Mirela Ambeskovic - Academia.edu (original) (raw)

Papers by Mirela Ambeskovic

Exposure to adverse environments such as prenatal stress early in life is associated with anxiety... more Exposure to adverse environments such as prenatal stress early in life is associated with anxiety-like behaviours in adulthood, which is potentially further exacerbated by aging. Recent studies have indicated that ancestral prenatal stress can propagate across generations to alter emotional wellbeing of unexposed offspring. Here we investigated if exposure to prenatal stress in the great-grandmother (transgenerational stress), or exposure across four consecutive generations (multigenerational stress) can alter anxiety-like behaviours in male and female fourth (F4) generation offspring. Anxiety-like behaviours were evaluated by means of the elevated plus maze in both males and females across three different groups: transgenerational stress (SNNN), multigenerational stress (SSSS), and non-stressed controls (NNNN). Both sexes were evaluated at the age of 12 months (middle age) and 18 months (old age). Our results demonstrate that aging and ancestral stress synergistically heightened an...

The sex of the experimenter may cause stress in animal models and be a major confounding factor i... more The sex of the experimenter may cause stress in animal models and be a major confounding factor in preclinical research. We studied the effects of the sex of the experimenter on female and male rat anxiety behaviours using thigmotaxis in the open field test, anxiety-induced changes in brain and back temperature using infra-red thermography, and alterations in plasma concentrations of stress hormones, corticosterone and oxytocin. Female rats displayed consistently exacerbated anxiety-related behaviours along with increased infrared cutaneous temperature during repeated exposure to male experimenters. Experimental stress further intensified thermal responses to a male experimenter, especially in female rats. These behavioural responses to a male experimenter in females were associated with higher circulating corticosterone and lower oxytocin levels. Similar responses were induced by a T-shirt worn by a human male. These findings suggest that emotional and physiological responses of fe...

Neuroscience & Biobehavioral Reviews, 2017

Adverse early life experiences are major influences on developmental trajectories with potentiall... more Adverse early life experiences are major influences on developmental trajectories with potentially life-long consequences. Prenatal or early postnatal exposure to stress, undernutrition or environmental toxicants may reprogram brain development and increase risk of behavioural and neurological disorders later in life. Not only experience within a single lifetime, but also ancestral experience affects health trajectories and chances of successful aging. The central mechanism in transgenerational programming of a disease may be the formation of epigenetic memory. This review explores transgenerational effects of early adverse experience on health and disease incidence in older age. First, we address mechanisms of developmental and transgenerational programming of disease and inheritance. Second, we discuss experimental and clinical findings linking early environmental determinants to adverse aging trajectories in association with possible parental contributions and sex-specific effects. Third, we outline the main mechanisms of age-related functional decline and suggest potential interventions to reverse negative effects of transgenerational programming. Thus, strategies that support healthy development and successful aging should take into account the potential influences of transgenerational inheritance.

Cellular and Molecular Life Sciences, 2016

Stress is among the primary causes of mental health disorders, which are the most common reason f... more Stress is among the primary causes of mental health disorders, which are the most common reason for disability worldwide. The ubiquity of these disorders, and the costs associated with them, lends a sense of urgency to the efforts to improve prediction and prevention. Downstream metabolic changes are highly feasible and accessible indicators of pathophysiological processes underlying mental health disorders. Here, we show that remote and cumulative ancestral stress programs central metabolic pathways linked to mental health disorders. The studies used a rat model consisting of a multigenerational stress lineage (the great-great-grandmother and each subsequent generation experienced stress during pregnancy) and a transgenerational stress lineage (only the great-greatgrandmother was stressed during pregnancy). Urine samples were collected from adult male F4 offspring and analyzed using 1 H NMR spectroscopy. The results of variable importance analysis based on random variable combination were used for unsupervised multivariate principal component analysis and hierarchical clustering analysis, as well as metabolite set enrichment analysis (MSEA) and pathway analysis. We identified distinct metabolic profiles associated with the multigenerational and transgenerational stress phenotype, with consistent upregulation of hippurate and downregulation of tyrosine, threonine, and histamine. MSEA and pathway analysis showed that these metabolites are involved in catecholamine biosynthesis, immune responses, and microbial host interactions. The identification of metabolic signatures linked to ancestral programming assists in the discovery of gene targets for future studies of epigenetic regulation in pathogenic processes. Ultimately, this research can lead to biomarker discovery for better prediction and prevention of mental health disorders.

