Inverse association of highly chlorinated dioxin congeners in maternal breast milk with dehydroepiandrosterone levels in three-year-old Vietnamese children

This study aims to evaluate the endocrine-disrupting effect of dioxin congeners on adrenal steroid hormones in mother-child pairs. In our previous study, we found that cortisol and cortisone levels were higher in the blood and the saliva of mothers living in a dioxin hotspot area than in mothers from a non-exposed region in Vietnam. In this follow-up study, we determined the salivary steroid hormone levels in 49 and 55 three-year-old children of these mothers in the hotspot and non-exposed region, respectively. Steroid hormones were determined by liquid chromatography-tandem mass spectrometry, and dioxin in the maternal breast milk was determined by gas chromatography-mass spectrometry. Dioxin levels in the breast milk of mothers from the hotspot (median total toxic equivalents polychlorinated dibenzodioxins/polychlorinated dibenzofurans; (TEQ PCDD/Fs) of 11. pg/g lipid) were three to four times higher than those of mothers in the non-exposed region (median TEQ PCDD/Fs of 3.07. pg/g lipid). Salivary dehydroepiandrosterone (DHEA) levels in children were found to be significantly lower in the hotspot than in the non-exposed region, while cortisol and cortisone levels were not different between the two regions. Highly chlorinated dioxin congeners, such as octacholorodibenzodioxin (OCDD), 1,2,3,4,6,7,8-heptacholorodibenzodioxin (HpCDD) and 1,2,3,4 (or 6), 7,8-hexachlorodibenzodioxin Hx(CDD), showed stronger inverse associations with the children\u27s salivary DHEA than other lowly chlorinated dioxin congeners. Glucocorticoid levels in the mothers exhibited a significantly positive correlation with OCDD and HpCDD/F (polychlorinated dibenzofurans). In conclusion, highly chlorinated dioxin congeners are more strongly correlated with endocrine-disrupting effects on adrenal hormones, resulting in high cortisol levels in the mothers and low DHEA levels in their three-year-old children. © 2016 Elsevier B.V.Embargo Period 24 month

Levels of polychlorinated dibenzodioxins and polychlorinated dibenzofurans in breast milk samples from three dioxin-contaminated hotspots of Vietnam

We determined polychlorinated dibenzodioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in breast milk of 143 primiparae living around the three most dioxin-contaminated areas of Vietnam. The women sampled lived in the vicinity of former U.S. air bases at Bien Hoa (n. =. 51), Phu Cat (n. =. 23), and Da Nang (n. =. 69), which are known as dioxin hotspots. Breast milk samples from Bien Hoa City, where residents live very close to the air base, showed high levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with 18% of the samples containing >. 5. pg. TCDD/g lipid. However, Phu Cat residents lived far from the air base and their samples showed lower TCDD levels, with none containing >. 5. pg. TCDD/g lipid. In Da Nang, TCDD levels in mothers from Thanh Khe (close to the air base, n. =. 43) were significantly higher than those in mothers from Son Tra (far from the air base, n. =. 26), but not other PCDD and PCDF (PCDD/F) congeners. Although TCDD levels in Bien Hoa were the highest among these hotspots, levels of other PCDD/F congeners as well as the geometric mean concentration of total PCDD/F level in Bien Hoa (9.3. pg toxic equivalents [TEQ]/g lipid) were significantly lower than the level observed in Phu Cat (14.1. pg. TEQ/g lipid), Thanh Khe (14.3. pg. TEQ/g lipid), and Son Tra (13.9. pg. TEQ/g lipid). Our findings indicated that residents living close to former U.S. air bases were exposed to elevated levels of TCDD, but not of other PCDD/F congeners

Influence of dioxin exposure upon levels of prostate-specific antigen and steroid hormones in Vietnamese men

