Interplay between stress and reproduction: Novel epigenetic markers in response to shearing patterns in Australian Merino sheep (Ovis aries)

In this study, we determined the effect(s) of shearing on Australian Merino ewes (Ovis aries). To test this research question, we used a suite of field and laboratory methods including GPS collars, wool cortisol and novel epigenetic markers identified using Illumina NovaSeq RRBS. Single shorn ewes (n =24) kept on their full fleece throughout the entire gestation period while twice shorn ewes (n =24) had their wool shorn early in gestation. We have discovered one locus (Chr20:50404014) which was significantly associated with different shearing treatments (twice or single shorn ewes), (FDR = 0.005). This locus is upstream of a protein coding gene (ENSOARG00000002778.1), which shows similarities to the forkhead box C1 (FOXC1) mRNA using BLAST searches. We discovered that 36 gene loci were significantly modulated either between different shearing treatments or late vs early pregnancy ewes. Similarly, in lambs we identified 16 annotated gene loci that were significant between late vs early pregnancy. Early shorn ewes grazed 10% higher and maintained stronger body condition. Wool cortisol levels were significantly lower in the early shorn ewes during mid- and late gestation. Lambs bred from twice shorn ewes had on average better visual wool quality parameters in terms of micron, spin finesses and curvature. Collectively, this research provides a new dataset combining physiological, molecular epigenetics and digital tracking indices that advances our understanding of how Merino ewes respond to shearing frequency and this information could guide further research on sheep breeding and welfare.

Investigating differential effects of socio-emotional and mindfulness-based online interventions on mental health, resilience and social capacities during the COVID-19 pandemic: The study protocol

Background The SARS-CoV-2 pandemic has led to a mental health crisis on a global scale. Epidemiological studies have reported a drastic increase in mental health problems, such as depression and anxiety, increased loneliness and feelings of disconnectedness from others, while resilience levels have been negatively affected, indicating an urgent need for intervention. The current study is embedded within the larger CovSocial project which sought to evaluate longitudinal changes in vulnerability, resilience and social cohesion during the pandemic. The current second phase will investigate the efficacy of brief online mental training interventions in reducing mental health problems, and enhancing psychological resilience and social capacities. It further provides a unique opportunity for the prediction of intervention effects by individual biopsychosocial characteristics and preceding longitudinal change patterns during the pandemic in 2020/21. Methods We will examine the differential effects of a socio-emotional (including ‘Affect Dyad’) and a mindfulness-based (including ‘Breathing Meditation’) intervention, delivered through a web- and cellphone application. Participants will undergo 10 weeks of intervention, and will be compared to a retest control group. The effectiveness of the interventions will be evaluated in a community sample (N = 300), which is recruited from the original longitudinal CovSocial sample. The pre- to post-intervention changes, potential underlying mechanisms, and prediction thereof, will be assessed on a wide range of outcomes: levels of stress, loneliness, depression and anxiety, resilience, prosocial behavior, empathy, compassion, and the impact on neuroendocrine, immunological and epigenetic markers. The multi-method nature of the study will incorporate self-report questionnaires, behavioral tasks, ecological momentary assessment (EMA) approaches, and biological, hormonal and epigenetic markers assessed in saliva. Discussion Results will reveal the differential effectiveness of two brief online interventions in improving mental health outcomes, as well as enhancing social capacities and resilience. The present study will serve as a first step for future application of scalable, low-cost interventions at a broader level to reduce stress and loneliness, improve mental health and build resilience and social capacities in the face of global stressors. Trial registration This trial has been registered on May 17, 2020 with the ClinicalTrials.gov NCT04889508 registration number (clinicaltrials.gov/ct2/show/NCT04889508).

Epigenetic Regulation of Angiogenesis in Development and Tumors Progression: Potential Implications for Cancer Treatment