Biogerontology, 2013

Aging is associated with an increased incidence of pathological conditions such as neurodegenerat... more Aging is associated with an increased incidence of pathological conditions such as neurodegeneration, cardiovascular and renal disease, and cancer. These conditions are believed to be linked to a disruption in cell homeodynamics, which is regulated by essential trace elements. In this study we used hair elementary analysis by inductively coupled plasma mass spectrometry (ICPMS) to examine age-related profiles of 47 elements in both rats and common marmoset monkeys. Hair was collected from young adult (6 months) and aged (18 months) Long-Evans male rats, and young adult (2 years), middleaged (4 years) and aged ([8 years) marmosets. The results revealed that aging reduces content levels of cobalt, potassium and selenium while content levels of aluminium, arsenic, boron, mercury, molybdenum, and titanium were elevated in aged rats. Similarly, aged marmosets showed reduced levels of cobalt and elevated levels of aluminium. Case studies in aged rats revealed that myocardial infarction was associated with elevated levels of sodium, potassium and cadmium and reduced zinc, while renal failure was linked to elevated content of potassium, chloride and boron and reduced contents of manganese. Carcinoma was linked to elevated arsenic and reduced selenium levels. These findings indicate that hair elementary profiles in healthy aging and age-related diseases reflect altered cell and organ metabolic functions. Cobalt and aluminium in particular may serve as biomarkers of aging in animal models. Thus, elementary deposition in hair may have predictive and diagnostic value in age-related pathological conditions, including cardiovascular and kidney disease and cancer.

Aging, 2020

The incidence of non-communicable diseases (NCDs) is rising globally but their causes are general... more The incidence of non-communicable diseases (NCDs) is rising globally but their causes are generally not understood. Here we show that cumulative ancestral stress leads to premature aging and raises NCD risk in a rat population. This longitudinal study revealed that cumulative multigenerational prenatal stress (MPS) across four generations (F0-F3) raises age-and sex-dependent adverse health outcomes in F4 offspring. MPS accelerated biological aging processes and exacerbated sex-specific incidences of respiratory and kidney diseases, inflammatory processes and tumors. Unbiased deep sequencing of frontal cortex revealed that MPS altered expression of microRNAs and their target genes involved in synaptic plasticity, stress regulation, immune function and longevity. Multi-layer top-down deep learning metabolite enrichment analysis of urine markers revealed altered metabolic homeodynamics in MPS males. Thus, peripheral metabolic signatures may provide sensitive biomarkers of stress vulnerability and disease risk. Programming by MPS appears to be a significant determinant of lifetime mental health trajectories, physical wellbeing and vulnerability to NCDs through altered epigenetic regulation.

Exposure to adverse environmental factors such as prenatal stress (PS) can have longlasting effec... more Exposure to adverse environmental factors such as prenatal stress (PS) can have longlasting effects on brain health and disease. Through direct and transgenerational genetic and epigenetic influences on healthy development and aging, PS may promote adaptive developmental plasticity, but at the same time also lead to increased health risks. Ultimately, the main goal of this research was to determine if PS-associated alterations of the fetal developmental programing can be transmitted across generations to affect brain development and behaviour, and ultimately increase the susceptibility to disease throughout lifespan. Work in Chapter 2 showed sexually dimorphic effects of multigenerational prenatal stress on behavioural traits, laterality and hemispheric dominance in male and female rats. In Chapter 3, hair elementary analysis was shown to be a sensitive, comprehensive and accurate screening tool of age-related metabolic and overall health status. Chapter 4 determined the manifestati...

