Dysregulation of Immature Sertoli Cell Functions by Exposure to Acetaminophen and Genistein in Rodent Cell Models.

Sertoli cells are essential for germ cell development and function. Their disruption by endocrine disrupting chemicals (EDCs) or drugs could jeopardize spermatogenesis, contributing to male infertility. Perinatal exposure to EDCs and acetaminophen (APAP) disrupts male reproductive functions in animals and humans. Infants can be exposed simultaneously to the dietary soy phytoestrogen genistein (GEN) and APAP used for fever or pain relief. Our goal was to determine the effects of 10-100 µM APAP and GEN, alone or mixed, on immature Sertoli cells using mouse TM4 Sertoli cell line and postnatal-day 8 rat Sertoli cells, by measuring cell viability, proliferation, prostaglandins, genes and protein expression, and functional pathways. A value of 50 µM APAP decreased the viability, while 100 µM APAP and GEN decreased the proliferation. Sertoli cell and eicosanoid pathway genes were affected by GEN and mixtures, with downregulation of Sox9, Cox1, Cox2, and genes relevant for Sertoli cell function, while genes involved in inflammation were increased. RNA-seq analysis identified p53 and TNF signaling pathways as common targets of GEN and GEN mixture in both cell types. These results suggest that APAP and GEN dysregulate immature Sertoli cell function and may aid in elucidating novel EDC and drug targets contributing to the etiology of male infertility.

Obesity III: Obesogen assays: Limitations, strengths, and new directions.

There is increasing evidence of a role for environmental contaminants in disrupting metabolic health in both humans and animals. Despite a growing need for well-understood models for evaluating adipogenic and potential obesogenic contaminants, there has been a reliance on decades-old in vitro models that have not been appropriately managed by cell line providers. There has been a quick rise in available in vitro models in the last ten years, including commercial availability of human mesenchymal stem cell and preadipocyte models; these models require more comprehensive validation but demonstrate real promise in improved translation to human metabolic health. There is also progress in developing three-dimensional and co-culture techniques that allow for the interrogation of a more physiologically relevant state. While diverse rodent models exist for evaluating putative obesogenic and/or adipogenic chemicals in a physiologically relevant context, increasing capabilities have been identified for alternative model organisms such as Drosophila, C. elegans, zebrafish, and medaka in metabolic health testing. These models have several appreciable advantages, including most notably their size, rapid development, large brood sizes, and ease of high-resolution lipid accumulation imaging throughout the organisms. They are anticipated to expand the capabilities of metabolic health research, particularly when coupled with emerging obesogen evaluation techniques as described herein.

Obesogens: How They Are Identified and Molecular Mechanisms Underlying Their Action.

Adult and childhood obesity have reached pandemic level proportions. The idea that caloric excess and insufficient levels of physical activity leads to obesity is a commonly accepted answer for unwanted weight gain. This paradigm offers an inconclusive explanation as the world continually moves towards an unhealthier and heavier existence irrespective of energy balance. Endocrine disrupting chemicals (EDCs) are chemicals that resemble natural hormones and disrupt endocrine function by interfering with the body's endogenous hormones. A subset of EDCs called obesogens have been found to cause metabolic disruptions such as increased fat storage, in vivo. Obesogens act on the metabolic system through multiple avenues and have been found to affect the homeostasis of a variety of systems such as the gut microbiome and adipose tissue functioning. Obesogenic compounds have been shown to cause metabolic disturbances later in life that can even pass into multiple future generations, post exposure. The rising rates of obesity and related metabolic disease are demanding increasing attention on chemical screening efforts and worldwide preventative strategies to keep the public and future generations safe. This review addresses the most current findings on known obesogens and their effects on the metabolic system, the mechanisms of action through which they act upon, and the screening efforts through which they were identified with. The interplay between obesogens, brown adipose tissue, and the gut microbiome are major topics that will be covered.

Epigenetic Transgenerational Inheritance of the Effects of Obesogen Exposure.

