Abstract
Background
Per- and polyfluoroalkyl substances (PFAS) are highly persistent chemicals that have been detected in the serum of over 98% of the US population. Studies among highly exposed ...individuals suggest an association with perfluorooctanoic acid (PFOA) exposure and kidney cancer. It remains unclear whether PFOA or other PFAS are renal carcinogens or if they influence risk of renal cell carcinoma (RCC) at concentrations observed in the general population.
Methods
We measured prediagnostic serum concentrations of PFOA and 7 additional PFAS in 324 RCC cases and 324 individually matched controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) relating serum PFAS concentrations and RCC risk. Individual PFAS were modeled continuously (log2-transformed) and categorically, with adjustment for kidney function and additional potential confounders. All statistical tests were 2-sided.
Results
We observed a positive association with RCC risk for PFOA (doubling in serum concentration, ORcontinuous = 1.71, 95% CI = 1.23 to 2.37, P = .002) and a greater than twofold increased risk among those in the highest quartile vs the lowest (OR = 2.63, 95% CI = 1.33 to 5.20, Ptrend = .007). The association with PFOA was similar after adjustment for other PFAS (ORcontinuous = 1.68, 95% CI = 1.07 to 2.63, P = .02) and remained apparent in analyses restricted to individuals without evidence of diminished kidney function and in cases diagnosed 8 or more years after phlebotomy.
Conclusions
Our findings add substantially to the weight of evidence that PFOA is a renal carcinogen and may have important public health implications for the many individuals exposed to this ubiquitous and highly persistent chemical.
Glyphosate is the most commonly used herbicide worldwide, with both residential and agricultural uses. In 2015, the International Agency for Research on Cancer classified glyphosate as "probably ...carcinogenic to humans," noting strong mechanistic evidence and positive associations for non-Hodgkin lymphoma (NHL) in some epidemiologic studies. A previous evaluation in the Agricultural Health Study (AHS) with follow-up through 2001 found no statistically significant associations with glyphosate use and cancer at any site.
The AHS is a prospective cohort of licensed pesticide applicators from North Carolina and Iowa. Here, we updated the previous evaluation of glyphosate with cancer incidence from registry linkages through 2012 (North Carolina)/2013 (Iowa). Lifetime days and intensity-weighted lifetime days of glyphosate use were based on self-reported information from enrollment (1993-1997) and follow-up questionnaires (1999-2005). We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) using Poisson regression, controlling for potential confounders, including use of other pesticides. All statistical tests were two-sided.
Among 54 251 applicators, 44 932 (82.8%) used glyphosate, including 5779 incident cancer cases (79.3% of all cases). In unlagged analyses, glyphosate was not statistically significantly associated with cancer at any site. However, among applicators in the highest exposure quartile, there was an increased risk of acute myeloid leukemia (AML) compared with never users (RR = 2.44, 95% CI = 0.94 to 6.32, Ptrend = .11), though this association was not statistically significant. Results for AML were similar with a five-year (RRQuartile 4 = 2.32, 95% CI = 0.98 to 5.51, Ptrend = .07) and 20-year exposure lag (RRTertile 3 = 2.04, 95% CI = 1.05 to 3.97, Ptrend = .04).
In this large, prospective cohort study, no association was apparent between glyphosate and any solid tumors or lymphoid malignancies overall, including NHL and its subtypes. There was some evidence of increased risk of AML among the highest exposed group that requires confirmation.