Most studies on the relationship between Agent Orange and prostate cancer have focused on US veterans of the Vietnam War. There have been few studies focusing on the relationship between levels of prostate-specific antigen (PSA) and dioxins or steroid hormones in Vietnamese men. In 2009–2011, we collected blood samples from 97 men who had resided in a “dioxin hotspot” and 85 men from a non-sprayed region in Vietnam. Then levels of PSA, dioxins, and steroid hormones were analyzed. Levels of most dioxins, furans, and non-ortho polychlorinated biphenyls were higher in the hotspot than those in the non-sprayed region. Levels of testosterone, dehydroepiandrosterone, and estradiol differed significantly between the hotspot and the non-sprayed region, but there were no correlations between levels of PSA and steroid hormones and dioxins in either of the two regions. Our findings suggest that PSA levels in Vietnamese men are not associated with levels of dioxin or steroid hormones in these two regions. © 2016 Springer-Verlag Berlin HeidelbergEmbargo Period 12 month

High cortisol and cortisone levels are associated with breast milk dioxin concentrations in Vietnamese women

Objective: Dioxin (polychlorinated dibenzodioxins Cpolychlorinated dibenzofurans) is one of the most toxic chemical substances known. Although it is suspected to cause endocrine disruption, very few epidemiological studies have been carried out on its effects on human steroid hormones. The aim of this study was to elucidate the association of dioxin exposure with steroid hormone levels in the saliva and serum of Vietnamese women. Study design : Two areas, namely Phu Cat (hot spot) and Kim Bang (nonexposed area), were selected for the study. The study subjects consisted of 51 and 58 women respectively. Saliva, blood, and breast milk samples were collected from the subjects in both the areas. Methods: Cortisol, cortisone, DHEA, androstenedione, estrone, and estradiol levels in serum and saliva were determined by liquid chromatography-tandem mass spectrometry; dioxin concentrations in breast milk were measured by gas chromatography-mass spectrometry. Results: Dioxin concentrations in the breast milk of women from the dioxin hot spot were three to four times higher than those in the breast milk of women from the nonexposed area. Good correlations were found between the levels of six steroid hormones in saliva and those in serum respectively. Salivary and serum cortisol and cortisone levels in women from the dioxin hot spot were significantly higher than those in women from the nonexposed area (P<0.001) and those in all the subjects were positively associated with dioxin concentrations in Vietnamese women (P<0.01). Conclusion: These results suggest that dioxin influences steroidogenesis in humans. Saliva samples can be used for hormone analysis and are therefore excellent specimens in epidemiological studies. © 2014 European Society of Endocrinology

Low birth weight of Vietnamese infants is related to their mother’s dioxin and glucocorticoid levels

We aimed to determine the relationship between dioxin congeners in maternal breast milk and maternal glucocorticoid levels with newborn birth weight after nearly 45 years of use of herbicides in the Vietnam War. The study subjects comprised 58 mother–infant pairs in a region with high dioxin levels in the soil (hotspot) and 62 pairs from a control region. Dioxin levels in maternal breast milk were measured by HRGC-HRMS. Salivary glucocorticoid levels were determined by LC-MS/MS. Dioxin congener levels in mothers from the hotspot were found to be two to fivefold higher than those in mothers from the control region. Birth weight was inversely correlated with 2,3,7,8-TeCDD and 2,3,4,7,8-PeCDF congener levels. The rate of newborns whose birth weight was less than 2500 g was threefold higher in the hotspot (12 %) than in the control region (4 %). Salivary glucocorticoid levels in mothers with low birth weight infants were significantly higher than those in the normal birth weight group. Low birth weight of Vietnamese newborns in a hotspot for dioxin levels is related to some dioxin congener levels and high glucocorticoid levels in mothers. This finding in mother–infant pairs suggests that excess maternal glucocorticoid levels are related to dioxin burden and they result in low birth weight. © 2016 Springer-Verlag Berlin HeidelbergEmbargo Period 12 month

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Histamine Derived from Probiotic Lactobacillus reuteri Suppresses TNF via Modulation of PKA and ERK Signaling

