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Kidney/Renal Cancer

• Environmental Exposures Related to Parental Habits in the Perinatal Period and the Risk of Wilms' Tumor in Children
  Wilms' tumor is the most frequently diagnosed renal tumor in children. Little is known about its etiology. The aim of this study was to investigate the potential role of specific exposures related to parental habits such as parental smoking, maternal alcohol consumption and the use of household pesticides during pregnancy. The ESTELLE study was a nationwide case-control study that included 117 Wilms' tumor cases and 1100 control children from the general French population, frequency-matched by age and gender. Unconditional logistic regression was used to estimate odds ratios and 95 % confidence intervals. After controlling for matching variables and potential confounders, the maternal use of any type of pesticide during pregnancy was associated with the risk of Wilms' tumor in children (OR 1.6 [95 % CI 1.1-2.3]). Insecticides were the most commonly reported type of pesticide and there was a positive association with their use (OR 1.7 [95 % CI 1.1-2.6]. The association was stronger when they were used more often than once a month (OR 1.9 [95 % CI 1.2-3.0]. Neither maternal smoking during pregnancy nor paternal smoking during preconception/pregnancy was associated with a risk of Wilms' tumor (ORs 1.1[95 % CI 0.7-1.8] and 1.1 [95 % CI 0.7-1.7], respectively). No association was observed with maternal alcohol intake during pregnancy (OR 1.2 [95 % CI 0.8-2.0]). Our findings suggest an association between the maternal use of household pesticides during pregnancy and the risk of Wilms' tumor.
  [Rios, P., Bauer, H., Schleiermacher, G., Pasqualini, C., Boulanger, C., Thebaud, E., Gandemer, V., Pellier, I., Verschuur, A., Sudour-Bonnange, H. and Coulomb-l'Hermine, A., 2020. Cancer Epidemiology, 66, p.101706.]
• Evidence of risks of renal function reduction due to occupational exposure to agrochemicals: A systematic review.
  Agriculture accounts for an important economic activity worldwide and the search for the increased productivity incorporated the use of pesticides in this practice. Such compounds have significant environmental and human health effects, especially for workers exposed to them. Among the main health problems caused by pesticides are the renal alterations, which in more advanced stages comprise an important public health problem. For this reason, this systematic review aimed at gathering evidence of the risk of renal changes induced by occupational exposure to pesticides. The search was made in PubMed, Scopus, Lilacs and Scielo in December 2017, using keywords as pesticides, poisoning, kidney, renal insufficiency. After the application of inclusion criteria, 11 studies were selected. It was possible to gather evidence on the prevalence and risk (3.12-6.71) of renal injury from the occupational exposure of agricultural workers and its association with the exposure to agrichemicals, as organophosphates and herbicides.
  [Prudente IRG, Cruz CL, Nascimento LC, Kaiser CC, Guimarães AG. 2018. Environ Toxicol Pharmacol. 63:21-28]
• Occupational exposures and genetic susceptibility to urinary tract cancers: a systematic review and meta-analysis.
  This study aims to summarize the current knowledge on the relationship between genetic polymorphisms, occupational exposures, and urinary tract cancers. Authors searched MEDLINE, ISI Web of science, and SCOPUS online databases for all articles published in English language up to September 2016. A meta-analysis was performed to provide summary estimates for the association between a certain genetic polymorphism, occupational exposure and bladder cancer (BC) or kidney cancer (KC), when appropriate. Fifteen studies on BC and six on KC were deemed eligible for the review. With regard to BC, an overall odds ratio (OR) of 2.07 [95% confidence interval (CI): 1.38-3.09] for those with GSTM1 and an OR of 2.07 (95% CI: 1.38-3.09) for those with GSTT1 null genotype were reported when exposed to polycyclic aromatic hydrocarbons (PAHs). NAT2 slow genotype carriers had an OR of 3.59 (95% CI: 2.62-4.93) for BC when exposed to aromatic amines and an OR of 2.07 (95% CI: 1.36-3.15) when exposed to PAHs. With regard to KC and pesticide exposure, the meta-analysis reported an OR of 4.38 (95% CI: 2.28-8.41) for GSTM1 present genotype, an OR of 2.59 (95% CI: 1.62-4.15) for GSTT1-present genotype and an OR of 6.51 (95% CI: 2.85-14.89) for combined effects of GSTM1 and GSTT1 active genotypes. This meta-analysis indicates a possible association between the variant genotypes of GSTM1, GSTT1, NAT2 and SULT1A1, occupational exposure to aromatic amines or PAHs, and development of BC. Our results suggest that polymorphisms in GSTM1 and GSTT1 genes could influence the risk for developing KC in individuals occupationally exposed to pesticides.
  [Stojanovic J, Milovanovic S, Pastorino R, et al. 2017. Eur J Cancer Prev. doi: 10.1097/CEJ.0000000000000364]
• Renal cell carcinoma, occupational pesticide exposure and modification by glutathione S-transferase polymorphisms.