We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the ...relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We evaluated agricultural use of specific ...insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL and MM) in a U.S.-based prospective cohort of farmers and commercial pesticide applicators. A total of 523 cases occurred among 54,306 pesticide applicators from enrollment (1993-97) through December 31, 2011 in Iowa, and December 31, 2010 in North Carolina. Information on pesticide use, other agricultural exposures and other factors was obtained from questionnaires at enrollment and at follow-up approximately five years later (1999-2005). Information from questionnaires, monitoring, and the literature were used to create lifetime-days and intensity-weighted lifetime days of pesticide use, taking into account exposure-modifying factors. Poisson and polytomous models were used to calculate relative risks (RR) and 95% confidence intervals (CI) to evaluate associations between 26 pesticides and NHL and five NHL-subtypes, while adjusting for potential confounding factors. For total NHL, statistically significant positive exposure-response trends were seen with lindane and DDT. Terbufos was associated with total NHL in ever/never comparisons only. In subtype analyses, terbufos and DDT were associated with small cell lymphoma/chronic lymphocytic leukemia/marginal cell lymphoma, lindane and diazinon with follicular lymphoma, and permethrin with MM. However, tests of homogeneity did not show significant differences in exposure-response among NHL-subtypes for any pesticide. Because 26 pesticides were evaluated for their association with NHL and its subtypes, some chance finding could have occurred. Our results showed pesticides from different chemical and functional classes were associated with an excess risk of NHL and NHL subtypes, but not all members of any single class of pesticides were associated with an elevated risk of NHL or NHL subtypes. These findings are among the first to suggest links between DDT, lindane, permethrin, diazinon and terbufos with NHL subtypes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Many pesticides are known to have thyroid-disrupting properties.•Prospective study of farmers to evaluate 44 pesticides and thyroid cancer.•Thyroid cancer associated with metalaxyl, lindane, and ...carbaryl (inverse).•First study to comprehensively evaluate occupational pesticides and thyroid cancer.
Many pesticides are known to have thyroid-disrupting properties. However, few studies have evaluated the association between specific pesticide ingredients and risk of thyroid cancer. We investigated self-reported pesticide use and incident thyroid cancer in the Agricultural Health Study (AHS), a large cohort of occupationally-exposed male pesticide applicators.
The AHS is a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. At enrollment (1993–1997) and follow-up (1999–2005), participants reported use of 50 pesticides. We characterized exposure as ever use (44 pesticides with ≥5 exposed cases) and by cumulative intensity-weighted lifetime days (22 pesticides with ≥10 exposed cases), a metric that accounts for factors that influence exposure. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression for incident thyroid (n = 85 cases) cancer among male participants using follow-up through 2014/2015.
Use of the fungicide metalaxyl (HR = 2.03, CI:1.16–3.52) and the organochlorine insecticide lindane (HR = 1.74, CI:1.06–2.84) was associated with increased risk of thyroid cancer. The herbicide chlorimuron-ethyl was inversely associated with risk when we restricted to papillary thyroid cancer, the most common subtype (HR = 0.52, CI:0.28–0.96). High use of the insecticide carbaryl (>median intensity-weighted days) was inversely associated with thyroid cancer (HR = 0.20, CI:0.08–0.53, ptrend = 0.001).
In this large cohort study, we observed increased risk of thyroid cancer associated with use of metalaxyl and lindane, and an inverse association with carbaryl. More work is needed to understand the potential role of these chemicals in thyroid carcinogenesis.
Abstract
Background
Pesticides are commonly used in agriculture, and previous studies endorsed the need to further investigate the possible association between their use and risk of lymphoid ...malignancies in agricultural workers.
Methods
We investigated the relationship of ever use of 14 selected pesticide chemical groups and 33 individual active chemical ingredients with non-Hodgkin lymphoid malignancies (NHL) overall or major subtypes, in a pooled analysis of three large agricultural worker cohorts. Pesticide use was derived from self-reported history of crops cultivated combined with crop-exposure matrices (France and Norway) or self-reported lifetime use of active ingredients (USA). Cox regression models were used to estimate cohort-specific hazard ratios (HRs) and 95% confidence intervals (CIs), which were combined using random effects meta-analysis to calculate meta-HRs.