In a continuously stressful environment, the effects of recurrent prenatal stress (PS) may accumu... more In a continuously stressful environment, the effects of recurrent prenatal stress (PS) may accumulate across generations and alter stress vulnerability and resilience. Here, we report in female rats that a family history of recurrent ancestral PS facilitates certain aspects of movement performance, and that these benefits are abolished by the experience of a second hit, induced by a silent ischemia during adulthood. Female F4-generation rats with and without a family history of cumulative multigenerational PS (MPS) were tested for skilled motor function before and after the induction of a minor ischemic insult by endothelin-1 infusion into the primary motor cortex. MPS resulted in improved skilled motor abilities and blunted hypothalamic-pituitary-adrenal (HPA) axis function compared to non-stressed rats. Deep sequencing revealed downregulation of miR-708 in MPS rats along with upregulation of its predicted target genes Mapk10 and Rasd2. Through miR-708 stress may regulate mitogen-activated protein kinase (MAPK) pathway activity. Hair trace elemental analysis revealed an increased Na/K ratio, which suggests a chronic shift in adrenal gland function. The ischemic lesion activated the HPA axis in MPS rats only; the lesion, however, abolished the advantage of MPS in skilled reaching. The findings indicate that MPS generates adaptive flexibility in movement, which is challenged by a second stressor, such as a neuropathological condition. Thus, a second "hit" by a stressor may limit behavioral flexibility and neural plasticity associated with ancestral stress.

BMC Public Health

Background Tobacco use, alcohol use, and sugar-sweetened beverage consumption are each associated... more Background Tobacco use, alcohol use, and sugar-sweetened beverage consumption are each associated with increased cancer-risk. Psychological trauma is a common experience and a key driver of these behaviours among adults. The primary aim of this study is to evaluate the effect of trauma-informed yoga, drumming, and psychoeducation compared to control on tobacco use, alcohol use, and sugar-sweetened beverage consumption among community-based adults. Secondary aims are to evaluate the effect of these interventions compared to control on psychological and physiological stress symptomology, social connection, and coping behaviour. Methods Recruitment for this single-blinded randomized trial began in April 2019 in the Faculty of Health Sciences at the University of Lethbridge. Adults who consumed tobacco, alcohol, or sugar-sweetened beverages in the past month and live in Lethbridge, Alberta are being recruited using ads placed in public spaces. Participants are randomly allocated to a 12...

Scientific Reports

experiences during early development are powerful determinants of lifetime mental health. Here we... more experiences during early development are powerful determinants of lifetime mental health. Here we investigated if ancestral stress regulates the brain's epigenetic memory to alter neuromorphology and emotionality in the remote F4 progeny. Pregnant female rat dams of the parental F0 generation were exposed to stress on gestational days 12-18. To generate a transgenerational stress lineage, their pregnant daughters (F1), granddaughters (F2) and great-granddaughters (F3) remained undisturbed. To generate a multigenerational stress lineage, pregnant dams of each generation (F1-F3) were stressed. A lineage of non-stress controls (F0-F3) was also produced. Multigenerational stress exceeded the impact of transgenerational stress by increasing anxiety-like behaviours and stress response in young and middle-aged F4 males but not females. Functional changes were accompanied by reduced spine density in the male medial prefrontal cortex with opposite effects in the orbital frontal cortex. Ancestral stress regulated cortical miR-221 and miR-26 expression and their target genes, thus downregulating ntrk2 and map1a genes in males while downregulating crh and upregulating map1a genes in females. These miRNA-dependent pathways are candidates for developmental programming of lifetime mental health. thus, multigenerational stress in particular determines sexually dimorphic predisposition to stress vulnerability and generates a phenotype resembling symptoms of posttraumatic stress disorder. The prevalence of mental health disorders worldwide has surged to 36.7% in the last decade 1. Evidence suggests that the exposure to adverse environments during early development plays a role in programming mental illness, such as attention deficit hyperactive disorder (ADHD), anxiety, depression, and vulnerability to post-traumatic stress disorder (PTSD) 2. The developmental origins of health and disease (DOHaD) theory posits that the exposure to adverse environments during the fetal period and early childhood can program the vulnerability to disease in later life 3. Accordingly, numerous studies have shown that prenatal stress, undernutrition, and perinatal inflammation may alter the stress response and behavioural phenotype leading to increased risk of psychiatric disorders later in life 2,4-6. Prenatal exposure to stress in particular alters fetal brain development which manifest in behavioural alterations associated with mental health disorders later in life. For example, human studies have reported increased incidence of anxiety and depression in children born to mothers who experienced distress, such as war, family violence, natural disaster or death of a close relative, during pregnancy 2,7,8. Similarly, animal models of prenatal stress have shown increased latency to play 9 , and anxiety-like behaviours 10 in offspring. Stress programming is likely associated with altered neuronal plasticity 11,12. Reports demonstrated alterations in spine density and dendritic branching in both medial prefrontal cortex (mPFC) and orbital frontal cortex (OFC), two frontal regions associated with emotional behaviours 5,12 with significant sexual dimorphisms 13,14. Human and animal studies support the notion of inter-generational programming by prenatal stress. Prenatal undernutrition has lifelong impact on health and disease incidence of children and grand-children 15,16 .