  This study investigated associations between occupational pesticide exposure and renal cell carcinoma (RCC) risk. Study also considered whether this association could be modified by glutathione S-transferase M1 and T1 (GSTM1 and GSTT1) genotypes. About 1097 RCC cases and 1476 controls from Central and Eastern Europe were interviewed to collect data on lifetime occupational histories. Occupational information for jobs held for at least 12 months duration was coded for pesticide exposures and assessed for frequency and intensity of exposure. GSTM1 and GSTT1 gene deletions were analyzed using TaqMan assays. A significant increase in RCC risk was observed among subjects ever exposed to pesticides. After stratification by genotypes, increased risk was observed among exposed subjects with at least one GSTM1 active allele but not among exposed subjects with two GSTM1 inactive alleles compared with unexposed subjects with two inactive alleles. Risk was highest among exposed subjects with both GSTM1 and GSTT1 active genotypes compared with unexposed subjects with at least one GSTM1 or T1 inactive genotype. In the largest RCC case-control study with genotype information conducted to date, it was observed that risk associated with pesticide exposure was exclusive to individuals with active GSTM1/T1 genotypes. These findings further support the hypothesis that glutathione S-transferase polymorphisms can modify RCC risk associated with occupational pesticide exposure.
  [Karami S, Boffetta P, Rothman N, Hung RJ, Stewart T, et al. 2008. Carcinogenesis. 29(8):1567-71]
• Risk of childhood cancers associated with residence in agriculturally intense areas in the United States
  An ecological study analyzing incidence data from U.S. children ages 0-14 years diagnosed with cancer between 1995 and 2001 and residence in a county with moderate to high agriculture activity finds statistically significantly elevated risk for renal carcinoma at moderate agriculture activity (OR 2.3) and at high agriculture activity (OR 3.3). In regards to specific crops grown, the study finds a link between cotton crops and renal carcinomas (OR 6.9).
  [Carrozza, S.E., et al. 2008. Environ Health Perspect 116(4):559-565.]
• Wilm’s tumor and exposure to residential and occupational hazardous chemicals
  A case-control study by the CDC finds elevated risk for pesticides during pregnancy and during the 2-year period prior to birth.
  [Tsai, J., et al. 2006. Int J Hyg Environ Health 209(1):57-64.]
• Glutathione S-transferases M1-1 and T1-1 as risk modifiers for renal cell cancer associated with occupational exposure to chemicals.
  Study aimed to investigate the possible interaction between occupational risk factors and genotype for glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) in renal cell cancer (RCC).One hundred patients with RCC and 200 outpatient controls were enrolled at Parma University Hospital. The polymorphisms of glutathione S-transferase M1-1 (GSTM1) and T1-1 (GSTT1) were investigated by PCR; occupational history was collected by a structured questionnaire. Subjects with GSTM1 present genotype showed higher risks for RCC, compared to GSTM1 null subjects, if exposed to metals or pesticides. The GSTT1 present genotype also enhanced the risk (about twofold) of RCC among subjects exposed to solvents and pesticides, compared with those GSTT1 null.Results support the hypothesis that GSTM1 and GSTT1 polymorphisms can interact with several occupational exposures to significantly modify the risk of RCC among exposed subjects.
  [Buzio L, De Palma G, Mozzoni P, et al. 2003. Occup Environ Med. 60(10):789-93]
• Occupational risk factors for renal cell cancer. An Italian case-control study.
  “Prolonged” occupational exposures to pesticides is associated with an increased risk for renal cell cancer (OR 2.0).
  [Buzio, L., et al. 2002. Med Lav 93(4):303-309.]
• Renal cell carcinoma and occupational exposure to chemicals in Canada
  An increased risk of renal cell carcinoma in males is associated with exposure to herbicides (1.6 OR) and pesticides (1.8 OR) and in particular a dose-response relationship for herbicides.
  [Hu, J., et al. 2002. Occup Med 52(3):157-164.]
• Childhood cancer and paternal employment in agriculture: the role of pesticides
  Previous studies have suggested that the offspring of men potentially exposed to pesticides at work may be at increased risk of kidney cancer (Wilms' tumour), brain tumours, Ewing's bone sarcoma and acute leukaemia. This paper examines the association between potential occupational exposure of fathers to pesticides and offspring's death from cancer in a large national database. Records for 167703 childhood deaths occurring during 1959-63, 1970-78 and 1979-90 in England and Wales have been analysed. Among the offspring of men with potential occupational exposure to pesticides there were 5270 deaths, of which 449 were due to cancer. Associations were assessed using proportional mortality ratios (PMRs), with adjustment for age, year of death and paternal social class. Of the childhood cancers previously linked with potential paternal occupational exposure to pesticides, the only statistically significant excess was for kidney cancer (PMR=1.59, 95% CI=1.18-2.15, based on 42 deaths). Although these results offer some support for the suggestion that paternal occupational exposure to pesticides may be related to the subsequent development of kidney cancer in offspring, other explanations cannot be excluded. In the light of the findings presented here and elsewhere, further, more detailed, research into the nature of this relationship is warranted.
  [Fear, N.T., et al. 1998. Br J Cancer 77(5):825-829.]
• Cancer in offspring of parents engaged in agricultural activities in Norway: incidence and risk factors in the farm environment.
  Parental agricultural exposure to pesticides is associated with Wilms’ tumor, as well as other forms of cancer.
  [Kristensen, P., et al. 1996. Int J Cancer 65(1):39-50]
• Parental exposures to pesticides and risk of Wilms’ tumor in Brazil
  Elevated risk is found for farm work involving paternal (3.24 OR) and maternal (128.6 OR) frequent use of pesticides.
  [Sharpe, C.R., et al. 1995. Am J Epidemiol 141(3):210-217.]
