Browsing by Subject "Sex differences"
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Item Open Access Do sex differences affect behavioral thermoregulatory strategies in lemur species?(2013) Hukins, Mariah S.Thermoregulation is the ability for an animal to maintain its internal body temperature. Due to the high costs of regulating temperature physiologically, behavioral thermoregulation is more energy efficient. While previous studies have characterized thermoregulatory behaviors in mammals, few have examined how sex differences influence thermoregulatory behaviors. Sex differences in energy costs can be attributed to the contrast in male and female parental investment. Females endure more energetic costs while pregnant as well as costs of lactation. Males on the other hand acquire smaller energetic costs for sperm production and male-male competition during the breeding season. Lemurs make for interesting models to test for sex differences in behavioral thermoregulation as they have relatively low metabolic rates and clear sex differences in parental investment. Here we test the hypothesis that females will exhibit greater use of thermoregulatory behaviors than males using 21 individuals from 3 species of lemurs (Lemur catta, Eulemur flavifrons, Eulemur mongoz) housed at the Duke Lemur Center. Data collection involved scan samples recording behavior, sun or shade exposure, substrate, individual identification, ambient temperature, wind and humidity. Data analysis indicates no clear sex difference in behavioral thermoregulation. Males and females both showed use of thermoregulatory behaviors through decreasing energy conserving behaviors as temperature increased. In some instances, females also displayed patterns opposite of what was expected. Data was further distinguished between breeders and non-breeders but no clear patterns were found. Overall, these results suggest no clear sex difference of behavioral thermoregulation.Item Open Access Sex Differences in Mitochondrial Function and Susceptibility: Mechanisms of Establishment and Evolutionary Origins(2023) King, DillonMitochondria are complex organelles best known for their role in cellular metabolism and energy production. In addition to their role in generating ATP, these organelles are central to a variety of diverse signaling pathways involved with maintaining ion balance, regulating immune responses, apoptotic pathways, and many others. Disruptions to mitochondrial health and function have been linked to numerous diseases, including diabetes, Parkinson's disease, Alzheimer's disease, and more. Many environmental chemicals cause mitochondrial dysfunction through a variety of different mechanisms.
Sex-linked differences in mitochondrial ATP production, enzyme activities, and reactive oxygen species generation have been reported in multiple tissue and cell types. Additionally, sex-variable toxicologic responses to environmental pollutants and drugs that cause mitochondrial toxicity have been observed. Recent research highlighting sex differences in mitochondrial function has provided evidence for the influence of hormones as a key driver of these sex differences. Additional biologic factors that may contribute to the establishment and maintenance of sex differences in mitochondrial function include the double dosing of many genes present on the X-chromosome and epigenetic regulation. It has also been hypothesized that uniparental inheritance of the mitochondrial genome may influence these sex differences, as this inheritance pattern has led to evolution of mtDNA in a female nuclear background, potentially resulting in enhanced mitochondrial-nuclear compatibility in females. Understanding the mechanisms responsible for the establishment and maintenance of these sex differences is critical to understanding the factors that may contribute to sex differences in mitochondrial-related disease incidence rates and outcomes.
The overarching goal of this dissertation is to understand how epigenetic regulation of the nuclear and mitochondrial genomes, as well as uniparental inheritance of mtDNA, contribute to the establishment and maintenance of sex differences in mitochondrial function and sex-variable toxicological responses. Understanding sex differences in mitochondrial function contributes to our fundamental understanding of biology. Understanding the mechanisms that contribute to sex-variable toxicological responses is crucial to ensuring that the field of toxicology is well equipped to conduct chemical safety testing in a way that ensures people of all sexes are considered.
The first aim of this dissertation addresses sex differences in a nuclear epigenetic modification, DNA methylation, at nuclear-encoded mitochondrial genes. We leveraged the Newborn Epigenetics STudy (NEST) cohort to assess sex differences in DNA methylation data specifically focused on nuclear-encoded mitochondrial genes. We also tested for sex-specific differences in DNA methylation alterations associated with exposure to in utero tobacco smoke exposure. We identified 596 differentially methylated sites corresponding to 324 different genes. We identified 17 genes with both sex differences in DNA methylation and gene expression, with a strong enrichment of electron transport chain genes, particularly genes associated with ATP synthase, or complex V of the electron transport chain. We also found that alterations in DNA methylation associated with in utero tobacco smoke exposure were highly sex-specific in these nuclear-encoded mitochondrial genes. Overall, our findings suggest that sex-specific DNA methylation may help establish sex differences in expression and function of a subset of nuclear-encoded mitochondrial proteins, and that sex-specific alterations in DNA methylation in response to exposures could contribute to sex-variable toxicological responses.