In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate... more In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate across generations and generate new behavioral traits in the absence of genetic variation. Here, we investigated if PS or multigenerational PS across 4 generations differentially affect behavioral traits, laterality, and hemispheric dominance in male and female rats. Using skilled reaching and skilled walking tasks, 3 findings support the formation of new behavioral traits and shifted laterality by multigenerational stress. First, while PS in the F1 generation did not alter paw preference, multigenerational stress in the F4 generation shifted paw preference to favor left-handedness only in males. Second, multigenerational stress impaired skilled reaching and skilled walking movement abilities in males, while improving these abilities in females beyond the levels of controls. Third, the shift toward left-handedness in multigenerationally stressed males was accompanied by increased dendritic complexity and greater spine density in the right parietal cortex. Thus, cumulative multigenerational stress generates sexually dimorphic left-handedness and dominance shift toward the right hemisphere in males. These findings explain the origins of apparently heritable behavioral traits and handedness in the absence of DNA sequence variations while proposing epigenetic mechanisms.

Biogerontology, 2013

Aging is associated with an increased incidence of pathological conditions such as neurodegenerat... more Aging is associated with an increased incidence of pathological conditions such as neurodegeneration, cardiovascular and renal disease, and cancer. These conditions are believed to be linked to a disruption in cell homeodynamics, which is regulated by essential trace elements. In this study we used hair elementary analysis by inductively coupled plasma mass spectrometry (ICPMS) to examine age-related profiles of 47 elements in both rats and common marmoset monkeys. Hair was collected from young adult (6 months) and aged (18 months) Long-Evans male rats, and young adult (2 years), middleaged (4 years) and aged ([8 years) marmosets. The results revealed that aging reduces content levels of cobalt, potassium and selenium while content levels of aluminium, arsenic, boron, mercury, molybdenum, and titanium were elevated in aged rats. Similarly, aged marmosets showed reduced levels of cobalt and elevated levels of aluminium. Case studies in aged rats revealed that myocardial infarction was associated with elevated levels of sodium, potassium and cadmium and reduced zinc, while renal failure was linked to elevated content of potassium, chloride and boron and reduced contents of manganese. Carcinoma was linked to elevated arsenic and reduced selenium levels. These findings indicate that hair elementary profiles in healthy aging and age-related diseases reflect altered cell and organ metabolic functions. Cobalt and aluminium in particular may serve as biomarkers of aging in animal models. Thus, elementary deposition in hair may have predictive and diagnostic value in age-related pathological conditions, including cardiovascular and kidney disease and cancer.