• Occupational risk factors for renal-cell carcinoma in Denmark
  Risk of renal-cell carcinoma was found to be associated with employment as a truck driver, exposure to gasoline, other hydrocarbons, and insecticides and herbicides. The risk of renal-cell carcinoma was higher in the lower socioeconomic strata for both the men and the women.
  [Mellemgaard, A., et al. 1994. Scand J Work Environ Health 20(3):160-165.]
• Cancer among farmers in central Italy
  A case-referent study of Italian farmers finds a significantly increased risk of kidney cancer among farmers with greater than 10 years experience and a possible relationship between olives and potato growing and kidney cancer.
  [Forastiere, F, et al. 1993. Scand J Work Environ Health 19(6):382-389.]
• Risk factors for Wilms tumor
  A study examining nonoccupational risk factors for Wilms tumor finds an association with a history of household insect extermination.
  [Olshan, A.F., et al. 1993. Cancer 72(3):938-944.]

Kidney Function/Disease

• Assessment of the impact of glyphosate and 2,4-D herbicides on the kidney injury and transcriptome changes in obese mice fed a Western diet.
  The development of chronic kidney disease has been associated with comorbidities resulting from the consumption of Westernized dietary (WD) patterns, including obesity and other metabolic dysfunctions. Kidneys also have a crucial role in the metabolism and excretion of xenobiotics, including herbicides. There is limited knowledge regarding the simultaneous exposure to WD and glyphosate (glypho) and 2,4-D, the most used herbicides globally. Thus, this study examined whether exposure to glypho and/or 2,4-D, either individually or in mixed, could impact the early effects of WD intake on kidney histology and gene expression in a rodent model. Male C57BL6J mice were fed a WD containing 20% lard, 0.2% cholesterol, 20% sucrose, and high sugar solution with 23.1 and 18.9 g/L of D-fructose and D-glucose for six months. During this period, the mice also received glypho (0.05 or 5 mg/kg/day), 2,4-D (0.02 or 2 mg/kg/day), or a mixture of both (0.05 +0.02, 5 +2 mg/kg/day) via intragastric administration five times per week. The doses were within or below the established regulatory limits. While single or mixed exposures did not alter WD-induced obesity, tubular lipid vacuolation, or increased serum creatinine levels; the exposure to higher doses of the mixture (5 +2) reduced the mesangial matrix area and tubular cell proliferation, while increasing the density of F4/80 macrophages in the renal interstitium. In terms of transcriptomic analysis, the herbicide mixture altered the expression of 415 genes in the kidney, which were found to be associated with immune response processes, particularly those related to phagocyte activity. While discrete, findings indicate that herbicide mixtures, rather than single exposures, might induce minor deleterious effects on the kidneys of obese mice under WD intake.
  [Romualdo, G.R., de Souza, J.L.H., Valente, L.C. and Barbisan, L.F., 2023. Toxicology Letters, 385, pp.1-11.]
• Association of indoor use of pesticides with CKD of unknown origin
  Chronic kidney disease (CKD) is a growing global health problem. Recently, an epidemic of CKD of unknown origin (CKDu), a form of CKD seen mostly in agricultural communities, has been emerged. One of the proposed causes of CKDu is pesticide use in farmers. On the other hand, the research on relation between indoor use of pesticides and CKDu is little. In this study, we aimed to investigate the association between indoor use of pesticide as well as the exposure time with CKDu. This study was done as part of the population-based cohort of Prospective Epidemiological Research Studies in Iran. We used the baseline data of the Zahedan Adult Cohort Study. All subjects with diabetes mellitus and/or hypertension, estimated glomerular filtration rate (eGFR) between 60–89 ml/min/1.73 m2, and unavailable creatinine measurement were excluded. Subjects with an eGFR of less than 60 ml/min/1.73 m2 were defined as having CKDu, and their data were compared with those with an eGFR of more than 90 ml/min/1.73 m2. Data regarding indoor pesticide use and duration of exposure were obtained through a questionnaire. After applying the exclusion criteria, 1079 subjects remained in the study. Female sex, single marital status, low physical activity, triglyceride (TG) levels of more than 150 mg/dl, body mass index (BMI) of more than 25 kg/m2, non-smokers, indoor pesticide use, and high pesticide exposure time were associated with CKDu. The effects of age, female sex, TG levels more than 150 mg/dl, pesticide use (OR 1.36; 95% CI 1.01–1.84), and high exposure time (third tertile of exposure time) compared to non-users (OR 1.64; 95% CI 1.07–2.51) remained significant in multivariable analysis.
  [Alvand, S., Alatab, S., Dalvand, S., Shahraki-Sanavi, F., Kaykhaei, M.A., Shahraki, E., Barar, E., Sepanlou, S.G. and Ansari-Moghaddam, A., 2023. Plos one, 18(7), p.e0277151.]