The second aim of this dissertation focused on understanding the role that one aspect of the mitochondrial epigenome, the mtDNA packaging protein Transcription Factor A Mitochondrial (TFAM), may have in mediating mtDNA damage recognition and removal. A second goal was to understand the role that TFAM, which is downstream of estrogen response elements, may also have in providing protection against mtDNA damage. We identified a role for TFAM in mtDNA damage recognition through observations that TFAM compacts DNA containing photodimers more than it compacts intact, undamaged DNA. Additionally, we observed a reduction in TFAM sequence specificity associated with DNA containing photodimers. Overall, these results indicate that TFAM is able to sense photolesions on DNA, differentially bind to them, and alter the physical structure and compaction of DNA following damage. Further, overexpression of TFAM to levels similar to those observed previously via stimulation with 17- estradiol does not result in protection of the mtDNA from UVC-induced lesions. Thus, TFAM protein levels do not represent a mechanism through which sex differences in hormone production and regulation could lead to sex differences in mtDNA damage accumulation in the context of UVC exposure.
The final aim of this work sought to address the extent to which uniparental inheritance of mtDNA could drive elevated mito-nuclear crosstalk and enhanced mitochondrial function in females, as previously hypothesized. To test the relevance of this hypothesis, we utilized the model organism, Caenorhabditis elegans, which exhibits maternal inheritance of the mitochondrial genome but lacks canonical sex hormones. We assessed sex differences in mitochondrial function in the C. elegans system via whole worm respirometry and determined whole worm ATP levels and mtDNA copy number. To probe whether sex differences might manifest only after stress, and to inform the growing use of C. elegans as a mitochondrial health and toxicologic model, we also assessed susceptibility to a classic mitochondrial toxicant, rotenone. Our results suggest few to no detectable differences in mitochondrial function in C. elegans sexes, which is inconsistent with the hypothesis that uniparental inheritance of mtDNA enhances mito-nuclear crosstalk. Additionally, this work provides useful information on the limitations of C. elegans as a toxicological model in the context of capturing sex-variable toxicological responses that exist in mammalian systems.
The research chapters of this dissertation (Chapters 2, 3, and 4) further contribute to understanding how nuclear epigenetics, mitochondrial epigenetics, and inheritance patterns of mtDNA influence sex differences in mitochondrial function and the extent to which these differences impact certain chemical exposures. Collectively, it will be critical to continue to investigate the biologic factors that help to establish these sex differences and identify the extent to which they may influence health span and disease outcomes, as well as investigate the strengths and limitations of toxicological model systems for their ability to reliably detect sex-specific toxicological outcomes.
Item Open Access Sex Differences in the Modifiable Risk Factors for Atrial Fibrillation at Moi Teaching and Referral Hospital(2017) Ng'ang'a, Loise MwihakiBackground: Evidence mainly from high-income countries has demonstrated sex related differences in the incidence, presentation and management of patients with non-valvular AF. Such evidence is scarce in sub-Saharan Africa, yet there is a rising prevalence of AF. This study aimed to determine sex differences in the distribution and treatment pattern for modifiable risk factors in Western Kenya.
Methods: The study included two phases. Phase 1 comprised of secondary data analysis from a case control study – Study of Genetics of Atrial Fibrillation in an African population. Phase 2 included retrospective analysis of medical records at the cardiac clinic in a large referral hospital in Kenya. We determined the distribution and treatment pattern for modifiable risk factors for AF using chi-square and fisher’s exact test.
Results: Hypertension is the most prevalent modifiable risk factor for AF in western Kenya. The prevalence among men and women was 65% and 76% respectively, but this difference was not significant. Three percent of men were obese compared to 24 % of women (p =0.013). Men were more likely to drink alcohol (p = 0.001) and have a history of smoking compared to women (p = <0.001). Among men, tetra choric correlation showed a very strong association between smoking and alcohol intake (correlation coefficient > 0.9), and hypertension and obesity/overweight (correlation coefficient >0.9). These correlations were weaker among women with a correlation coefficient of 0.40 and 0.38 respectively. Among the participants, only 21% had weight and height measurements recorded. Nutritional counselling was recorded for only 3% of those who had a BMI > 29.9. Similarly, less than 10% of those with a history of smoking or alcohol intake received counselling on cessation strategies.
Conclusion: Hypertension is the most common modifiable risk factor for AF in western Kenya. There are significant differences among men and women in the distribution of dyslipidemia, alcohol intake, smoking and obesity. These modifiable risk factors have strikingly low rates of interventions. Management of patients with AF should include both screening and interventions for modifiable risk factors. Packaging of intervention should consider sex-specific differences.
Item Open Access Sex-specific Computational Models of Blood Pressure Regulation(2020) Leete, JessicaHypertension is a global health challenge: it affects one billion people worldwide and is estimated to account for >60% of all cases or types of cardiovascular disease. Due to our partial understanding of sex differences in blood pressure regulation mechanisms, fewer hypertensive women achieve blood pressure control compared to men, even though compliance and treatment rates are generally higher in women. Furthermore, concurrent use of typical antihypertensive treatments such as a diuretic, a renin-angiotensin system (RAS) inhibitor, and a non-steroidal anti-inflammatory drug (NSAID) significantly increases the risk of acute kidney injury (AKI). This phenomenon is known as “triple whammy” AKI. Diuretics and RAS inhibitors are often prescribed in tandem for the treatment of hypertension, whereas some NSAIDs, such as ibuprofen, are available over the counter. As such, concurrent treatment with all three drugs is common.