Exposure to adverse environments such as prenatal stress early in life is associated with anxiety... more Exposure to adverse environments such as prenatal stress early in life is associated with anxiety-like behaviours in adulthood, which is potentially further exacerbated by aging. Recent studies have indicated that ancestral prenatal stress can propagate across generations to alter emotional wellbeing of unexposed offspring. Here we investigated if exposure to prenatal stress in the great-grandmother (transgenerational stress), or exposure across four consecutive generations (multigenerational stress) can alter anxiety-like behaviours in male and female fourth (F4) generation offspring. Anxiety-like behaviours were evaluated by means of the elevated plus maze in both males and females across three different groups: transgenerational stress (SNNN), multigenerational stress (SSSS), and non-stressed controls (NNNN). Both sexes were evaluated at the age of 12 months (middle age) and 18 months (old age). Our results demonstrate that aging and ancestral stress synergistically heightened an...

The sex of the experimenter may cause stress in animal models and be a major confounding factor i... more The sex of the experimenter may cause stress in animal models and be a major confounding factor in preclinical research. We studied the effects of the sex of the experimenter on female and male rat anxiety behaviours using thigmotaxis in the open field test, anxiety-induced changes in brain and back temperature using infra-red thermography, and alterations in plasma concentrations of stress hormones, corticosterone and oxytocin. Female rats displayed consistently exacerbated anxiety-related behaviours along with increased infrared cutaneous temperature during repeated exposure to male experimenters. Experimental stress further intensified thermal responses to a male experimenter, especially in female rats. These behavioural responses to a male experimenter in females were associated with higher circulating corticosterone and lower oxytocin levels. Similar responses were induced by a T-shirt worn by a human male. These findings suggest that emotional and physiological responses of fe...

Neuroscience & Biobehavioral Reviews, 2017

Adverse early life experiences are major influences on developmental trajectories with potentiall... more Adverse early life experiences are major influences on developmental trajectories with potentially life-long consequences. Prenatal or early postnatal exposure to stress, undernutrition or environmental toxicants may reprogram brain development and increase risk of behavioural and neurological disorders later in life. Not only experience within a single lifetime, but also ancestral experience affects health trajectories and chances of successful aging. The central mechanism in transgenerational programming of a disease may be the formation of epigenetic memory. This review explores transgenerational effects of early adverse experience on health and disease incidence in older age. First, we address mechanisms of developmental and transgenerational programming of disease and inheritance. Second, we discuss experimental and clinical findings linking early environmental determinants to adverse aging trajectories in association with possible parental contributions and sex-specific effects. Third, we outline the main mechanisms of age-related functional decline and suggest potential interventions to reverse negative effects of transgenerational programming. Thus, strategies that support healthy development and successful aging should take into account the potential influences of transgenerational inheritance.

Cellular and Molecular Life Sciences, 2016

Stress is among the primary causes of mental health disorders, which are the most common reason f... more Stress is among the primary causes of mental health disorders, which are the most common reason for disability worldwide. The ubiquity of these disorders, and the costs associated with them, lends a sense of urgency to the efforts to improve prediction and prevention. Downstream metabolic changes are highly feasible and accessible indicators of pathophysiological processes underlying mental health disorders. Here, we show that remote and cumulative ancestral stress programs central metabolic pathways linked to mental health disorders. The studies used a rat model consisting of a multigenerational stress lineage (the great-great-grandmother and each subsequent generation experienced stress during pregnancy) and a transgenerational stress lineage (only the great-greatgrandmother was stressed during pregnancy). Urine samples were collected from adult male F4 offspring and analyzed using 1 H NMR spectroscopy. The results of variable importance analysis based on random variable combination were used for unsupervised multivariate principal component analysis and hierarchical clustering analysis, as well as metabolite set enrichment analysis (MSEA) and pathway analysis. We identified distinct metabolic profiles associated with the multigenerational and transgenerational stress phenotype, with consistent upregulation of hippurate and downregulation of tyrosine, threonine, and histamine. MSEA and pathway analysis showed that these metabolites are involved in catecholamine biosynthesis, immune responses, and microbial host interactions. The identification of metabolic signatures linked to ancestral programming assists in the discovery of gene targets for future studies of epigenetic regulation in pathogenic processes. Ultimately, this research can lead to biomarker discovery for better prediction and prevention of mental health disorders.