• Human serum lipidomics analysis revealed glyphosate may lead to lipid metabolism disorders and health risks
  Glyphosate-based herbicides (GBH) are one of the most widely used pesticides worldwide. Industrial workers in glyphosate-based herbicides manufacture are the populations who experience long-term exposure to high glyphosate levels. The impacts of glyphosate on human health are the important public health problem of great concern. Up to date, the potential adverse effects of glyphosate on humans or other mammals have been reported in multiple studies. However, limited research is available on lipid alternations related to human exposure to glyphosate. In fact, the perturbations in some lipid metabolisms have been found in industrial workers in previous work. This study aims to explore the serum lipidomic characterization and to understand the underlying mechanisms of health risks associated with glyphosate exposure. A nontargeted lipidomics study was conducted to investigate the 391 serum samples from the general population and chemical factory workers. It was demonstrated that glyphosate caused significant perturbations of 115 differentially expressed lipids. The main manifestations were the elevation of circulating diacylglycerols (DG), cholesteryl esters (CE), ceramides (Cer), sphingomyelins (SM), lysophosphatidylethanolamines (LPE) and phosphatidylcholines (PC), and the decrease of ysophosphatidylcholines (LPC), triacylglycerols (TG), fatty acids (FA) and phosphatidylethanolamines (PE). A total of 88 lipids were further screened as potential lipid biomarkers associated closely with glyphosate using partial correlation analysis, and five of which (including PC 16:0/18:2; O, PC 18:0/18:2; O, PC 18:0/20:4; O, PC O-40:9 and CE 18:3) showed excellent superior performance (AUC = 1) to evaluate and monitor health risks due to glyphosate exposure. The present work discovered glyphosate-induced potential health risks, including chronic hepatic and renal dysfunction, atherosclerosis, cardiovascular disease and neurodegenerative diseases from a lipidomic perspective, and could inform the identification of early indicators and interpretation of biological mechanisms to detect health risks of the glyphosate-exposed populations as early as possible.
  [Zhang, F., Zhang, Q., Liu, X., Gao, M., Li, X., Wang, Y., Chang, Y., Zhang, X., Huo, Z., Zhang, L. and Shan, J., 2023. Environment International, 171, p.107682.]
• Pesticides and insulin resistance-related metabolic diseases: Evidences and mechanisms.
  The use of pesticides in the past century has lot helped humankind in improving crops' field and general hygiene level. Nevertheless, there has been countless evidences on the toxic effects of pesticides on the living systems. The link of exposure to pesticides with different human chronic diseases in the context of carcinogenicity, neurotoxicity, developmental toxicity, etc., have been evaluated in various types of studies. There are also some evidences on the link of exposure to pesticides with higher incidence of metabolic diseases associated with insulin resistance like diabetes, obesity, metabolic syndrome, hypertension, polycystic ovary syndrome and chronic kidney diseases. Physiologically, weakening intracellular insulin signaling is considered as a compensatory mechanism for cells to cope with cellular stresses like xenobiotic effects, oxidative stress and inflammatory responses, but it can pathologically lead to a defective cycle with lowered sensitivity of the cells to insulin which happens in metabolic disorders. In this work, the data related to metabolic toxicity of pesticides categorized in the mentioned metabolic diseases with a focus on the effects of pesticides on insulin signaling pathway and the mechanisms of development of insulin resistance will be systematically reviewed and presented.
  [Arab, A. and Mostafalou, S., 2023. Pesticide Biochemistry and Physiology, p.105521.]
• Harmful health effects of pesticides used on museum textile artifacts - overview
  The paper discusses the types of fibers contained in the museum textile artifacts and the types of pests and pesticides. Also, the main health problems associated with pesticide exposure are presented. Textile fibers represent an excellent source of food for microbes and insects. The key to the long-term preservation of textiles is by implementing an integrated management program for pest and environmental conditions control. The main types of pesticides are insecticides, herbicides, fungicides, rodenticides, acaricides, and fumigants and a way for classification can be made according to the LD50 (lethal dose) value which evaluates the toxicity of a pesticide. Depending on the LD50 values, pesticides can be very toxic, moderately toxic, slightly toxic, and relatively non-toxic. Exposure to pesticides can occur through 4 four routes: oral, dermal, respiratory, and eye exposure. The main diseases that can be associated with exposure to pesticides are discussed in the paper. In the end, a basic set of precautionary recommendations when handling museum objects that may contain hazardous materials was presented.
  [Tănăsescu, E.C. and Lite, M.C., 2022. Ecotoxicology and Environmental Safety, 247, p.114240.]
• Association of Pesticides and Kidney Function among Adults in the US Population 2001–2010
  Chronic kidney disease of unknown cause is prevalent in a range of communities; however, its etiology remains unclear. We examined the association between pesticide exposures and the risk of kidney function loss using four waves of the National Health and Nutrition Examination Survey (NHANES) to identify a pathological pathway. We pooled data from four cross-sectional waves of NHANES, with 41,847 participants in total. Exposure to malathion increased the risk of low kidney function (aOR = 1.26, 95% CI = 1.01–1.56) in the adjusted model. Increased risk of low kidney function was not found among those exposed to 2,4-D (aOR = 0.88, 95% CI = 0.72–1.09), 3,5,6-trichloropyridinol (aOR = 0.96, 95% CI = 0.83–1.12), and 3-PBA (aOR = 1.03, 95% CI = 0.94–1.13). Our findings provide evidence of altered kidney function in people exposed to malathion, highlighting the potential of organophosphate pesticides’ role in renal injury.
  [Wan, E.T., Darssan, D., Karatela, S., Reid, S. and Osborne, N. Int. J. Environ. Res. Public Health.]