Results
During follow-up, 2430 NHL cases were diagnosed in 316 270 farmers accruing 3 574 815 person-years under risk. Most meta-HRs suggested no association. Moderately elevated meta-HRs were seen for: NHL and ever use of terbufos (meta-HR = 1.18, 95% CI: 1.00–1.39); chronic lymphocytic leukaemia/small lymphocytic lymphoma and deltamethrin (1.48, 1.06–2.07); and diffuse large B-cell lymphoma and glyphosate (1.36, 1.00–1.85); as well as inverse associations of NHL with the broader groups of organochlorine insecticides (0.86, 0.74–0.99) and phenoxy herbicides (0.81, 0.67–0.98), but not with active ingredients within these groups, after adjusting for exposure to other pesticides.
Conclusions
Associations of pesticides with NHL appear to be subtype- and chemical-specific. Non-differential exposure misclassification was an important limitation, showing the need for refinement of exposure estimates and exposure–response analyses.
Manipulation of host ubiquitin signaling is becoming an increasingly apparent evolutionary strategy among bacterial and viral pathogens. By removing host ubiquitin signals, for example, invading ...pathogens can inactivate immune response pathways and evade detection. The ovarian tumor (OTU) family of deubiquitinases regulates diverse ubiquitin signals in humans. Viral pathogens have also extensively co‐opted the OTU fold to subvert host signaling, but the extent to which bacteria utilize the OTU fold was unknown. We have predicted and validated a set of OTU deubiquitinases encoded by several classes of pathogenic bacteria. Biochemical assays highlight the ubiquitin and polyubiquitin linkage specificities of these bacterial deubiquitinases. By determining the ubiquitin‐bound structures of two examples, we demonstrate the novel strategies that have evolved to both thread an OTU fold and recognize a ubiquitin substrate. With these new examples, we perform the first cross‐kingdom structural analysis of the OTU fold that highlights commonalities among distantly related OTU deubiquitinases.
Synopsis
OTU‐family deubiquitinases (DUBs) regulate human ubiquitin signaling and have been subverted by viruses, while their use by pathogenic bacteria remains less‐well characterized. Broader identification and characterization of bacterial OTU DUBs now allows for first cross‐kingdom comparison of this deubiquitination enzyme fold.
Bioinformatic prediction identifies eukaryote‐like OTU deubiquitinase domains across a broad set of bacterial species.
Eight predicted bacterial OTU DUBs were recombinantly expressed and biochemically validated.
Enzymology and crystal structures reveal novel ubiquitin interaction modes.
An alternate direction of sequence threading through the OTU fold exemplifies a tolerance to permutation.
Cross‐kingdom structural analysis of the OTU deubiquitinase fold allows categorizing the variable structural motifs responsible for interactions with substrate ubiquitin.
Prediction and validation of pathogenic bacterial DUBs and insights into their structures and (poly)ubiquitin linkage specificities allows for first cross‐kingdom comparison of the OTU deubiquitination enzyme fold.
•AGRICOH analyzed cancer incidence in >248,000 agricultural workers from 6 countries.•Cancer overall occurred less in agricultural workers than in the general population.•An excess was found for ...multiple myeloma, melanoma of the skin, and prostate cancer.•Direction of risk was largely consistent across cohorts with a few deviations.•A large deficit of larynx and lung cancers was observed in nearly all cohorts.
Agricultural work can expose workers to potentially hazardous agents including known and suspected carcinogens. This study aimed to evaluate cancer incidence in male and female agricultural workers in an international consortium, AGRICOH, relative to their respective general populations.
The analysis included eight cohorts that were linked to their respective cancer registries: France (AGRICAN: n = 128,101), the US (AHS: n = 51,165, MESA: n = 2,177), Norway (CNAP: n = 43,834), Australia (2 cohorts combined, Australian Pesticide Exposed Workers: n = 12,215 and Victorian Grain Farmers: n = 919), Republic of Korea (KMCC: n = 8,432), and Denmark (SUS: n = 1,899). For various cancer sites and all cancers combined, standardized incidence ratios (SIR) and 95% confidence intervals (CIs) were calculated for each cohort using national or regional rates as reference rates and were combined by random-effects meta-analysis.