Beneficial microbes and probiotic species, such as Lactobacillus reuteri, produce biologically active compounds that can modulate host mucosal immunity. Previously, immunomodulatory factors secreted by L. reuteri ATCC PTA 6475 were unknown. A combined metabolomics and bacterial genetics strategy was utilized to identify small compound(s) produced by L. reuteri that were TNF-inhibitory. Hydrophilic interaction liquid chromatography-high performance liquid chromatography (HILIC-HPLC) separation isolated TNF-inhibitory compounds, and HILIC-HPLC fraction composition was determined by NMR and mass spectrometry analyses. Histamine was identified and quantified in TNF-inhibitory HILIC-HPLC fractions. Histamine is produced from L-histidine via histidine decarboxylase by some fermentative bacteria including lactobacilli. Targeted mutagenesis of each gene present in the histidine decarboxylase gene cluster in L. reuteri 6475 demonstrated the involvement of histidine decarboxylase pyruvoyl type A (hdcA), histidine/histamine antiporter (hdcP), and hdcB in production of the TNF-inhibitory factor. The mechanism of TNF inhibition by L. reuteri-derived histamine was investigated using Toll-like receptor 2 (TLR2)-activated human monocytoid cells. Bacterial histamine suppressed TNF production via activation of the H2 receptor. Histamine from L. reuteri 6475 stimulated increased levels of cAMP, which inhibited downstream MEK/ERK MAPK signaling via protein kinase A (PKA) and resulted in suppression of TNF production by transcriptional regulation. In summary, a component of the gut microbiome, L. reuteri, is able to convert a dietary component, L-histidine, into an immunoregulatory signal, histamine, which suppresses pro-inflammatory TNF production. The identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immune-mediated diseases

Association of apolipoprotein E gene polymorphisms with blood lipids and their interaction with dietary factors

Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors. METHODS: The population studied for this investigation included 660 individuals from the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ) in PRECISE and a validated semi-quantitative FFQ in the CaPS. Interaction analyses were performed by including the interaction term in the linear regression model adjusted for age, body mass index, sex and country. RESULTS: There was no association between dietary factors and blood lipids after Bonferroni correction and adjustment for confounding factors in either cohort. In the PRECISE study, after correction for multiple testing, there was a statistically significant association of the APOE haplotype (rs7412 and rs429358; E2, E3, and E4) and APOE tagSNP rs445925 with total cholesterol (P = 4 × 10- 4 and P = 0.003, respectively). Carriers of the E2 allele had lower total cholesterol concentration (5.54 ± 0.97 mmol/L) than those with the E3 (5.98 ± 1.05 mmol/L) (P = 0.001) and E4 (6.09 ± 1.06 mmol/L) (P = 2 × 10- 4) alleles. The association of APOE haplotype (E2, E3, and E4) and APOE SNP rs445925 with total cholesterol (P = 2 × 10- 6 and P = 3 × 10- 4, respectively) was further replicated in the CaPS. Additionally, significant association was found between APOE haplotype and APOE SNP rs445925 with low density lipoprotein cholesterol in CaPS (P = 4 × 10- 4 and P = 0.001, respectively). After Bonferroni correction, none of the cohorts showed a statistically significant SNP-diet interaction on lipid outcomes. CONCLUSION: In summary, our findings from the two cohorts confirm that genetic variations at the APOE locus influence plasma total cholesterol concentrations, however, the gene-diet interactions on lipids require further investigation in larger cohorts

Sequential Bottlenecks Drive Viral Evolution in Early Acute Hepatitis C Virus Infection

Hepatitis C is a pandemic human RNA virus, which commonly causes chronic infection and liver disease. The characterization of viral populations that successfully initiate infection, and also those that drive progression to chronicity is instrumental for understanding pathogenesis and vaccine design. A comprehensive and longitudinal analysis of the viral population was conducted in four subjects followed from very early acute infection to resolution of disease outcome. By means of next generation sequencing (NGS) and standard cloning/Sanger sequencing, genetic diversity and viral variants were quantified over the course of the infection at frequencies as low as 0.1%. Phylogenetic analysis of reassembled viral variants revealed acute infection was dominated by two sequential bottleneck events, irrespective of subsequent chronicity or clearance. The first bottleneck was associated with transmission, with one to two viral variants successfully establishing infection. The second occurred approximately 100 days post-infection, and was characterized by a decline in viral diversity. In the two subjects who developed chronic infection, this second bottleneck was followed by the emergence of a new viral population, which evolved from the founder variants via a selective sweep with fixation in a small number of mutated sites. The diversity at sites with non-synonymous mutation was higher in predicted cytotoxic T cell epitopes, suggesting immune-driven evolution. These results provide the first detailed analysis of early within-host evolution of HCV, indicating strong selective forces limit viral evolution in the acute phase of infection