• Water sources and kidney function: investigating chronic kidney disease of unknown etiology in a prospective study
  A chronic Kidney Disease of unknown etiology (CKDu) has emerged with disproportionately high prevalence across dry lowland agricultural communities globally. Here we present the results of a prospective cohort of 293 patients with CKDu in the endemic region of Wilgamuwa, Sri Lanka, in whom we measured baseline kidney function and undertook quarterly follow up over 2 years. Well water was the primary historic drinking water source in the region, although a majority (68%) of participants reported switching to reverse osmosis water during study follow ups. Participants who reported ever drinking from well water had estimated glomerular filtration rates −6.7 (SD: 2.8) ml/min/1.73 m2 lower than participants who did not drink from well water historically (p = 0.0184) during the study period. Geospatial analysis identifies a cluster within the region where CKDu progression is significantly higher than the surrounding area. Samples of household wells (n = 262) indicated 68% had detectable agrochemical compounds with concentration above global water quality standards. It is expected that the detected contaminants compounds are indicators of poor water quality and that there is likely additional agrochemical exposure including commercial additives that may contribute to CKDu onset and/or progression. Thus, our study finds that well water exposure during a person’s lifetime in this region is associated with kidney function decline and identifies and quantifies putative nephrotoxic agrochemicals above safe drinking water concentrations in these wells.
  [Vlahos, P., Schensul, S.L., Anand, S., Shipley, E., Diyabalanage, S., Hu, C., Ha, T., Staniec, A., Haider, L., Schensul, J.J. and Hewavitharane, P. npj Clean Water, 4(1), pp.1-7.]
• Cellular injury leading to oxidative stress in acute poisoning with potassium permanganate/oxalic acid, paraquat, and glyphosate surfactant herbicide
  Previous studies on human acute kidney injury (AKI) following poisoning with potassium permanganate/oxalic acid (KMnO4/H2C2O4), paraquat, and glyphosate surfactant herbicide (GPSH) have shown rapid and large increases in serum creatinine (sCr) that cannot be entirely explained by direct nephrotoxicity. One plausible mechanism for a rapid increase in sCr is oxidative stress. Thus, we aimed to explore biomarkers of oxidative stress, cellular injury, and their relationship with sCr, after acute KMnO4/H2C2O4, paraquat, and GPSH poisonings. Serum biomarkers [sCr, creatine (sCn), cystatin C (sCysC)] and urinary biomarkers [cytochrome C (CytoC), 8-isoprostane (8-IsoPs)] were evaluated in 105 patients [H2C2O4/KMnO4 (N = 57), paraquat, (N = 21), GPSH (N = 27)] recruited to a multicenter cohort study. We used area under the receiver operating characteristics curve (AUC-ROC) to quantify the extent of prediction of moderate to severe AKI (acute kidney injury network stage 2/3 (AKIN2/3)). Patients with AKIN2/3 showed increased levels of CytoC. Early high CytoC predicted AKIN2/3 in poisoning with KMnO4/H2C2O4 (AUC-ROC4-8h: 0.81), paraquat (AUC-ROC4-8h: 1.00), and GPSH (AUC-ROC4-8h: 0.91). 8-Isoprostane levels were not significantly elevated. Reduced sCn and increased sCr/sCn ratios were observed for 48 h post KMnO4/H2C2O4 ingestion. Paraquat exhibited a similar pattern (N = 11), however only 3 were included in our study. Increased CytoC suggests there is mitochondrial injury coupled with energy depletion. The increased sCr within 24 h could be due to increased conversion of cellular creatine to creatinine during the process of adenosine triphosphate (ATP) generation and then efflux from cells. Later increases of sCr are more likely to represent a true decrease in kidney function.
  [Wijerathna, T.M., Mohamed, F., Gawarammana, I.B., Wunnapuk, K., Dissanayake, D.M., Shihana, F. and Buckley, N.A., 2020. Environmental toxicology and pharmacology, 80, p.103510.]
• Chronic kidney disease and household behaviors in Sri Lanka: Historical choices of drinking water and agrochemical use
  This paper examines whether there are systematic differences in the historical behaviors of households that are affected and unaffected by chronic kidney disease (CKD) in Sri Lanka pertaining to their water source choices, water treatment practices, and agrochemical use. This analysis is motivated by the Sri Lankan government's largest policy response to this epidemic - to encourage communities to switch from untreated well water to publicly provided alternatives. We use recall methods to elicit information on the drinking water source and treatment choices of households over an 18-year period from 2000-2017. Our analysis is based on a survey of 1497 rural ground-water dependent households in the most CKD-affected areas of the 10 districts of Sri Lanka with the highest prevalence of CKD. Our main findings are that (a) households that have ever used a pump to extract (typically deep) drinking water from a household well are more likely to be affected by CKD; (b) we fail to find a relationship between disease status and households' use of buckets to extract (typically shallow) groundwater from their wells; and (c) those who have ever treated their shallow well water by boiling it are less likely to be affected by CKD. We also find that a greater share of CKD affected households historically used agrochemicals, used wells that were geographically removed from surface water sources, and displayed lower proxies of wealth. The implications of these findings are fourfold. First, since the systematic differences in the historical patterns of water sources and treatments used by CKD affected and non-affected households are modest, the sources of water and the treatment practices themselves may not be the sole risk factors in developing CKD. Second, although we find a negative association between boiling water and the probability of CKD, it is not obvious that a public policy campaign to promote boiling water is an appropriate response. Third, the hydrochemistry of deep and shallow well water needs to be better understood in order to shed light on the positive relationship between deep well water and disease status, and on why boiling shallow but not deep well water is associated with a lower probability of CKD. Fourth, there is a need for a deeper understanding of other risk factors and of the efficacy of preventative programs that provide alternative sources of household drinking water.