Angiogenesis is a multi-stage process of new blood vessel development from pre-existing vessels toward an angiogenic stimulus. The process is essential for tissue maintenance and homeostasis during embryonic development and adult life as well as tumor growth. Under normal conditions, angiogenesis is involved in physiological processes, such as wound healing, cyclic regeneration of the endometrium, placental development and repairing certain cardiac damage, in pathological conditions, it is frequently associated with cancer development and metastasis. The control mechanisms of angiogenesis in carcinogenesis are tightly regulated at the genetic and epigenetic level. While genetic alterations are the critical part of gene silencing in cancer cells, epigenetic dysregulation can lead to repression of tumor suppressor genes or oncogene activation, becoming an important event in early development and the late stages of tumor development, as well. The global alteration of the epigenetic spectrum, which includes DNA methylation, histone modification, chromatin remodeling, microRNAs, and other chromatin components, is considered one of the hallmarks of cancer, and the efforts are concentrated on the discovery of molecular epigenetic markers that identify cancerous precursor lesions or early stage cancer. This review aims to highlight recent findings on the genetic and epigenetic changes that can occur in physiological and pathological angiogenesis and analyze current knowledge on how deregulation of epigenetic modifiers contributes to tumorigenesis and tumor maintenance. Also, we will evaluate the clinical relevance of epigenetic markers of angiogenesis and the potential use of “epi-drugs” in modulating the responsiveness of cancer cells to anticancer therapy through chemotherapy, radiotherapy, immunotherapy and hormone therapy as anti-angiogenic strategies in cancer.

Epigenetic Markers Are Associated With Differences in Isocyanate Biomarker Levels in Exposed Spray-Painters

Isocyanates are respiratory and skin sensitizers that are one of the main causes of occupational asthma globally. Genetic and epigenetic markers are associated with isocyanate-induced asthma and, before asthma develops, we have shown that genetic polymorphisms are associated with variation in plasma and urine biomarker levels in exposed workers. Inter-individual epigenetic variance may also have a significant role in the observed biomarker variability following isocyanate exposure. Therefore, we determined the percent methylation for CpG islands from DNA extracted from mononuclear blood cells of 24 male spray-painters exposed to 1,6-hexamethylene diisocyanate (HDI) monomer and HDI isocyanurate. Spray-painters’ personal inhalation and skin exposure to these compounds and the respective biomarker levels of 1,6-diaminohexane (HDA) and trisaminohexyl isocyanurate (TAHI) in their plasma and urine were measured during three repeated industrial hygiene monitoring visits. We controlled for inhalation exposure, skin exposure, age, smoking status, and ethnicity as covariates and performed an epigenome-wide association study (EWAS) using likelihood-ratio statistical modeling. We identified 38 CpG markers associated with differences in isocyanate biomarker levels (Bonferroni < 0.05). Annotations for these markers included 18 genes: ALG1, ANKRD11, C16orf89, CHD7, COL27A, FUZ, FZD9, HMGN1, KRT6A, LEPR, MAPK10, MED25, NOSIP, PKD1, SNX19, UNC13A, UROS, and ZFHX3. We explored the functions of the genes that have been published in the literature and used GeneMANIA to investigate gene ontologies and predicted protein-interaction networks. The protein functions of the predicted networks include keratinocyte migration, cell–cell adhesions, calcium transport, neurotransmitter release, nitric oxide production, and apoptosis regulation. Many of the protein pathway functions overlap with previous findings on genetic markers associated with variability both in isocyanate biomarker levels and asthma susceptibility, which suggests there are overlapping protein pathways that contribute to both isocyanate toxicokinetics and toxicodynamics. These predicted protein networks can inform future research on the mechanism of allergic airway sensitization by isocyanates and aid in the development of mitigation strategies to better protect worker health.

Germ Cell Drivers: Transmission of Preconception Stress Across Generations

Exposure to stress can accelerate maturation and hasten reproduction. Although potentially adaptive, the trade-off is higher risk for morbidity and mortality. In humans, the intergenerational effects of stress have been demonstrated, but the precise mechanisms are unknown. Strikingly, even if parental stress occurs prior to conception, as adults, their offspring show worse mental and physical health. Emerging evidence primarily from preclinical models suggests that epigenetic programming may encode preconception stress exposures in germ cells, potentially impacting the phenotype of the offspring. In this narrative review, we evaluate the strength of the evidence for this mechanism across animals and humans in both males and females. The strongest evidence comes from studies of male mice, in which paternal preconception stress is associated with a host of phenotypic changes in the offspring and stress-induced changes in the small non-coding RNA content in sperm have been implicated. Two recent studies in men provide evidence that some small non-coding RNAs in sperm are responsive to past and current stress, including some of the same ones identified in mice. Although preliminary evidence suggests that findings from mice may map onto men, the next steps will be (1) considering whether stress type, severity, duration, and developmental timing affect germ cell epigenetic markers, (2) determining whether germ cell epigenetic markers contribute to disease risk in the offspring of stress-exposed parents, and (3) overcoming methodological challenges in order to extend this research to females.