Interleukin (IL)-12 and IL-18 Synergize to Promote MAIT Cell IL-17A and IL-17F Production Independently of IL-23 Signaling.

IL-23 is considered a critical regulator of IL-17 in Th17 cells; however, its requirement for inducing IL-17 production in other human immune subsets remains incompletely understood. Mucosal associated invariant T (MAIT) cells uniformly express retinoic acid receptor-related orphan receptor gamma t (RORγt) but only a minor population have been shown to produce IL-17A. Here we show that IL-17F is the dominant IL-17 isoform produced by MAIT cells, not IL-17A. For optimal MAIT cell derived IL-17A and IL-17F production, T cell receptor (TCR) triggering, IL-18 and monocyte derived IL-12 signaling is required. Unlike Th17 cells, this process is independent of IL-23 signaling. Using an in vitro skin cell activation assay, we demonstrate that dual neutralization of both IL-17A and IL-17F resulted in greater suppression of inflammatory proteins than inhibition of IL-17A alone. Finally, we extend our findings by showing that other innate-like lymphocytes such as group 3 innate lymphoid cells (ILC3) and gamma delta (γδ) T cells are also capable of IL-23 independent IL-17A and IL-17F production. These data indicate both IL-17F and IL-17A production from MAIT cells may contribute to tissue inflammation independently of IL-23, in part explaining the therapeutic disconnect between targeting IL-17 or IL-23 in certain inflammatory diseases.

Biomonitoring of phthalate metabolites in the Canadian population through the Canadian Health Measures Survey (2007-2009).

Human exposure to phthalates occurs through multiple sources and pathways. In the Canadian Health Measures Survey 2007-2009, 11 phthalate metabolites, namely, MMP, MEP, MnBP, MBzP, MCHP, MCPP, MEHP, MEOHP, MEHHP, MnOP, and MiNP were measured in urine samples of 6-49 year old survey respondents (n=3236). The phthalate metabolites biomonitoring data from this nationally-representative Canadian survey are presented here. The metabolites MEP, MnBP, MBzP, MCPP, MEHP, MEOHP and MEHHP were detected in >90% of Canadians while MMP, MCHP, MnOP and MiNP were detected in <20% of the Canadian population. Step-wise regression analyses were carried out to identify important predictors of volumetric concentrations (µg/L) of the metabolites in the general population. Individual multiple regression models with covariates age, sex, creatinine, fasting status, and the interaction terms age×creatinine, age×sex and fasting status×creatinine were constructed for MEP, MnBP, MBzP, MCPP, MEHP, MEOHP and MEHHP. The least square geometric mean (LSGM) estimates for volumetric concentration (µg/L) of the metabolites derived from respective regression models were used to assess the patterns in the metabolite concentrations among population sub-groups. The results indicate that children had significantly higher urinary concentrations of MnBP, MBzP, MEHP, MEHHP, MEOHP and MCPP than adolescents and adults. Moreover, MEP, MBzP, MnBP and MEOHP concentrations in females were significantly higher than in males. We observed that fasting status significantly affects the concentrations of MEHP, MEHHP, MEOHP, and MCPP metabolites analyzed in this study. Moreover, our results indicate that the sampling time could affect the DEHP metabolite concentrations in the general Canadian population.

Human biological monitoring of diisononyl phthalate and diisodecyl phthalate: a review.

High molecular-weight phthalates, such as diisononyl phthalate (DINP), and diisodecyl phthalate (DIDP), are widely used as plasticizers in the manufacturing of polymers and consumer products. Human biological monitoring studies have employed the metabolites of DINP and DIDP as biomarkers to assess human exposure. In this review, we summarize and analyze publicly available scientific data on chemistry, metabolism, and excretion kinetics, of DINP and DIDP, to identify specific and sensitive metabolites. Human biological monitoring data on DINP and DIDP are scrutinised to assess the suitability of these metabolites as biomarkers of exposure. Results from studies carried out in animals and humans indicate that phthalates are metabolised rapidly and do not bioaccmulate. During Phase-I metabolism, ester hydrolysis of DINP and DIDP leads to the formation of hydrolytic monoesters. These primary metabolites undergo further oxidation reactions to produce secondary metabolites. Hence, the levels of secondary metabolites of DINP and DIDP in urine are found to be always higher than the primary metabolites. Results from human biological monitoring studies have shown that the secondary metabolites of DINP and DIDP in urine were detected in almost all tested samples, while the primary metabolites were detected in only about 10% of the samples. This indicates that the secondary metabolites are very sensitive biomarkers of DINP/DIDP exposure while primary metabolites are not. The NHANES data indicate that the median concentrations of MCIOP and MCINP (secondary metabolites of DINP and DIDP, resp.) at a population level are about 5.1 µg/L and 2.7 µg/L, respectively. Moreover, the available biological monitoring data suggest that infants/children are exposed to higher levels of phthalates than adults.