Obesity and metabolic disorders have become a worldwide pandemic affecting millions of people. Although obesity is a multifaceted disease, there is growing evidence supporting the obesogen hypothesis, which proposes that exposure to a subset of endocrine disrupting chemicals (EDCs), known as obesogens, promotes obesity. While these effects can be observed in vitro using cell models, in vivo and human epidemiological studies have strengthened this hypothesis. Evidence from animal models showed that the effects of obesogen exposure can be inherited transgenerationally through at least the F4 generation. Transgenerational effects of EDC exposure predispose future generations to undesirable phenotypic traits and diseases, including obesity and related metabolic disorders. The exact mechanisms through which phenotypic traits are passed from an exposed organism to their offspring, without altering the primary DNA sequence, remain largely unknown. Recent research has provided strong evidence suggesting that a variety of epigenetic mechanisms may underlie transgenerational inheritance. These include differential DNA methylation, histone methylation, histone retention, the expression and/or deposition of non-coding RNAs and large-scale alterations in chromatin structure and organization. This review highlights the most recent advances in the field of epigenetics with respect to the transgenerational effects of environmental obesogens. We highlight throughout the paper the strengths and weaknesses of the evidence for proposed mechanisms underlying transgenerational inheritance and why none of these is sufficient to fully explain the phenomenon. We propose that changes in higher order chromatin organization and structure may be a plausible explanation for how some disease predispositions are heritable through multiple generations, including those that were not exposed. A solid understanding of these possible mechanisms is essential to fully understanding how environmental exposures can lead to inherited susceptibility to diseases such as obesity.

Glucocorticoids rapidly activate cAMP production via Gαs to initiate non-genomic signaling that contributes to one-third of their canonical genomic effects.

Glucocorticoids are widely used for the suppression of inflammation, but evidence is growing that they can have rapid, non-genomic actions that have been unappreciated. Diverse cell signaling effects have been reported for glucocorticoids, leading us to hypothesize that glucocorticoids alone can swiftly increase the 3',5'-cyclic adenosine monophosphate (cAMP) production. We found that prednisone, fluticasone, budesonide, and progesterone each increased cAMP levels within 3 minutes without phosphodiesterase inhibitors by measuring real-time cAMP dynamics using the cAMP difference detector in situ assay in a variety of immortalized cell lines and primary human airway smooth muscle (HASM) cells. A membrane- impermeable glucocorticoid showed similarly rapid stimulation of cAMP, implying that responses are initiated at the cell surface. siRNA knockdown of Gαs virtually eliminated glucocorticoid-stimulated cAMP responses, suggesting that these drugs activate the cAMP production via a G protein-coupled receptor. Estradiol had small effects on cAMP levels but G protein estrogen receptor antagonists had little effect on responses to any of the glucocorticoids tested. The genomic and non-genomic actions of budesonide were analyzed by RNA-Seq analysis of 24 hours treated HASM, with and without knockdown of Gαs . A 140-gene budesonide signature was identified, of which 48 genes represent a non-genomic signature that requires Gαs signaling. Collectively, this non-genomic cAMP signaling modality contributes to one-third of the gene expression changes induced by glucocorticoid treatment and shifts the view of how this important class of drugs exerts its effects.

Factors enabling community health workers and volunteers to overcome socio-cultural barriers to behaviour change: meta-synthesis using the concept of social capital.

BACKGROUND: Community-based health workers and volunteers are not just low-level health workforce; their effectiveness is also due to their unique relationship with the community and is often attributed to social capital, an area not well studied or acknowledged in the literature. METHODS: A qualitative meta-synthesis was conducted using the SPIDER framework and based on critical interpretive synthesis. The protocol was registered with PROSPERO, ID = CRD42018084130. This article reports on the qualitative data extracted from the final 33 articles selected from 147 full-text articles on social capital and community-based health systems. RESULTS: Three constructs were identified that enable community health workers to bring about changes in behaviour in the community: seeing their role as a service or a calling motivated by altruistic values, accompanying community members on their journey and the aim of the journey being empowerment rather than health. Community health workers feel under-resourced to provide for expectations from the community, to fulfil their non-health needs, to meet the expectations of their employers and to be able to deliver health services. CONCLUSION: The dichotomy of needs between the community and health services can be resolved if policy makers and programme designers examine the possibility of two cadres of community-based health workforce: full-time workers and part-time volunteers, with clear scopes of practice and supervision. Community health workers would primarily be concerned with task shifting roles demanded by programmes, and volunteers can focus on the wider empowerment-based needs of communities.

Motivation of Community Health Volunteers in rural Uganda: the interconnectedness of knowledge, relationship and action.