Thus, the objective of this study is to identify which factors contribute to the sexual dimorphism in response to anti-hypertensive therapies targeting the RAS. We also aim to better understand the mechanisms underlying the development of triple whammy AKI and to identify physiological factors that may increase an individual’s susceptibility.
To accomplish these goals, we develop sex-specifc models of blood pressure regulation in humans. Model components include variables describing the heart and circulation, kidney function, sodium and water reabsorption in the nephron, and the RAS. Sex differences in the RAS, baseline aldosterone level, and the reactivity of renal sympathetic nervous activity (RSNA) are represented.
Model results suggest that the main source of sexual dimorphism in treatment efficacy is how the effects of the bound RAS receptors differ between males and females -- specifically the feedback mechanisms of the angiotensin II type 1 receptor on renin secretion and the effects of the angiotensin II type two receptor on renal resistance. In regards to triple whammy AKI, model simulations suggest that individual variations in water intake or the myogenic response as well as high dosages of these drugs may predispose patients with hypertension to develop triple whammy AKI.
These proposed models hold great potential for extensions to study other components of blood pressure regulation, such as the interconnectedness of K+ regulation and Na+ regulation. We present a model of K+ regulation including the aldosterone and renal function feedback controls, as well as the feedforward control stimulated by dietary K+ intake. Model results suggest that the feedforward effect is necessary for increased urinary K+ excretion during digestion and that muscle-kidney cross talk can accelerate recovery following perturbations in extracellular K+ concentration.
Item Open Access Spatiotemporal dynamics of EEG microstates in four- to eight-year-old children: Age- and sex-related effects.(Developmental cognitive neuroscience, 2022-07-12) Bagdasarov, Armen; Roberts, Kenneth; Bréchet, Lucie; Brunet, Denis; Michel, Christoph M; Gaffrey, Michael SThe ultrafast spatiotemporal dynamics of large-scale neural networks can be examined using resting-state electroencephalography (EEG) microstates, representing transient periods of synchronized neural activity that evolve dynamically over time. In adults, four canonical microstates have been shown to explain most topographic variance in resting-state EEG. Their temporal structures are age-, sex- and state-dependent, and are susceptible to pathological brain states. However, no studies have assessed the spatial and temporal properties of EEG microstates exclusively during early childhood, a critical period of rapid brain development. Here we sought to investigate EEG microstates recorded with high-density EEG in a large sample of 103, 4-8-year-old children. Using data-driven k-means cluster analysis, we show that the four canonical microstates reported in adult populations already exist in early childhood. Using multiple linear regressions, we demonstrate that the temporal dynamics of two microstates are associated with age and sex. Source localization suggests that attention- and cognitive control-related networks govern the topographies of the age- and sex-dependent microstates. These novel findings provide unique insights into functional brain development in children captured with EEG microstates.Item Open Access The Role of Gonadal Hormones in Mesencephalic Dopaminergic Systems(2008-08-11) Johnson, Misha LynetteDopamine regulates movement, cognition and the rewarding effects of addictive drugs. Sex differences mediated by gonadal hormones affect each of these processes. An extensive literature suggests that estrogen augments dopaminergic function. Our laboratory found that female rats exhibit increased locomotor stimulation in response to cocaine and greater cocaine-induced dopamine overflow compared to males, sex differences that emerge in early adulthood. Currently, the underlying mechanisms for these differences are poorly understood. I hypothesized that female rats would have more dopamine neurons in midbrain regions and that ovarian hormones would exert trophic effects on dopamine neurons. Immunohistochemical and stereological techniques were used to quantitate the number of cells in the SNpc and VTA of male and female rats and mice to assess: (1) if sex differences in dopamine neuron number exist and when they emerge, (2) how gonadal hormones influence dopaminergic cell number and dopamine-mediated behaviors (3) the role of specific hormone receptors in the effects on cell number (4) the possibility that dopamine neuron number is directly linked to cocaine-stimulated behavior and electrically-stimulated dopamine release and that these responses to cocaine are mediated through gonadal hormone modulation of midbrain dopamine neuron number. I discovered sex differences in midbrain dopamine neuron number; adult female rodents have more neurons in the SNpc and VTA. We also found that gonadectomy in adulthood reduced midbrain dopamine neuron number in females and increased neuron number in males, establishing the trophic effects of estrogen in the intact midbrain and possible suppressive effects of androgens. Treatment with agonists for estrogen receptor subtypes alpha and beta and androgen receptor reversed the effects of gonadectomy on cell number in females and males, respectively. In an effort to bridge cocaine-stimulated behavior and cell number in sham ovariectomized and ovariectomized females, we discovered cocaine-stimulated behavior, dopamine release and SNpc cell density were positively correlated in intact female rats, an effect that is lost with ovariectomy. This dissertation demonstrates that estrogen is critical for the maintenance of dopaminergic cell populations that enhance behavioral responses to psychostimulants in females, thereby contributing to the observed sex differences.