During nearly 2,800,000 person-years, a total of 23,188 cancers were observed. Elevated risks were observed for melanoma of the skin (number of cohorts = 3, meta-SIR = 1.18, CI: 1.01–1.38) and multiple myeloma (n = 4, meta-SIR = 1.27, CI: 1.04–1.54) in women and prostate cancer (n = 6, meta-SIR = 1.06, CI: 1.01–1.12), compared to the general population. In contrast, a deficit was observed for the incidence of several cancers, including cancers of the bladder, breast (female), colorectum, esophagus, larynx, lung, and pancreas and all cancers combined (n = 7, meta-SIR for all cancers combined = 0.83, 95% CI: 0.77–0.90). The direction of risk was largely consistent across cohorts although we observed large between-cohort variations in SIR for cancers of the liver and lung in men and women, and stomach, colorectum, and skin in men.
The results suggest that agricultural workers have a lower risk of various cancers and an elevated risk of prostate cancer, multiple myeloma (female), and melanoma of skin (female) compared to the general population. Those differences and the between-cohort variations may be due to underlying differences in risk factors and warrant further investigation of agricultural exposures.
Per‐ and polyfluoroalkyl substances (PFAS) are highly persistent endocrine‐disrupting chemicals that may contribute to breast cancer development; however, epidemiologic evidence is limited. We ...investigated associations between prediagnostic serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) and postmenopausal breast cancer risk, overall and by hormone receptor status, in a nested case‐control study of 621 cases and 621 matched controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. PFOS and PFOA levels were determined based on serum metabolomic profiling performed using ultraperformance liquid chromatography‐tandem mass spectrometry. We used multivariable conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each PFAS and breast cancer risk, overall, by estrogen receptor (ER) or progesterone receptor (PR) status, and by joint ER/PR status. We found little evidence of association between PFOS or PFOA and breast cancer risk overall. However, in subtype‐specific analyses, we observed statistically significant increased risks of ER+, PR+, and ER+/PR+ tumors for the third vs lowest quartile of serum PFOS (ORs 95% CIs = 1.59 1.01‐2.50, 2.34 1.29‐4.23, and 2.19 1.21‐3.98, respectively) and elevated but nonstatistically significant ORs for the fourth quartile. Conversely, for PFOA, modest positive associations with ER−, PR−, ER+/PR−, and ER−/PR− tumors were generally seen in the upper quartiles. Our findings contribute evidence supporting positive associations between serum PFOS and hormone receptor‐positive tumors, and possibly between PFOA and receptor‐negative tumors. Future prospective studies incorporating tumor hormone receptor status are needed to better understand the role of PFAS in breast cancer etiology.
What's new?
Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are synthetic chemicals with widespread use in industrial applications and consumer products. They also are endocrine disruptors with suspected links to cancer. Here, the authors investigated potential associations between prediagnostic serum PFOS and PFOA levels and risk of breast cancer subtypes among postmenopausal women. No association was found between PFOS or PFOA and breast cancer risk overall. However, PFOS levels were positively associated with hormone receptor‐positive breast tumors, and modest positive associations were observed between PFOA levels and receptor‐negative tumors. The findings warrant further investigation in studies incorporating breast tumor hormone receptor status.
To assess the association of objectively measured levels of physical activity and sedentary time with major blood cell counts (e.g. white blood cells, red blood cells, platelets) among adults.
Data ...collected from the 2003-2004 and 2005-2006 cycles of the National Health and Nutrition Examination Survey (NHANES) was used to assess blood cell counts in relation to objectively measured physical activity and sedentary time (accelerometer). A series of linear regressions modes were used to assess these associations adjusting for a range of factors known to be associated with blood cell counts, including age, body mass index, dietary factors, and previous infections.
Higher levels of moderate-vigorous physical activity (ptrend<0.001) and lower sedentary time (ptrend = 0.040) were associated with lower white blood cell counts.
These results suggest that modifiable health behaviors, such as physical activity and sedentary time, may be associated with inflammatory status through white blood cell counts, which may be important for future disease risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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