Endocrine-Disrupting Chemicals and Breast Cancer: Disparities in Exposure and Importance of Research Inclusivity.

Endocrine-disrupting chemicals (EDCs) are known contributors to breast cancer development. Exposures to EDCs commonly occur through food packaging, cookware, fabrics, and personal care products, as well as external environmental sources. Increasing evidence highlights disparities in EDC exposure across racial/ethnic groups, yet breast cancer research continues to lack the inclusion necessary to positively impact treatment response and overall survival in socially disadvantaged populations. Additionally, the inequity in environmental exposures has yet to be remedied. Exposure to EDCs due to structural racism poses an unequivocal risk to marginalized communities. In this review, we summarize recent epidemiological and molecular studies on 2 lesser-studied EDCs, the per- and polyfluoroalkyl substances (PFAS) and the parabens, the health disparities that exist in EDC exposure between populations, and their association with breast carcinogenesis. We discuss the importance of understanding the relationship between EDC exposure and breast cancer development, particularly to promote efforts to mitigate exposures and improve breast cancer disparities in socially disadvantaged populations.

Potential Replacements for Antibiotic Growth Promoters in Poultry: Interactions at the Gut Level and Their Impact on Host Immunity.

The chicken gastrointestinal tract (GIT) has a complex, biodiverse microbial community of ~ 9 million bacterial genes plus archaea and fungi that links the host diet to its health. This microbial population contributes to host physiology through metabolite signaling while also providing local and systemic nutrients to multiple organ systems. In a homeostatic state, the host-microbial interaction is symbiotic; however, physiological issues are associated with dysregulated microbiota. Manipulating the microbiota is a therapeutic option, and the concept of adding beneficial bacteria to the intestine has led to probiotic and prebiotic development. The gut microbiome is readily changeable by diet, antibiotics, pathogenic infections, and host- and environmental-dependent events. The intestine performs key roles of nutrient absorption, tolerance of beneficial microbiota, yet responding to undesirable microbes or microbial products and preventing translocation to sterile body compartments. During homeostasis, the immune system is actively preventing or modulating the response to known or innocuous antigens. Manipulating the microbiota through nutrition, modulating host immunity, preventing pathogen colonization, or improving intestinal barrier function has led to novel methods to prevent disease, but also resulted in improved body weight, feed conversion, and carcass yield in poultry. This review highlights the importance of adding different feed additives to the diets of poultry in order to manipulate and enhance health and productivity of flocks.

Novel Models for Chronic Intestinal Inflammation in Chickens: Intestinal Inflammation Pattern and Biomarkers.

For poultry producers, chronic low-grade intestinal inflammation has a negative impact on productivity by impairing nutrient absorption and allocation of nutrients for growth. Understanding the triggers of chronic intestinal inflammation and developing a non-invasive measurement is crucial to managing gut health in poultry. In this study, we developed two novel models of low-grade chronic intestinal inflammation in broiler chickens: a chemical model using dextran sodium sulfate (DSS) and a dietary model using a high non-starch polysaccharide diet (NSP). Further, we evaluated the potential of several proteins as biomarkers of gut inflammation. For these experiments, the chemical induction of inflammation consisted of two 5-day cycles of oral gavage of either 0.25mg DSS/ml or 0.35mg DSS/ml; whereas the NSP diet (30% rice bran) was fed throughout the experiment. At four times (14, 22, 28 and 36-d post-hatch), necropsies were performed to collect intestinal samples for histology, and feces and serum for biomarkers quantification. Neither DSS nor NSP treatments affected feed intake or livability. NSP-fed birds exhibited intestinal inflammation through 14-d, which stabilized by 36-d. On the other hand, the cyclic DSS-treatment produced inflammation throughout the entire experimental period. Histological examination of the intestine revealed that the inflammation induced by both models exhibited similar spatial and temporal patterns with the duodenum and jejunum affected early (at 14-d) whereas the ileum was compromised by 28-d. Calprotectin (CALP) was the only serum protein found to be increased due to inflammation. However, fecal CALP and Lipocalin-2 (LCN-2) concentrations were significantly greater in the induced inflammation groups at 28-d. This experiment demonstrated for the first time, two in vivo models of chronic gut inflammation in chickens, a DSS and a nutritional NSP protocols. Based on these models we observed that intestinal inflammation begins in the upper segments of small intestine and moved to the lower region over time. In the searching for a fecal biomarker for intestinal inflammation, LCN-2 showed promising results. More importantly, calprotectin has a great potential as a novel biomarker for poultry measured both in serum and feces.

Role of JAK-STAT Pathway in Broiler Chicks Fed with Chestnut Tannins.

The objective of this study was to identify the phosphorylation events associated with host immunity with the inclusion of chestnut tannins (ChT) in the diet. A total of 200 male day-of-hatch Cobb 500 chicks were randomly assigned to two treatment groups, totaling 50 chicks per pen per experiment (this study was repeated two times). The treatments were as follows: (1) control feed-normal starter feed (n = 50), and (2) 1% ChT inclusion feed (n = 50). The ceca were collected on each necropsy day for analysis via (1) a peptide array to provide tissue immunometabolism information from the host, and (2) quantitative PCR for mRNA expression. Of the top three immune pathways, the data identified the T-cell receptor signaling pathway, the chemokine signaling pathway, and the JAK-STAT signaling pathway. The results showed significantly altered phosphorylation of JAK and STAT peptides within the JAK-STAT pathway. These results support the mRNA expression data with the upregulated IL-6 response, due to the significant phosphorylation of IL6ST, JAK, and STAT peptides. In regard to immune modulation, ChT appear to influence host immunity via an IL-6 mediated response which could be beneficial in host defenses against pathogens at the early stages of broiler growth and development. Therefore, it is suggested that the role of the JAK-STAT pathway is altered by including ChT in the diet.