  [Balasubramanya, S., Stifel, D., Horbulyk, T. and Kafle, K., 2020. Economics & Human Biology, 37, p.100862.]

Kidney Function/Disease

• Assessment of the impact of glyphosate and 2,4-D herbicides on the kidney injury and transcriptome changes in obese mice fed a Western diet.
  The development of chronic kidney disease has been associated with comorbidities resulting from the consumption of Westernized dietary (WD) patterns, including obesity and other metabolic dysfunctions. Kidneys also have a crucial role in the metabolism and excretion of xenobiotics, including herbicides. There is limited knowledge regarding the simultaneous exposure to WD and glyphosate (glypho) and 2,4-D, the most used herbicides globally. Thus, this study examined whether exposure to glypho and/or 2,4-D, either individually or in mixed, could impact the early effects of WD intake on kidney histology and gene expression in a rodent model. Male C57BL6J mice were fed a WD containing 20% lard, 0.2% cholesterol, 20% sucrose, and high sugar solution with 23.1 and 18.9 g/L of D-fructose and D-glucose for six months. During this period, the mice also received glypho (0.05 or 5 mg/kg/day), 2,4-D (0.02 or 2 mg/kg/day), or a mixture of both (0.05 +0.02, 5 +2 mg/kg/day) via intragastric administration five times per week. The doses were within or below the established regulatory limits. While single or mixed exposures did not alter WD-induced obesity, tubular lipid vacuolation, or increased serum creatinine levels; the exposure to higher doses of the mixture (5 +2) reduced the mesangial matrix area and tubular cell proliferation, while increasing the density of F4/80 macrophages in the renal interstitium. In terms of transcriptomic analysis, the herbicide mixture altered the expression of 415 genes in the kidney, which were found to be associated with immune response processes, particularly those related to phagocyte activity. While discrete, findings indicate that herbicide mixtures, rather than single exposures, might induce minor deleterious effects on the kidneys of obese mice under WD intake.
  [Romualdo, G.R., de Souza, J.L.H., Valente, L.C. and Barbisan, L.F., 2023. Toxicology Letters, 385, pp.1-11.]
• Association of indoor use of pesticides with CKD of unknown origin
  Chronic kidney disease (CKD) is a growing global health problem. Recently, an epidemic of CKD of unknown origin (CKDu), a form of CKD seen mostly in agricultural communities, has been emerged. One of the proposed causes of CKDu is pesticide use in farmers. On the other hand, the research on relation between indoor use of pesticides and CKDu is little. In this study, we aimed to investigate the association between indoor use of pesticide as well as the exposure time with CKDu. This study was done as part of the population-based cohort of Prospective Epidemiological Research Studies in Iran. We used the baseline data of the Zahedan Adult Cohort Study. All subjects with diabetes mellitus and/or hypertension, estimated glomerular filtration rate (eGFR) between 60–89 ml/min/1.73 m2, and unavailable creatinine measurement were excluded. Subjects with an eGFR of less than 60 ml/min/1.73 m2 were defined as having CKDu, and their data were compared with those with an eGFR of more than 90 ml/min/1.73 m2. Data regarding indoor pesticide use and duration of exposure were obtained through a questionnaire. After applying the exclusion criteria, 1079 subjects remained in the study. Female sex, single marital status, low physical activity, triglyceride (TG) levels of more than 150 mg/dl, body mass index (BMI) of more than 25 kg/m2, non-smokers, indoor pesticide use, and high pesticide exposure time were associated with CKDu. The effects of age, female sex, TG levels more than 150 mg/dl, pesticide use (OR 1.36; 95% CI 1.01–1.84), and high exposure time (third tertile of exposure time) compared to non-users (OR 1.64; 95% CI 1.07–2.51) remained significant in multivariable analysis.
  [Alvand, S., Alatab, S., Dalvand, S., Shahraki-Sanavi, F., Kaykhaei, M.A., Shahraki, E., Barar, E., Sepanlou, S.G. and Ansari-Moghaddam, A., 2023. Plos one, 18(7), p.e0277151.]