Biogerontology, 2013

Aging is associated with an increased incidence of pathological conditions such as neurodegenerat... more Aging is associated with an increased incidence of pathological conditions such as neurodegeneration, cardiovascular and renal disease, and cancer. These conditions are believed to be linked to a disruption in cell homeodynamics, which is regulated by essential trace elements. In this study we used hair elementary analysis by inductively coupled plasma mass spectrometry (ICPMS) to examine age-related profiles of 47 elements in both rats and common marmoset monkeys. Hair was collected from young adult (6 months) and aged (18 months) Long-Evans male rats, and young adult (2 years), middleaged (4 years) and aged ([8 years) marmosets. The results revealed that aging reduces content levels of cobalt, potassium and selenium while content levels of aluminium, arsenic, boron, mercury, molybdenum, and titanium were elevated in aged rats. Similarly, aged marmosets showed reduced levels of cobalt and elevated levels of aluminium. Case studies in aged rats revealed that myocardial infarction was associated with elevated levels of sodium, potassium and cadmium and reduced zinc, while renal failure was linked to elevated content of potassium, chloride and boron and reduced contents of manganese. Carcinoma was linked to elevated arsenic and reduced selenium levels. These findings indicate that hair elementary profiles in healthy aging and age-related diseases reflect altered cell and organ metabolic functions. Cobalt and aluminium in particular may serve as biomarkers of aging in animal models. Thus, elementary deposition in hair may have predictive and diagnostic value in age-related pathological conditions, including cardiovascular and kidney disease and cancer.

Aging, 2020

The incidence of non-communicable diseases (NCDs) is rising globally but their causes are general... more The incidence of non-communicable diseases (NCDs) is rising globally but their causes are generally not understood. Here we show that cumulative ancestral stress leads to premature aging and raises NCD risk in a rat population. This longitudinal study revealed that cumulative multigenerational prenatal stress (MPS) across four generations (F0-F3) raises age-and sex-dependent adverse health outcomes in F4 offspring. MPS accelerated biological aging processes and exacerbated sex-specific incidences of respiratory and kidney diseases, inflammatory processes and tumors. Unbiased deep sequencing of frontal cortex revealed that MPS altered expression of microRNAs and their target genes involved in synaptic plasticity, stress regulation, immune function and longevity. Multi-layer top-down deep learning metabolite enrichment analysis of urine markers revealed altered metabolic homeodynamics in MPS males. Thus, peripheral metabolic signatures may provide sensitive biomarkers of stress vulnerability and disease risk. Programming by MPS appears to be a significant determinant of lifetime mental health trajectories, physical wellbeing and vulnerability to NCDs through altered epigenetic regulation.

Exposure to adverse environmental factors such as prenatal stress (PS) can have longlasting effec... more Exposure to adverse environmental factors such as prenatal stress (PS) can have longlasting effects on brain health and disease. Through direct and transgenerational genetic and epigenetic influences on healthy development and aging, PS may promote adaptive developmental plasticity, but at the same time also lead to increased health risks. Ultimately, the main goal of this research was to determine if PS-associated alterations of the fetal developmental programing can be transmitted across generations to affect brain development and behaviour, and ultimately increase the susceptibility to disease throughout lifespan. Work in Chapter 2 showed sexually dimorphic effects of multigenerational prenatal stress on behavioural traits, laterality and hemispheric dominance in male and female rats. In Chapter 3, hair elementary analysis was shown to be a sensitive, comprehensive and accurate screening tool of age-related metabolic and overall health status. Chapter 4 determined the manifestati...