Occurrence of glyphosate and acidic herbicides in select urban rivers and streams in Canada, 2007.

INTRODUCTION: Public and scientific concern has grown over the last decade in Canada over the cosmetic use of pesticides in urban centers. With this in mind, a national survey was designed to monitor eight commonly used herbicides in urban rivers and streams across Canada. MATERIALS AND METHODS: To coordinate sample collections across the country, samples were collected monthly on one of two predetermined dates from April to September, 2007 from 19 sites within 16 watersheds, including 15 sites downstream of urban lands and two reference sites. Water samples were also collected approximately three times from each watershed during or after precipitation events. All samples were collected using a common sampling protocol and all were analyzed using the same analytical laboratories. RESULTS AND DISCUSSION: The herbicides 2,4-D, mecoprop, dicamba, glyphosate and its major metabolite aminomethylphosphonic acid (AMPA) were most frequently detected. Using either herbicide concentrations upstream/downstream of urban centers or bromoxynil and clopyralid as indictors of agricultural inputs of herbicides to streams, it was clear that environmental concentrations of these herbicides downstream of urban areas were linked to urban use in Canada. Herbicide concentrations in streams draining urban areas were greater during or after significant rainfall events and, with the exception of glyphosate, were significantly greater in the Province of Ontario. Herbicide concentrations were not correlated to the proportion of the watersheds in urban land use. Also, there was no difference in seasonal patterns of herbicide concentrations across urban centers when grouped in five geographic areas. None of the herbicide concentrations measured exceeded existing Canadian Water Quality Guidelines for the protection of aquatic life. CONCLUSIONS: This is the first time a national survey of pesticides in urban rivers has been carried out in a consistent fashion across Canada. Concentrations of 2,4-D, mecoprop, dicamba, glyphosate, and AMPA were linked to urban use and frequently detected in all geographic areas. However, geographic differences in concentration suggested differences in usage or stream connectivity patterns among urban centers. Some jurisdictions in Canada have recently restricted cosmetic use of pesticides and it would be interesting to determine whether such restrictions will lead to reduced pesticide concentrations in urban streams.

Human biomonitoring of environmental chemicals--early results of the 2007-2009 Canadian Health Measures Survey for males and females.

Human biomonitoring is an important indicator and measure of exposure to environmental chemicals and provides information to support health protection policies and programs. Cycle 1 (2007-2009) of the Canadian Health Measures Survey (CHMS) collected and analyzed biological samples from over 5600 males and females aged 6-79 years, which established national representative blood and urine concentrations for a number of environmental chemicals including metals, organophosphate insecticide metabolites, polychlorinated biphenyls (PCBs), organochlorines (OCs), perfluorinated compounds (PFCs), bisphenol A (BPA), and cotinine. The results of CHMS Cycle 1 indicate that while some organophosphate insecticide metabolites were below limits of detection for most participants, metals, PCBs, OCs, PFCs and BPA were detected in almost all blood or urine samples. Significant differences (p<0.05) in blood concentrations between males and females were also determined for several metals (e.g., lead for males and females was 15.1 and 11.8 µg/L, respectively), PFCs (e.g., PFOS for males and females was 11.13 and 7.07 µg/L, respectively), and OCs (e.g., p,p'-DDE for males and females was 134.43 and 172.07 µg/kg lipid, respectively) and in urine concentrations for BPA (1.29 and 1.04 µg/L for males and females, respectively). Future cycles of the CHMS will permit temporal trend analysis for a number of these chemicals.