Pubertal high fat diet: effects on mammary cancer development

INTRODUCTION: Epidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of these can promote mammary tumorigenesis. To test the effect of HFD initiated during puberty on tumorigenesis, we utilized BALB/c mice, for which HFD neither induces obesity nor metabolic syndrome, allowing dissociation of HFD effects from other conditions associated with HFD. METHODS: Pubertal BALB/c mice were fed a low fat diet (12% kcal fat) or a HFD (60% kcal fat), and subjected to carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis. RESULTS: HFD elevated mammary gland expression of inflammatory and growth factor genes at 3 and 4 weeks of diet. Receptor activator of nuclear factor kappa-B ligand (RANKL), robustly induced at 4 weeks, has direct mitogenic activity in mammary epithelial cells and, as a potent inducer of NF-κB activity, may induce inflammatory genes. Three weeks of HFD induced a transient influx of eosinophils into the mammary gland, consistent with elevated inflammatory factors. At 10 weeks, prior to the appearance of palpable tumors, there were increased numbers of abnormal mammary epithelial lesions, enhanced cellular proliferation, increased growth factors, chemokines associated with immune-suppressive regulatory T cells, increased vascularization, and elevated M2 macrophages. HFD dramatically reduced tumor latency. Early developing tumors were more proliferative and were associated with increased levels of tumor-related growth factors, including increased plasma levels of HGF in tumor-bearing animals. Early HFD tumors also had increased vascularization, and more intra-tumor and stromal M2 macrophages. CONCLUSIONS: Taken together in this non-obesogenic context, HFD promotion of inflammatory processes, as well as local and systemically increased growth factor expression, are likely responsible for the enhanced tumorigenesis. It is noteworthy that although DMBA mutagenesis is virtually random in its targeting of genes in tumorigenesis, the short latency tumors arising in animals on HFD showed a unique gene expression profile, highlighting the potent overarching influence of HFD

Differential effects of energy balance on experimentally-induced colitis

AIM: To characterize the influence of diet-induced changes in body fat on colitis severity in SMAD3-/- mice

Silica-Triggered Autoimmunity in Lupus-Prone Mice Blocked by Docosahexaenoic Acid Consumption.

Occupational exposure to respirable crystalline silica (cSiO2, quartz) is etiologically linked to systemic lupus erythematosus (lupus) and other human autoimmune diseases (ADs). In the female NZBWF1 mouse, a widely used animal model that is genetically prone to lupus, short-term repeated intranasal exposure to cSiO2 triggers premature initiation of autoimmune responses in the lungs and kidneys. In contrast to cSiO2's triggering action, consumption of the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) prevents spontaneous onset of autoimmunity in this mouse strain. The aim of this study was to test the hypothesis that consumption of DHA will prevent cSiO2-triggered autoimmunity in the female NZBWF1 mouse. Mice (6 wk old) were fed isocaloric AIN-93G diets containing 0.0, 0.4, 1.2 or 2.4% DHA. Two wk after initiating feeding, mice were intranasally instilled with 1 mg cSiO2 once per wk for 4 wk and maintained on experimental diets for an additional 12 wk. Mice were then sacrificed and the lung, blood and kidney assessed for markers of inflammation and autoimmunity. DHA was incorporated into lung, red blood cells and kidney from diet in a concentration-dependent fashion. Dietary DHA dose-dependently suppressed cSiO2-triggered perivascular leukocyte infiltration and ectopic lymphoid tissue neogenesis in the lung. DHA consumption concurrently inhibited cSiO2-driven elevation of proinflammatory cytokines, B-cell proliferation factors, IgG and anti-dsDNA Ig in both bronchoalveolar lavage fluid and plasma. DHA's prophylactic effects were further mirrored in reduced proteinuria and glomerulonephritis in cSiO2-treated mice. Taken together, these results reveal that DHA consumption suppresses cSiO2 triggering of autoimmunity in female NZBWF1 mice as manifested in the lung, blood and kidney. Our findings provide novel insight into how dietary modulation of the lipidome might be used to prevent or delay triggering of AD by cSiO2. Such knowledge opens the possibility of developing practical, low-cost preventative strategies to reduce the risk of initiating AD and subsequent flaring in cSiO2-exposed individuals. Additional research in this model is required to establish the mechanisms by which DHA suppresses cSiO2-induced autoimmunity and to ascertain unique lipidome signatures predictive of susceptibility to cSiO2-triggered AD

Streptococcus dysgalactiae : A Pathogen of Feral Populations of Silver Carp from a Fish Kill Event