In a continuously stressful environment, the effects of recurrent prenatal stress (PS) may accumu... more In a continuously stressful environment, the effects of recurrent prenatal stress (PS) may accumulate across generations and alter stress vulnerability and resilience. Here, we report in female rats that a family history of recurrent ancestral PS facilitates certain aspects of movement performance, and that these benefits are abolished by the experience of a second hit, induced by a silent ischemia during adulthood. Female F4-generation rats with and without a family history of cumulative multigenerational PS (MPS) were tested for skilled motor function before and after the induction of a minor ischemic insult by endothelin-1 infusion into the primary motor cortex. MPS resulted in improved skilled motor abilities and blunted hypothalamic-pituitary-adrenal (HPA) axis function compared to non-stressed rats. Deep sequencing revealed downregulation of miR-708 in MPS rats along with upregulation of its predicted target genes Mapk10 and Rasd2. Through miR-708 stress may regulate mitogen-activated protein kinase (MAPK) pathway activity. Hair trace elemental analysis revealed an increased Na/K ratio, which suggests a chronic shift in adrenal gland function. The ischemic lesion activated the HPA axis in MPS rats only; the lesion, however, abolished the advantage of MPS in skilled reaching. The findings indicate that MPS generates adaptive flexibility in movement, which is challenged by a second stressor, such as a neuropathological condition. Thus, a second "hit" by a stressor may limit behavioral flexibility and neural plasticity associated with ancestral stress.

BMC Public Health

Background Tobacco use, alcohol use, and sugar-sweetened beverage consumption are each associated... more Background Tobacco use, alcohol use, and sugar-sweetened beverage consumption are each associated with increased cancer-risk. Psychological trauma is a common experience and a key driver of these behaviours among adults. The primary aim of this study is to evaluate the effect of trauma-informed yoga, drumming, and psychoeducation compared to control on tobacco use, alcohol use, and sugar-sweetened beverage consumption among community-based adults. Secondary aims are to evaluate the effect of these interventions compared to control on psychological and physiological stress symptomology, social connection, and coping behaviour. Methods Recruitment for this single-blinded randomized trial began in April 2019 in the Faculty of Health Sciences at the University of Lethbridge. Adults who consumed tobacco, alcohol, or sugar-sweetened beverages in the past month and live in Lethbridge, Alberta are being recruited using ads placed in public spaces. Participants are randomly allocated to a 12...

Scientific Reports

experiences during early development are powerful determinants of lifetime mental health. Here we... more experiences during early development are powerful determinants of lifetime mental health. Here we investigated if ancestral stress regulates the brain's epigenetic memory to alter neuromorphology and emotionality in the remote F4 progeny. Pregnant female rat dams of the parental F0 generation were exposed to stress on gestational days 12-18. To generate a transgenerational stress lineage, their pregnant daughters (F1), granddaughters (F2) and great-granddaughters (F3) remained undisturbed. To generate a multigenerational stress lineage, pregnant dams of each generation (F1-F3) were stressed. A lineage of non-stress controls (F0-F3) was also produced. Multigenerational stress exceeded the impact of transgenerational stress by increasing anxiety-like behaviours and stress response in young and middle-aged F4 males but not females. Functional changes were accompanied by reduced spine density in the male medial prefrontal cortex with opposite effects in the orbital frontal cortex. Ancestral stress regulated cortical miR-221 and miR-26 expression and their target genes, thus downregulating ntrk2 and map1a genes in males while downregulating crh and upregulating map1a genes in females. These miRNA-dependent pathways are candidates for developmental programming of lifetime mental health. thus, multigenerational stress in particular determines sexually dimorphic predisposition to stress vulnerability and generates a phenotype resembling symptoms of posttraumatic stress disorder. The prevalence of mental health disorders worldwide has surged to 36.7% in the last decade 1. Evidence suggests that the exposure to adverse environments during early development plays a role in programming mental illness, such as attention deficit hyperactive disorder (ADHD), anxiety, depression, and vulnerability to post-traumatic stress disorder (PTSD) 2. The developmental origins of health and disease (DOHaD) theory posits that the exposure to adverse environments during the fetal period and early childhood can program the vulnerability to disease in later life 3. Accordingly, numerous studies have shown that prenatal stress, undernutrition, and perinatal inflammation may alter the stress response and behavioural phenotype leading to increased risk of psychiatric disorders later in life 2,4-6. Prenatal exposure to stress in particular alters fetal brain development which manifest in behavioural alterations associated with mental health disorders later in life. For example, human studies have reported increased incidence of anxiety and depression in children born to mothers who experienced distress, such as war, family violence, natural disaster or death of a close relative, during pregnancy 2,7,8. Similarly, animal models of prenatal stress have shown increased latency to play 9 , and anxiety-like behaviours 10 in offspring. Stress programming is likely associated with altered neuronal plasticity 11,12. Reports demonstrated alterations in spine density and dendritic branching in both medial prefrontal cortex (mPFC) and orbital frontal cortex (OFC), two frontal regions associated with emotional behaviours 5,12 with significant sexual dimorphisms 13,14. Human and animal studies support the notion of inter-generational programming by prenatal stress. Prenatal undernutrition has lifelong impact on health and disease incidence of children and grand-children 15,16 .