Supplementing chestnut tannins in the broiler diet mediates a metabolic phenotype of the ceca.

As the demand for alternatives to antibiotic growth promoters (AGP) increases in food animal production, phytobiotic compounds gain popularity because of their ability to mimic the desirable bioactive properties of AGP. Chestnut tannins (ChT) are one of many phytobiotic compounds used as feed additives, particularly in South America, for broilers because of its favorable antimicrobial and growth promotion capabilities. Although studies have observed the microbiological and immunologic effects of ChT, there is a lack of studies evaluating the metabolic function of ChT. Therefore, the objective of this study was to characterize the cecal metabolic changes induced by ChT inclusion and how they relate to growth promotion. A total of 200 day-of-hatch broiler chicks were separated into 2 feed treatment groups: control and 1% ChT. The ceca from all the chicks in the treatment groups were collected on day 2, 4, 6, 8, and 10 after hatch. The cytokine mRNA quantitative RT-PCR was determined using TaqMan gene expression assays for IL-1B, IL-6, IL-8, IL-10, and interferon gamma quantification. The cytokine expression showed highly significant increased expressions of IL-6 and IL-10 on day 2 and 6, whereas the other proinflammatory cytokines did not have significantly increased expression. The results from the kinome array demonstrated that the ceca from birds fed with 1% ChT had significant (P < 0.05) metabolic alterations based on the number of peptides when compared with the control group across all day tested. The increased expression of IL-6 appeared to be strongly indicative of altered metabolism, whereas the increased expression of IL-10 indicated the regulatory effect against other proinflammatory cytokines other than IL-6. The ChT initiate a metabolic mechanism during the first 10 d in the broiler. For the first time, we show that a phytobiotic product initially modulates metabolism while also potentially supporting growth and feed efficiency downstream. In conclusion, a metabolic phenotype alteration in the ceca of chickens fed ChT may indicate the importance of enhanced broiler gut health.

A Role for the Microbiota in the Immune Phenotype Alteration Associated with the Induction of Disease Tolerance and Persistent Asymptomatic Infection of Salmonella in the Chicken.

Previous studies have shown a tissue immune phenotype-altering event occurring on days 2 and 4 in the ceca post-Salmonella challenge. To evaluate the involvement of the cecal microbiota in the phenotype reprogramming, we hypothesized that the addition of subtherapeutic bacitracin (BMD) will affect the cecal microbiota. Therefore, the objective of this study was to determine if the antibiotic-mediated changes in the microbiota composition influenced the immune phenotype induced by Salmonella enteritidis infection of the chicken cecum. A total of 112 fertile eggs were obtained for each experiment, repeated for a total of three separate times. The ceca and cecal contents were collected on days 2 and 4 post-infection for mRNA expression TaqMan assay and 16S rRNA gene microbiota sequencing. The results demonstrate the effects of bacitracin on cecal composition and its interaction with Salmonella enteritidis in young chicks. There is a preliminary indication of phenotype change in the Salmonella-challenged group provided subtherapeutic BMD due to the shifting cecal microbiota and cecal immune response, indicating the addition of bacitracin during infection altered the cecal phenotype. These data demonstrate the potential involvement of the microbiota in reprogramming immune phenotype (disease resistance to disease tolerance) induced by Salmonella in the chicken cecum.

Microbiome and pathogen interaction with the immune system.

The intestinal tract harbors a diverse community of microbes that have co-evolved with the host immune system. Although many of these microbes execute functions that are critical for host physiology, the host immune system must control the microbial community so that the dynamics of this interdependent relationship is maintained. To facilitate host homeostasis, the immune system ensures that the microbial load is tolerated, but anatomically contained, while remaining reactive to microbial invasion. Although the microbiota is required for intestinal immune development, immune responses regulate the structure and composition of the intestinal microbiota by evolving unique immune adaptations that manage this high-bacterial load. The immune mechanisms work together to ensure that commensal bacteria rarely breach the intestinal barrier and that any that do invade should be killed rapidly to prevent penetration to systemic sites. The communication between microbiota and the immune system is mediated by the interaction of bacterial components with pattern recognition receptors expressed by intestinal epithelium and various antigen-presenting cells resulting in activation of both innate and adaptive immune responses. Interaction between the microbial community and host plays a crucial role in the mucosal homeostasis and health status of the host. In addition to providing a home to numerous microbial inhabitants, the intestinal tract is an active immunological organ, with more resident immune cells than anywhere else in the body, organized in lymphoid structures called Peyer's patches and isolated lymphoid follicles such as the cecal tonsils. Macrophages, dendritic cells, various subsets of T cells, B cells and the secretory immunoglobulin A (IgA) they produce, all contribute to the generation of a proper immune response to invading pathogens while keeping the resident microbial community in check without generating an overt inflammatory response to it. IgA-producing plasma cells, intraepithelial lymphocytes, and γδT cell receptor-expressing T cells are lymphocytes that are uniquely present in the mucosa. In addition, of the γδT cells in the intestinal lamina propria, there are significant numbers of IL-17-producing T cells and regulatory T cells. The accumulation and function of these mucosal leukocytes are regulated by the presence of intestinal microbiota, which regulate these immune cells and enhance the mucosal barrier function allowing the host to mount robust immune responses against invading pathogens, and simultaneously maintains immune homeostasis.