• Human serum lipidomics analysis revealed glyphosate may lead to lipid metabolism disorders and health risks
  Glyphosate-based herbicides (GBH) are one of the most widely used pesticides worldwide. Industrial workers in glyphosate-based herbicides manufacture are the populations who experience long-term exposure to high glyphosate levels. The impacts of glyphosate on human health are the important public health problem of great concern. Up to date, the potential adverse effects of glyphosate on humans or other mammals have been reported in multiple studies. However, limited research is available on lipid alternations related to human exposure to glyphosate. In fact, the perturbations in some lipid metabolisms have been found in industrial workers in previous work. This study aims to explore the serum lipidomic characterization and to understand the underlying mechanisms of health risks associated with glyphosate exposure. A nontargeted lipidomics study was conducted to investigate the 391 serum samples from the general population and chemical factory workers. It was demonstrated that glyphosate caused significant perturbations of 115 differentially expressed lipids. The main manifestations were the elevation of circulating diacylglycerols (DG), cholesteryl esters (CE), ceramides (Cer), sphingomyelins (SM), lysophosphatidylethanolamines (LPE) and phosphatidylcholines (PC), and the decrease of ysophosphatidylcholines (LPC), triacylglycerols (TG), fatty acids (FA) and phosphatidylethanolamines (PE). A total of 88 lipids were further screened as potential lipid biomarkers associated closely with glyphosate using partial correlation analysis, and five of which (including PC 16:0/18:2; O, PC 18:0/18:2; O, PC 18:0/20:4; O, PC O-40:9 and CE 18:3) showed excellent superior performance (AUC = 1) to evaluate and monitor health risks due to glyphosate exposure. The present work discovered glyphosate-induced potential health risks, including chronic hepatic and renal dysfunction, atherosclerosis, cardiovascular disease and neurodegenerative diseases from a lipidomic perspective, and could inform the identification of early indicators and interpretation of biological mechanisms to detect health risks of the glyphosate-exposed populations as early as possible.
  [Zhang, F., Zhang, Q., Liu, X., Gao, M., Li, X., Wang, Y., Chang, Y., Zhang, X., Huo, Z., Zhang, L. and Shan, J., 2023. Environment International, 171, p.107682.]
• Pesticides and insulin resistance-related metabolic diseases: Evidences and mechanisms.
  The use of pesticides in the past century has lot helped humankind in improving crops' field and general hygiene level. Nevertheless, there has been countless evidences on the toxic effects of pesticides on the living systems. The link of exposure to pesticides with different human chronic diseases in the context of carcinogenicity, neurotoxicity, developmental toxicity, etc., have been evaluated in various types of studies. There are also some evidences on the link of exposure to pesticides with higher incidence of metabolic diseases associated with insulin resistance like diabetes, obesity, metabolic syndrome, hypertension, polycystic ovary syndrome and chronic kidney diseases. Physiologically, weakening intracellular insulin signaling is considered as a compensatory mechanism for cells to cope with cellular stresses like xenobiotic effects, oxidative stress and inflammatory responses, but it can pathologically lead to a defective cycle with lowered sensitivity of the cells to insulin which happens in metabolic disorders. In this work, the data related to metabolic toxicity of pesticides categorized in the mentioned metabolic diseases with a focus on the effects of pesticides on insulin signaling pathway and the mechanisms of development of insulin resistance will be systematically reviewed and presented.
  [Arab, A. and Mostafalou, S., 2023. Pesticide Biochemistry and Physiology, p.105521.]
• Harmful health effects of pesticides used on museum textile artifacts - overview
  The paper discusses the types of fibers contained in the museum textile artifacts and the types of pests and pesticides. Also, the main health problems associated with pesticide exposure are presented. Textile fibers represent an excellent source of food for microbes and insects. The key to the long-term preservation of textiles is by implementing an integrated management program for pest and environmental conditions control. The main types of pesticides are insecticides, herbicides, fungicides, rodenticides, acaricides, and fumigants and a way for classification can be made according to the LD50 (lethal dose) value which evaluates the toxicity of a pesticide. Depending on the LD50 values, pesticides can be very toxic, moderately toxic, slightly toxic, and relatively non-toxic. Exposure to pesticides can occur through 4 four routes: oral, dermal, respiratory, and eye exposure. The main diseases that can be associated with exposure to pesticides are discussed in the paper. In the end, a basic set of precautionary recommendations when handling museum objects that may contain hazardous materials was presented.
  [Tănăsescu, E.C. and Lite, M.C., 2022. Ecotoxicology and Environmental Safety, 247, p.114240.]
• Association of Pesticides and Kidney Function among Adults in the US Population 2001–2010
  Chronic kidney disease of unknown cause is prevalent in a range of communities; however, its etiology remains unclear. We examined the association between pesticide exposures and the risk of kidney function loss using four waves of the National Health and Nutrition Examination Survey (NHANES) to identify a pathological pathway. We pooled data from four cross-sectional waves of NHANES, with 41,847 participants in total. Exposure to malathion increased the risk of low kidney function (aOR = 1.26, 95% CI = 1.01–1.56) in the adjusted model. Increased risk of low kidney function was not found among those exposed to 2,4-D (aOR = 0.88, 95% CI = 0.72–1.09), 3,5,6-trichloropyridinol (aOR = 0.96, 95% CI = 0.83–1.12), and 3-PBA (aOR = 1.03, 95% CI = 0.94–1.13). Our findings provide evidence of altered kidney function in people exposed to malathion, highlighting the potential of organophosphate pesticides’ role in renal injury.
  [Wan, E.T., Darssan, D., Karatela, S., Reid, S. and Osborne, N. Int. J. Environ. Res. Public Health.]