In August 2018, a series of large fish kills involving only Silver Carp Hypophthalmichthys molitrix occurred on the Mississippi River in northern Louisiana. Clinical signs observed in moribund animals included erratic swimming behavior, such as spiraling and spinning at the surface. A moribund specimen was captured by dip net near the surface at Lake Providence Landing in East Carroll Parish, northern Louisiana, and was submitted for analysis. An aseptic necropsy was performed, and diagnostic procedures, including bacteriology, parasitology, histopathology, virology, and electron microscopy, revealed that a gram-positive coccus was the primary pathogen. Pure cultures of the organism were obtained from the brain, and it was the predominant colony type isolated from the spleen, kidney, and liver. Bacterial sepsis caused by the gram-positive coccus and involving multiple organ systems was diagnosed histologically. Bacterial colonization and necrotic lesions were seen in the spleen, liver, kidney, heart, eye, and brain. Numerous cocci were observed dividing intracellularly in phagocytic cells of the kidney and brain by transmission electron microscopy. The organism was identified as Streptococcus dysgalactiae ssp. dysgalactiae by conventional biochemical methods and subsequently by the API 20 Strep system. The identity of the pathogen was later confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and sequencing of the 16S ribosomal RNA gene. Multilocus sequence analysis clustered this isolate along with two other S. dysgalactiae isolates from fish in a divergent phyletic group that was separate from other S. dysgalactiae ssp. dysgalactiae isolates from terrestrial animals, implying a possible novel clade that is pathogenic for fish

Putative mechanisms for DHA-mediated suppression of cSiO₂-induced autoimmunity.

<p>The data presented here suggest that cSiO₂-triggered pulmonary inflammation and ectopic lymphoid neogenesis drive systemic autoimmunity and glomerulonephritis in the female NZBWF1 mouse. Red downward arrows indicate potential action sites for suppressive effects of DHA that can be further predicted from these data.</p

DHA dose-dependently reduces severity of lupus nephritis in cSiO2-exposed NZBWF1 mice.

<p>NZBWF1 and NZW/LacJ mice were individually graded following the modified ISN/RPS lupus nephritis classification system as described in Materials and Methods. Slide sections from kidneys were graded as follows: (0) no tubular proteinosis; (1) mild tubular proteinosis, early sclerosis, and mild crescent formation; (2) moderate tubular proteinosis, early sclerosis, and crescent formation; (3) marked tubular proteinosis with diffuse global proliferative and sclerosing glomerulonephritis. Data are ± SEM (n = 8). Symbols: * indicates significant difference from CON-fed mice instilled with VEH (p < 0.05); # indicates significant difference from CON-fed mice instilled with cSiO₂ (p < 0.05). DHA dose-dependently reduced cSiO₂-triggered lupus nephritis in NZBWF1 mice (r² = -0.414, p < 0.05).</p

cSiO₂ -induced elevations of proinflammatory cytokines MCP-1, TNF-α and IL-6 in BALF and plasma are decreased by DHA consumption in NZBWF1 mice.

<p>MCP-1 (A, D), TNF-α, (B, E) and IL-6 (C, F)) were quantitated in BALF (left panel) and plasma (right panel) by flow cytometric bead array. Data are ± SEM (n = 8). The designation n.d. indicates below the limit of detection. Bars without same letter are significantly different (p<0.05). Symbols: * indicates significant difference from CON-fed mice instilled with VEH (p < 0.05); # indicates significant difference from CON-fed mice instilled with cSiO₂ (p < 0.05). DHA dose-dependently decreased BALF concentrations of MCP-1 (r² = -0.791, p < 0.001), TNF- α (r² = -0.577 p < 0.001), and IL-6 (r² = -0.810, p < 0.001). DHA dose-dependently decreased plasma MCP-1 (r² = -0.871, p < 0.001) and TNF-α (r² = -0.527, p < 0.05).</p

DHA consumption abrogates cSiO₂-induced macrophage, lymphocyte, and polymorphonuclear leukocyte accumulation in BALF.

<p>Differential counts of macrophages (A), lymphocytes (B), and neutrophils (C) in BALF of NZBWF1 and NZW/LacJ mice. Data are ± SEM (n = 8). Symbols: * indicates significant difference from CON-fed mice instilled with VEH (p < 0.05); # indicates significant difference from CON-fed mice instilled with cSiO₂ (p < 0.05). DHA dose-dependently decreased macrophages (r² = -0.545, p < 0.05), lymphocytes (r² = -0.599, p < 0.001), and neutrophils (r² = -0.448, p < 0.05) in NZBWF1 mice.</p

cSiO₂ -induced elevation of B cell stimulating cytokines BAFF and osteopontin are decreased in BALF and plasma in NZBWF1 mice fed DHA.

<p>B cell stimulating cytokines B cell activating factor (BAFF) (A, C) and osteopontin (OPN) (B, D) were quantitated by ELISA in BALF (left panel) and plasma (right panel). Data are ± SEM (n = 8). Symbols: * indicates significant difference from CON-fed mice instilled with VEH (p < 0.05); # indicates significant difference from CON-fed mice instilled with cSiO₂ (p < 0.05). DHA dose-dependently decreased BAFF in BALF (r² = -0.507, p < 0.05) and plasma (r² = -0.539, p < 0.05). DHA dose-dependently decreased OPN in BALF (r² = -0.330, p = 0.06) and in plasma (r² = -0.493, p < 0.05).</p