To determine the long-term effects of ELS hypothyroidism, FHMs were exposed to the model thyroid suppressant propylthiouracil (PTU) from <1 to 30 days post hatch and reared under normal conditions. Upon reaching adulthood, ex vivo immune cell function and the in vivo immune response to Y. ruckeri were assessed. Fish exposed to PTU experienced significant alterations in gene networks associated with immune cell function as well as significant decreases in phagocytic cell activity. However, immune-related alterations at the molecular and cellular levels did not manifest themselves at higher levels of organization as ELS hypothyroidism did not affect any other immune-related endpoints, including pathogen resistance. To our knowledge, this is the first study to provide evidence that ELS hypothyroidism causes long-term effects on the immune system in fish.

The gastrointestinal tract specializes in digestion and nutrient absorption via its mucosal surface. Through this large mucosal surface, interactions between the host and its environment, including food antigens and microbes, occur. Therefore, it is imperative that the gut discriminates between innocuous food components, and potential threats such as infections. On some occasions, this fine-tuned discrimination fails, leading to chronic inflammation. Celiac disease (CeD) is an autoimmune enteropathy triggered by gluten, the name given to a family of storage proteins (prolamins) that are naturally found in wheat, barley, and rye. To develop CeD, an individual must carry the susceptibility genes, the HLA-DQ2 and/or HLA-DQ8 alleles and consume gluten. However, this is not sufficient to cause disease, indicating that environmental co-factors are at play. Individuals homozygous for the HLA-DQ2 allele are at high risk to developing CeD in infancy. Currently, there is no existing transgenic animal model that addresses early life exposure to gluten, co-factors, and their effects on CeD development. Therefore, the overall goal of my thesis is to characterize a mouse model transgenic for the HLA-DQ2 allele with exposure to gluten in early life. I first studied the physiological and immunological responses to gluten at the time of solid food introduction using DR3-DQ2 transgenic mice. I determined that after sensitization to gluten before weaning, mice developed moderate enteropathy and some developed both anti-tissue transglutaminase 2 and anti-gliadin antibodies. I then evaluated the recovery of gluten immunopathology after gluten was removed for an extended period. After 6 months on gluten-free food, enteropathy and intestinal anti-gliadin and anti-TG2 antibody levels improved. These findings show pre-weaning sensitization of DR3-DQ2 transgenic mice reproduces key features of CeD, which can be used in future studies to assess environmental triggers and mechanisms that are of importance during early life. / Thesis / Master of Science in Medical Sciences (MSMS) / Celiac disease is the destruction of the upper gut lining by an immune reaction caused by gluten in people with genetic risk. Celiac patients cannot absorb nutrients well and have many complications. While it can occur at any age, its onset in children is associated with the HLA-DQ2 gene. Because not every child with the HLA-DQ2 gene will develop celiac disease, additional factors are suspected. Understanding these factors could help prevent disease, as the only treatment – a life-long gluten-free diet – is not always effective. Thus, an animal model that mimics early life disease onset would be useful. Therefore, I characterized signs of celiac disease in young mice with the HLA-DQ2 gene. I determined that gluten and a microbial toxin given in early life induces inflammation and positive celiac blood tests. This model constitutes a useful tool to test the role of environmental factors in celiac disease in early life.

Yes / Early life is associated with high vulnerability to morbidity and mortality - risks which can be reduced in infancy and early childhood through strategically high levels of parental or alloparental investment, particularly in the case of maternal breastfeeding. Recent evidence has supported links between early-life health and care patterns and long-term population health. This growing body of research regarding the broader impacts of infant-parent interactions transcends a traditional partitioning of research into discrete life stages. It also highlights implications of childhood data for our understanding of population health and behaviour. Skeletal and environmental data indicate that the 5-7th century cemeteries at Littleport and Edix Hill (Barrington A), Cambridgeshire represent populations of similar material culture but contrasting environments and health. The high prevalence of skeletal stress markers at Littleport indicates a community coping with unusual levels of biological stress, potentially a consequence of endemic malaria present in the marshy Fen environs. In contrast, Edix Hill was an inland site which exhibited lower skeletal stress marker prevalence comparable to wider British data for the early medieval period. Early life patterns relating to diet and physiological stress at Littleport (n=5) and Edix Hill (n=8) were investigated through analyses of carbon and nitrogen stable isotopes from incrementally-sampled deciduous dentine. Meaningful variation in isotopic values within and between populations was observed, and should be a focus of future interdisciplinary archaeological childhood studies. / The Society for the Study of Human Biology, the Durham University Institute of Medieval and Early Modern Studies, and by the Rosemary Cramp Fund.

