Impacts of endocrine-disrupting chemicals on prostate function and cancer.

Because of their historical mode of action, endocrine-disrupting chemicals (EDCs) are associated with sex-steroid receptors, namely the two estrogen receptors (ERα and ERß) and the androgen receptor (AR). Broadly, EDCs can modulate sex-steroid receptor functions. They can also indirectly impact the androgen and estrogen pathways by influencing steroidogenesis, expression of AR or ERs, and their respective activity as transcription factors. Additionally, many of these chemicals have multiple cellular targets other than sex-steroid receptors, which results in a myriad of potential effects in humans. The current article reviews the association between prostate cancer and the endocrine-disrupting functions of four prominent EDC families: bisphenols, phthalates, phytoestrogens, and mycoestrogens. Results from both in vitro and in vivo models are included and discussed to better assess the molecular mechanisms by which EDCs can modify prostate biology. To overcome the heterogeneity of results published, we established common guidelines to properly study EDCs in the context of endocrine diseases. Firstly, the expression of sex-steroid receptors in the models used must be determined before testing. Then, in parallel to EDCs, pharmacological compounds acting as positive (agonists) and negative controls (antagonists) have to be employed. Finally, EDCs need to be used in a precise range of concentrations to modulate sex-steroid receptors and avoid off-target effects. By adequately integrating molecular endocrinology aspects in EDC studies and identifying their underlying molecular mechanisms, we will truly understand their impact on prostate cancer and distinguish those that favor the progression of the disease from those that slow down tumor development.

Bisphenol A, bisphenol S and their glucuronidated metabolites modulate glycolysis and functional responses of human neutrophils.

Bisphenol A (BPA) and its main substitute, bisphenol S (BPS), are synthetic organic compounds found in various consumer products, in particular food and beverage containers. Numerous reports have shown a link between bisphenol exposure, human contamination and increased health problems. BPA, BPS and their metabolites are detectable in bodily fluids (blood, urine) and were reported to affect immune cells and their responses. Though, the impact of those chemicals on neutrophils, the most abundant leukocytes in the circulation, remains poorly described. Therefore, we examined the effects of BPA, BPS and their monoglucuronide conjugates on neutrophil energy metabolism and anti-microbial functions, mainly phagocytosis, superoxide anion generation and CXCL8/IL-8 chemokine production. We observed that short and prolonged exposures of neutrophils to these chemicals modulate the basal and the bacterium-derived peptide N-formyl-methionyl-leucyl-phenylalanine-induced glycolysis, with BPS causing the most alterations. The variation in energy metabolism was not associated with dysfunctions in cell cytotoxicity, phagocytosis, nor superoxide anion production upon exposure to bisphenols. In contrast, bisphenols significantly reduced the production of CXCL8/IL-8 by neutrophils, an effect found to be greater with the glucuronidated metabolites. Our study highlights that BPA, BPS and their glucuronidated metabolites alter the energy metabolism and certain anti-microbial responses of neutrophils, with possible health implications. Importantly, we found that BPS and the glucuronidated metabolites of BPA and BPS showed higher endocrine-disrupting potential than BPA. More studies on bisphenols, especially the less-documented BPS and bisphenol metabolites, are needed to fully determine their risks, allow better regulation of these compounds, and restrict their extensive usage.

Eomes-dependent mitochondrial regulation promotes survival of pathogenic CD4+ T cells during inflammation.

The mechanisms whereby Eomes controls tissue accumulation of T cells and strengthens inflammation remain ill-defined. Here, we show that Eomes deletion in antigen-specific CD4+ T cells is sufficient to protect against central nervous system (CNS) inflammation. While Eomes is dispensable for the initial priming of CD4+ T cells, it is required for long-term maintenance of CNS-infiltrating CD4+ T cells. We reveal that the impact of Eomes on effector CD4+ T cell longevity is associated with sustained expression of multiple genes involved in mitochondrial organization and functions. Accordingly, epigenetic studies demonstrate that Eomes supports mitochondrial function by direct binding to either metabolism-associated genes or mitochondrial transcriptional modulators. Besides, the significance of these findings was confirmed in CD4+ T cells from healthy donors and multiple sclerosis patients. Together, our data reveal a new mechanism by which Eomes promotes severity and chronicity of inflammation via the enhancement of CD4+ T cell mitochondrial functions and resistance to stress-induced cell death.

The impact and toxicity of glyphosate and glyphosate-based herbicides on health and immunity.

Glyphosate, or N-phosphomethyl(glycine), is an organophosphorus compound and a competitive inhibitor of the shikimate pathway that allows aromatic amino acid biosynthesis in plants and microorganisms. Its utilization in broad-spectrum herbicides, such as RoundUp®, has continued to increase since 1974; glyphosate, as well as its primary metabolite aminomethylphosphonic acid, is measured in soils, water, plants, animals and food. In humans, glyphosate is detected in blood and urine, especially in exposed workers, and is excreted within a few days. It has long been regarded as harmless in animals, but growing literature has reported health risks associated with glyphosate and glyphosate-based herbicides. In 2017, the International Agency for Research on Cancer (IARC) classified glyphosate as "probably carcinogenic" in humans. However, other national agencies did not tighten their glyphosate restrictions and even prolonged authorizations of its use. There are also discrepancies between countries' authorized levels, demonstrating an absence of a clear consensus on glyphosate to date. This review details the effects of glyphosate and glyphosate-based herbicides on fish and mammal health, focusing on the immune system. Increasing evidence shows that glyphosate and glyphosate-based herbicides exhibit cytotoxic and genotoxic effects, increase oxidative stress, disrupt the estrogen pathway, impair some cerebral functions, and allegedly correlate with some cancers. Glyphosate effects on the immune system appear to alter the complement cascade, phagocytic function, and lymphocyte responses, and increase the production of pro-inflammatory cytokines in fish. In mammals, including humans, glyphosate mainly has cytotoxic and genotoxic effects, causes inflammation, and affects lymphocyte functions and the interactions between microorganisms and the immune system. Importantly, even as many outcomes are still being debated, evidence points to a need for more studies to better decipher the risks from glyphosate and better regulation of its global utilization.

MicroRNAs: Fine Tuners of Monocyte Heterogeneity.

Small non-coding microRNAs (miRNAs) have been found to play critical roles in many biological processes by controlling gene expression at the post-transcriptional level. They appear to fine-tune the immune response by targeting key regulatory molecules, and their abnormal expression is associated with immune-mediated inflammatory disorders. Monocytes actively contribute to tissue homeostasis by triggering acute inflammatory reactions as well as the resolution of inflammation and tissue regeneration, in case of injury or pathogen invasion. Their contribution to tissue homeostasis can have many aspects because they are able to differentiate into different cell types including macrophages, dendritic cells, and osteoclasts, which fulfill functions as different as bone remodeling and immune response. Monocytes consist of different subsets with subset-specific expression of miRNAs linked to distinct biological processes dedicated to specific roles. Therefore, understanding the role of miRNAs in the context of monocyte heterogeneity may provide clues as to which subset gives rise to which cell type in tissues. In addition, because monocytes are involved in the pathogenesis of chronic inflammation, associated with loss of tissue homeostasis and function, identifying subset-specific miRNAs might help in developing therapeutic strategies that target one subset while sparing the others. Here, we give an overview of the state-of-the-art research regarding miRNAs that are differentially expressed between monocyte subsets and how they influence monocyte functional heterogeneity in health and disease, with descriptions of specific miRNAs. We also revisit the existing miRNome data to propose a canonical signature for each subset.