Chronic exposure to cadmium causes preferential accumulation of cadmium in the kidney, leading to nephrotoxicity. In the process of renal cadmium accu

Significance: The essential micronutrient zinc is known to modulate adaptive immune responses and dysregulated zinc homeostasis leads to immunodeficiency. However, the molecular mechanisms underlying this zinc-mediated modulation are unknown. We show that the zinc transporter ZIP10 plays an important role in B-cell receptor (BCR) signaling.Zip10-deficiency in mature B cells attenuated both T-cell–dependent and –independent immune responses.Zip10-deficient mature B cells proliferated poorly in response to BCR cross-linking, as a result of dysregulated BCR signaling. Our data establish that ZIP10 functions as a cellular regulator to modulate BCR signaling in humoral immune responses.

An Integrative Study of the Genetic, Social and Environmental Determinants of Chronic Kidney Disease Characterized by Tubulointerstitial Damages in the North Central Region of Sri Lanka: Shanika NANAYAKKARA, et al. Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University—Objectives: Previous investigations on chronic kidney disease of unknown etiology characterized by tubulointerstitial damages (CKDu) in the North Central Region (NCR) of Sri Lanka have supported the involvement of social, environmental and genetic factors in its pathogenesis. Methods: We conducted a social‐environmental‐ and‐genetic epidemiology study on a male population in NCR to investigate the genetic and environmental contributors. We recruited 311 case‐series patients and 504 control candidates. Of the 504 control candidates, 218 (43%) were eliminated because of the presence of hypertension, proteinuria, high HbA1c, high serum creatinine or high alpha‐1 microglobulin in urine.Results and Discussion: None of 18 metals measured (μg/l) in urine, including Cd, As and Pb, showed significantly higher concentrations in cases compared with controls. As speciation results showed that 75.80% of total urinary As was in the form of arsenobetaine, which is non‐toxic to humans. None of the metal concentrations in drinking water samples exceeded guideline values. A genome‐wide association study (GWAS) was conducted to determine the genetic contributors. The GWAS yielded a genome‐wide significant association with CKDu for a single nucleotide polymorphism (SNP; rs6066043; p=5.23 ~ 10.9 in quantitative trait locus analysis; p=3.73 ~ 10.8 in dichotomous analysis) in SLC13A3 (sodium‐dependent dicarboxylate transporter member 3). The population attributable fraction and odds ratio for this SNP were 50% and 2.13. Genetic susceptibility was identified as the major risk factor for CKDu. However, 43% of the apparently healthy male population suffers from non‐communicable diseases, suggesting their possible influence on CKDu progression.

Background: Chronic arsenic exposure has been shown to cause liver damage. However, serum hepatic enzyme activity as recognized on liver function tests (LFTs) showing a dose-response relationship with arsenic exposure has not yet been clearly documented. The aim of our study was to investigate the dose-response relationship between arsenic exposure and major serum enzyme marker activity associated with LFTs in the population living in arsenic-endemic areas in Bangladesh. Methods: A total of 200 residents living in arsenic-endemic areas in Bangladesh were selected as study subjects. Arsenic concentrations in the drinking water, hair and nails were measured by Inductively Coupled Plasma Mass Spectroscopy (ICP-MS). The study subjects were stratified into quartile groups as follows, based on concentrations of arsenic in the drinking water, as well as in subjects' hair and nails: lowest, low, medium and high. The serum hepatic enzyme activities of alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT) were then assayed. Results: Arsenic concentrations in the subjects' hair and nails were positively correlated with arsenic levels in the drinking water. As regards the exposure-response relationship with arsenic in the drinking water, the respective activities of ALP, AST and ALT were found to be significantly increased in the high-exposure groups compared to the lowest-exposure groups before and after adjustments were made for different covariates. With internal exposure markers (arsenic in hair and nails), the ALP, AST and ALT activity profiles assumed a similar shape of dose-response relationship, with very few differences seen in the higher groups compared to the lowest group, most likely due to the temporalities of exposure metrics. Conclusions: The present study demonstrated that arsenic concentrations in the drinking water were strongly correlated with arsenic concentrations in the subjects' hair and nails. Further, this study revealed a novel exposure- and dose- response relationship between arsenic exposure metrics and serum hepatic enzyme activity. Elevated serum hepatic enzyme activities in the higher exposure gradients provided new insights into arsenic-induced liver toxicity that might be helpful for the early prognosis of arsenic-induced liver diseases.