no / Background: Developmental periods in early life may be particularly vulnerable to impacts of environmental exposures. Human research on this topic has generally focused on single exposure–health effect relationships. The “exposome” concept encompasses the totality of exposures from conception onward, complementing the genome. Objectives: The Human Early-Life Exposome (HELIX) project is a new collaborative research project that aims to implement novel exposure assessment and biomarker methods to characterize early-life exposure to multiple environmental factors and associate these with omics biomarkers and child health outcomes, thus characterizing the “early-life exposome.” Here we describe the general design of the project. Methods: In six existing birth cohort studies in Europe, HELIX will estimate prenatal and postnatal exposure to a broad range of chemical and physical exposures. Exposure models will be developed for the full cohorts totaling 32,000 mother–child pairs, and biomarkers will be measured in a subset of 1,200 mother–child pairs. Nested repeat-sampling panel studies (n = 150) will collect data on biomarker variability, use smartphones to assess mobility and physical activity, and perform personal exposure monitoring. Omics techniques will determine molecular profiles (metabolome, proteome, transcriptome, epigenome) associated with exposures. Statistical methods for multiple exposures will provide exposure–response estimates for fetal and child growth, obesity, neurodevelopment, and respiratory outcomes. A health impact assessment exercise will evaluate risks and benefits of combined exposures. Conclusions: HELIX is one of the first attempts to describe the early-life exposome of European populations and unravel its relation to omics markers and health in childhood. As proof of concept, it will form an important first step toward the life-course exposome.

This study examined the demography of giant kelp Macrocystis pyrifera (Linnaeus) and its interactions with understorey algae and invertebrates in southern New Zealand over two and a half years. Most of the study was done at two sites within Akaroa Harbour (Banks Peninsula) but ancillary sites at Tory Channel (Marlborough Sounds) were used for parts of the study. The kelp forests within Akaroa Harbour were generally highly productive, with a high annual turnover of giant kelp. Macrocystis plants were mostly annual and rarely reached ages greater than 12 months. Peak recruitment occurred in spring (November) during 1995-97, but lesser recruitment episodes occurred throughout the year. The maximum growth rates of Macrocystis fronds were comparable to rates reported elsewhere in southern hemisphere populations (22 mm - 24.5 mmlday), but considerably lower than those in northern hemisphere populations. The major experiment incorporated in the study tested the effects of the Macrocystis canopy and the understorey canopy of the stipitate laminarian Ecklonia radiata on macroalgae and invertebrates. The experiment was structured so that the effects of clearances at different times could be determined. One impetus for this experiment was the need to address issues relating to the commercial harvesting of giant kelp, its sustainability and its effects on other species. The effects of canopy removals on understorey algae, mostly juvenile Macrocystis, Ecklonia and Carpophyllum spp, were highly dependent on the timing of canopy removals and the combinations of canopies removed. For example, winter harvests of the Macrocystis canopy alone enhanced the survival of post-settlement Macrocystis recruits, but had little effect on Ecklonia recruitment. However, when both Macrocystis and Ecklonia canopies were removed in spring, there was heavy recruitment of Ecklonia that grew to dominate the understorey. Strong inter and intraspecific interactions from the Macrocystis surface canopy appeared to have been reduced by physical factors including water turbidity, sedimentation and the deterioration of the surface canopy during summer. These physical factors were not as limiting in Tory Channel. Fine scale extrinsic factor effects including nutrients, light and grazing on the early life history of Macrocystis were investigated in small experiments. Results suggest that recruitment may be nutrient limited even at moderately low temperatures, and that small herbivorous gastropods are an important source of mortality in the early life stages of Macrocystis. Culturing and transplantation cultivation techniques were also examined as a means of supplementing algal supplies. Macrocystis was cultured successfully through its life cycle onto culture ropes, but generally failed to produce visible sporophytes when placed in the field. Cultured plants did grow in Tory Channel, however. Juvenile plants transplanted to ropes for on-farm cultivation showed little growth during summer, but the addition of nutrients significantly enhanced growth rates of these plants during warmer months when natural nutrient levels were low. Increased growth rates at the onset of winter and with the addition of nutrients during summer confirmed that low nutrient levels during summer are growth limiting. Akaroa Harbour kelp forests exhibited considerable variation in Macrocystis canopy biomass through time. For example, the 32,000 m2 kelp forest at Wainui had a biomass of 144 t in October 1995, which then decreased to 21 t in October 1996. Canopies tended to deteriorate during summer. Thus, at Ohinepaka Bay kelp forest had a biomass of 31 t during winter 1997, which decreased to 0.06 t the following summer. The greatest reduction in biomass, however, coincided with a period of hugely increased sediment, which smothered blades in the sea-surface canopy, covered the substratum, and prevented successful recruitment of kelp for over a year. Nutrient depletion was one of several factors thought to cause the summer deterioration of the Macrocystis sea-surface canopy, which has important ramifications for the commercial harvesting of Macrocystis pyrifera in summer. Management considerations and options are discussed in relation the commercial harvesting of Macrocystis in New Zealand. The major conclusion of this study is that although Macrocystis was able to form dense surface canopies during winter its ability to dominate kelp forests was constrained by physical factors, especially sedimentation, high turbidity, nutrients, and storms. The lack of strong interactions between Macrocystis and Ecklonia are also largely a result of their different life history characteristics. Overall, there appear to be no significant negative flow-on effects resulting from kelp harvesting and it appears that Macrocystis can be harvested sustainably.