In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate... more In a continuously stressful environment, the effects of recurrent prenatal stress (PS) accumulate across generations and generate new behavioral traits in the absence of genetic variation. Here, we investigated if PS or multigenerational PS across 4 generations differentially affect behavioral traits, laterality, and hemispheric dominance in male and female rats. Using skilled reaching and skilled walking tasks, 3 findings support the formation of new behavioral traits and shifted laterality by multigenerational stress. First, while PS in the F1 generation did not alter paw preference, multigenerational stress in the F4 generation shifted paw preference to favor left-handedness only in males. Second, multigenerational stress impaired skilled reaching and skilled walking movement abilities in males, while improving these abilities in females beyond the levels of controls. Third, the shift toward left-handedness in multigenerationally stressed males was accompanied by increased dendritic complexity and greater spine density in the right parietal cortex. Thus, cumulative multigenerational stress generates sexually dimorphic left-handedness and dominance shift toward the right hemisphere in males. These findings explain the origins of apparently heritable behavioral traits and handedness in the absence of DNA sequence variations while proposing epigenetic mechanisms.

Biogerontology, 2013

Aging is associated with an increased incidence of pathological conditions such as neurodegenerat... more Aging is associated with an increased incidence of pathological conditions such as neurodegeneration, cardiovascular and renal disease, and cancer. These conditions are believed to be linked to a disruption in cell homeodynamics, which is regulated by essential trace elements. In this study we used hair elementary analysis by inductively coupled plasma mass spectrometry (ICPMS) to examine age-related profiles of 47 elements in both rats and common marmoset monkeys. Hair was collected from young adult (6 months) and aged (18 months) Long-Evans male rats, and young adult (2 years), middleaged (4 years) and aged ([8 years) marmosets. The results revealed that aging reduces content levels of cobalt, potassium and selenium while content levels of aluminium, arsenic, boron, mercury, molybdenum, and titanium were elevated in aged rats. Similarly, aged marmosets showed reduced levels of cobalt and elevated levels of aluminium. Case studies in aged rats revealed that myocardial infarction was associated with elevated levels of sodium, potassium and cadmium and reduced zinc, while renal failure was linked to elevated content of potassium, chloride and boron and reduced contents of manganese. Carcinoma was linked to elevated arsenic and reduced selenium levels. These findings indicate that hair elementary profiles in healthy aging and age-related diseases reflect altered cell and organ metabolic functions. Cobalt and aluminium in particular may serve as biomarkers of aging in animal models. Thus, elementary deposition in hair may have predictive and diagnostic value in age-related pathological conditions, including cardiovascular and kidney disease and cancer.