OBJECTIVES: In some countries, full-time Community Health Workers (CHWs) have contributed to improvements in under-5 morbidity and mortality. Based on these successes, other low- and middle-income countries are in the process of reconsidering their current health care delivery systems and integrating CHWs as a means by which to fill the gaps. It may be important to make the distinction between CHWs and Community Health Volunteers (CHVs), both of which have a unique but complementary role. While remuneration in motivation of CHWs has been extensively discussed in the literature, other motivators that may prevent high attrition rates amongst volunteers have gained less attention. The objective of this study was to understand whether full-time professional CHWs can potentially work with volunteers in the community to widen their reach and scope and if so what motivators might be of key importance to the CHVs remaining active in the field. STUDY DESIGN: CHVs were selected and trained in eight villages in East Uganda as part of a mixed-method trial conducted between March 2014 and February 2015. METHODS: Eight to twelve CHVs from each village were trained by CHWs to make home-visits to pregnant women and newborn babies and to improve hygiene. This paper reports on a) demographic data about CHVs (n = 81) and; b) in-depth interviews with retained CHVs (n = 81). RESULTS: There was a 95% retention rate amongst CHVs. In-depth interviews showed that acquisition and sharing of knowledge, relationship building and seeing health-related knowledge put into action were more important motivators than the transport allowances or the hope of gaining employment. Additionally, CHVs put what they learnt into practice by building tippy taps, having dish-racks and purifying water in their homes and as such were role models in the community. CONCLUSION: CHVs can be retained and motivated by factors other than remuneration. Gaining and sharing of knowledge with community members, relationship building and community action were inter-related and ranked higher by CHVs as motivators than the hope of employment or the transport allowance.

Widening the aim of health promotion to include the most disadvantaged: vulnerable adolescents and the social determinants of health.

Growing numbers of adolescents are marginalized by social factors beyond their control, leading to poor health outcomes for their families and future generations. Although the role of the social determinants of health has been recognized for many years, there is a gap in our knowledge about the strategies needed to address these factors in health promotion. Drawing on a review of literature on health promotion for marginalized and out-of-school adolescents, this paper highlights some urgent areas of focus for researchers and policy makers addressing adolescent health. Social determinants of health affecting marginalized adolescents identified by the review were education, gender, identity, homelessness, poverty, family structure, culture, religion and perceived racism, yet there is little solid evidence as to how to best address these factors. More systematic research, evaluation and global debate about long-term solutions to chronic poverty, lack of education and social marginalization are needed to break the cycle of ill health among vulnerable adolescents.

There should be more help out here! A qualitative study of the needs of Aboriginal adolescents in rural Australia.

INTRODUCTION: Aboriginal adolescents living in or near rural towns have different social and cultural needs than Aboriginal adolescents living in large cities or remote areas. Identification of health needs by the community is an established principle of health promotion for improving community health. The objective of this study was to identify the views of rural Aboriginal adolescents regarding health promotion topics, the most important health problems they faced, their support networks and their beliefs about who should help them meet their health needs. METHODS: Ninety-nine adolescents aged between 12 and 18 years were involved in in-depth interviews or focus group discussions using a tested and trialled questionnaire. Data collection took place at three sites in rural Australia from 2006 to 2008: two Aboriginal-controlled communities and one rural town. All locations were de-identified at the request of participants because confidentiality and anonymity were concerns of the adolescents, who felt that identifying their own community would result in stereotyping. After preliminary interviews with parents, teachers, youth and health workers, snowball sampling was used to identify 'vulnerable' adolescents with low school attendance. The mean age of respondents was 13 years. There were 40 male participants and 59 female participants, representing 6 language groups. Informed consent was obtained from both participants and their guardians. Data were analysed using thematic matrices and cross-checked in subsequent interactions with participants. RESULTS: Alcohol, drugs and violence were identified as the biggest problems facing Aboriginal adolescents in rural areas and the topic they would most like to know about. The youth from a smaller Aboriginal community near a town with a population of 1500 stated that boredom was an equally important problem. Racism and bullying were noted as reasons for poor school attendance. Family members were the most important supports, and the people they felt would help solve their health problems. They strongly identified with sports and were proud to be Aboriginal although there were many adolescents who had no future plans or ambitions. Most participants wanted a 'safe and fun' place to go to in the evenings. CONCLUSIONS: The importance of engaging the community and being sensitive to social and cultural contexts in research and programming was confirmed. Policy-makers, health providers and agencies working with youth need to focus on inclusion of families in youth health promotion and drug and alcohol prevention for Aboriginal adolescents in rural areas. Mentorship and peer-support programs are more effective than health professionals and agencies in working with youth. The expertise of those traditionally working with youth could be channelled into coordinating a mentorship program. Personal wellbeing and safety is an important issue and multipurpose youth centres may provide a secure place for adolescents to learn, interact and develop a vision for their futures.