The present study sought to determine some morphological and physiological critical windows during very early development in zebrafish exposed to crude oil. I hypothesized that exposed zebrafish would present a decrease in survival rate and body mass, and an increase in routine oxygen consumption (ṀO2), and critical oxygen tension (PCrit). To test these hypotheses, zebrafish were acutely exposed (24 h) during different days of development (1 to 6 days post-fertilization, dpf) to different concentrations of high-energy water-accommodated fractions (HEWAFs). The endpoints of survival, body mass, routine oxygen consumption, and critical oxygen partial pressure were measured at 7 dpf. Survival rate decreased based on the exposure concentration but not as a function of the day of crude oil exposure. No significant effects were found in PCrit. Body mass was reduced by the different concentrations of HEWAF, with the size of the effect varying with exposure day, with the effect strongest on when exposure occurred at 2 and 3 dpf. Oxygen consumption (ṀO2) differed significantly depending upon the day of exposure in fish exposed to crude oil. Specifically, HEWAF exposure significantly increased ṀO2 in larvae exposed at 3 dpf (9.081 µmol O2/g/h, ±0.559) versus 2 dpf (6.068 µmol O2/g/h, ±0.652) and 6 dpf (6.485 µmol O2/g/h, ±0.609). Overall, the main effects on body mass and ṀO2 occurred at crude oil exposures during 3 dpf. The presence of a critical window in fish is proposed at this developmental time, which coincides with the hatching period.

To minimize the damage caused by oil spills, responders may chemically disperse floating oil into the underlying water before it contacts shorelines and wildlife. Quantifying this strategy’s net ecological and commercial benefits requires an analysis of its effects on subsurface ecosystems and biota. Unfortunately, spill-responders have little empirical data on which to base such an analysis. Herein I report the effects of dispersed oil to early life stages of Atlantic herring (Clupea harengus). Medium South American crude oil (MESA) dispersed with Corexit 9500 caused blue sac disease (BSD) in embryos, but not in free-swimming embryos. The ages of embryos were negatively correlated with their sensitivity to oil, making those that were freshly fertilized the most sensitive. However, sensitivity was also high after hatch. Free-swimming embryos displayed signs of narcosis following brief exposure to dispersed oil. Gametes were also tested; dispersed oil dramatically impaired fertilization success. Toxicity was a function of concentration and duration of exposure, as well as of the life stage exposed. When the duration of exposure was < 24 h, gametes and free-swimming embryos were the most sensitive life stages (i.e. responded to the lowest concentrations). For durations > 24 h, young embryos (< 1 day old) were most sensitive. The results are presented as toxicity models that incorporate developmental stage, oil concentration, and exposure duration. Current effects-forecasting models for oil dispersion are based on published chronic toxicity data, which do not account for the effects of exposure duration and developmental events on toxicity. Thus, the results will better-enable modelers to estimate the effects of realistic exposures to dispersed oil in various locations, including spawning shoals. / Thesis (Master, Biology) -- Queen's University, 2009-04-26 12:55:12.266