• Water sources and kidney function: investigating chronic kidney disease of unknown etiology in a prospective study
  A chronic Kidney Disease of unknown etiology (CKDu) has emerged with disproportionately high prevalence across dry lowland agricultural communities globally. Here we present the results of a prospective cohort of 293 patients with CKDu in the endemic region of Wilgamuwa, Sri Lanka, in whom we measured baseline kidney function and undertook quarterly follow up over 2 years. Well water was the primary historic drinking water source in the region, although a majority (68%) of participants reported switching to reverse osmosis water during study follow ups. Participants who reported ever drinking from well water had estimated glomerular filtration rates −6.7 (SD: 2.8) ml/min/1.73 m2 lower than participants who did not drink from well water historically (p = 0.0184) during the study period. Geospatial analysis identifies a cluster within the region where CKDu progression is significantly higher than the surrounding area. Samples of household wells (n = 262) indicated 68% had detectable agrochemical compounds with concentration above global water quality standards. It is expected that the detected contaminants compounds are indicators of poor water quality and that there is likely additional agrochemical exposure including commercial additives that may contribute to CKDu onset and/or progression. Thus, our study finds that well water exposure during a person’s lifetime in this region is associated with kidney function decline and identifies and quantifies putative nephrotoxic agrochemicals above safe drinking water concentrations in these wells.
  [Vlahos, P., Schensul, S.L., Anand, S., Shipley, E., Diyabalanage, S., Hu, C., Ha, T., Staniec, A., Haider, L., Schensul, J.J. and Hewavitharane, P. npj Clean Water, 4(1), pp.1-7.]
• Cellular injury leading to oxidative stress in acute poisoning with potassium permanganate/oxalic acid, paraquat, and glyphosate surfactant herbicide
  Previous studies on human acute kidney injury (AKI) following poisoning with potassium permanganate/oxalic acid (KMnO4/H2C2O4), paraquat, and glyphosate surfactant herbicide (GPSH) have shown rapid and large increases in serum creatinine (sCr) that cannot be entirely explained by direct nephrotoxicity. One plausible mechanism for a rapid increase in sCr is oxidative stress. Thus, we aimed to explore biomarkers of oxidative stress, cellular injury, and their relationship with sCr, after acute KMnO4/H2C2O4, paraquat, and GPSH poisonings. Serum biomarkers [sCr, creatine (sCn), cystatin C (sCysC)] and urinary biomarkers [cytochrome C (CytoC), 8-isoprostane (8-IsoPs)] were evaluated in 105 patients [H2C2O4/KMnO4 (N = 57), paraquat, (N = 21), GPSH (N = 27)] recruited to a multicenter cohort study. We used area under the receiver operating characteristics curve (AUC-ROC) to quantify the extent of prediction of moderate to severe AKI (acute kidney injury network stage 2/3 (AKIN2/3)). Patients with AKIN2/3 showed increased levels of CytoC. Early high CytoC predicted AKIN2/3 in poisoning with KMnO4/H2C2O4 (AUC-ROC4-8h: 0.81), paraquat (AUC-ROC4-8h: 1.00), and GPSH (AUC-ROC4-8h: 0.91). 8-Isoprostane levels were not significantly elevated. Reduced sCn and increased sCr/sCn ratios were observed for 48 h post KMnO4/H2C2O4 ingestion. Paraquat exhibited a similar pattern (N = 11), however only 3 were included in our study. Increased CytoC suggests there is mitochondrial injury coupled with energy depletion. The increased sCr within 24 h could be due to increased conversion of cellular creatine to creatinine during the process of adenosine triphosphate (ATP) generation and then efflux from cells. Later increases of sCr are more likely to represent a true decrease in kidney function.
  [Wijerathna, T.M., Mohamed, F., Gawarammana, I.B., Wunnapuk, K., Dissanayake, D.M., Shihana, F. and Buckley, N.A., 2020. Environmental toxicology and pharmacology, 80, p.103510.]
• Chronic kidney disease and household behaviors in Sri Lanka: Historical choices of drinking water and agrochemical use
  This paper examines whether there are systematic differences in the historical behaviors of households that are affected and unaffected by chronic kidney disease (CKD) in Sri Lanka pertaining to their water source choices, water treatment practices, and agrochemical use. This analysis is motivated by the Sri Lankan government's largest policy response to this epidemic - to encourage communities to switch from untreated well water to publicly provided alternatives. We use recall methods to elicit information on the drinking water source and treatment choices of households over an 18-year period from 2000-2017. Our analysis is based on a survey of 1497 rural ground-water dependent households in the most CKD-affected areas of the 10 districts of Sri Lanka with the highest prevalence of CKD. Our main findings are that (a) households that have ever used a pump to extract (typically deep) drinking water from a household well are more likely to be affected by CKD; (b) we fail to find a relationship between disease status and households' use of buckets to extract (typically shallow) groundwater from their wells; and (c) those who have ever treated their shallow well water by boiling it are less likely to be affected by CKD. We also find that a greater share of CKD affected households historically used agrochemicals, used wells that were geographically removed from surface water sources, and displayed lower proxies of wealth. The implications of these findings are fourfold. First, since the systematic differences in the historical patterns of water sources and treatments used by CKD affected and non-affected households are modest, the sources of water and the treatment practices themselves may not be the sole risk factors in developing CKD. Second, although we find a negative association between boiling water and the probability of CKD, it is not obvious that a public policy campaign to promote boiling water is an appropriate response. Third, the hydrochemistry of deep and shallow well water needs to be better understood in order to shed light on the positive relationship between deep well water and disease status, and on why boiling shallow but not deep well water is associated with a lower probability of CKD. Fourth, there is a need for a deeper understanding of other risk factors and of the efficacy of preventative programs that provide alternative sources of household drinking water.
  [Balasubramanya, S., Stifel, D., Horbulyk, T. and Kafle, K., 2020. Economics & Human Biology, 37, p.100862.]