Abatacept Decreases Renal T-cell Infiltration and Renal Inflammation and Ameliorates Progressive Renal Injury in Obese Dahl Salt-sensitive Rats Before Puberty.

ABSTRACT: Prepubertal obesity is growing at an alarming rate and is now considered a risk factor for renal injury. Recently, we reported that the early development of renal injury in obese Dahl salt-sensitive (SS) leptin receptor mutant (SS LepR mutant) rats was associated with increased T-cell infiltration and activation before puberty. Therefore, the current study investigated the effect of inhibiting T-cell activation with abatacept on the progression of renal injury in young obese SS LepR mutant rats before puberty. Four-week-old SS and SS LepR mutant rats were treated with IgG or abatacept (1 mg/kg; ip, every other day) for 4 weeks. Abatacept reduced the renal infiltration of T cells by almost 50% in SS LepR mutant rats. Treatment with abatacept decreased the renal expression of macrophage inflammatory protein-3 alpha while increasing IL-4 in SS LepR mutant rats without affecting SS rats. While not having an impact on blood glucose levels, abatacept reduced hyperinsulinemia and plasma triglycerides in SS LepR mutant rats without affecting SS rats. We did not observe any differences in the mean arterial pressure among the groups. Proteinuria was markedly higher in SS LepR mutant rats than in SS rats throughout the study, and treatment with abatacept decreased proteinuria by about 40% in SS LepR mutant rats without affecting SS rats. We observed significant increases in glomerular and tubular injury and renal fibrosis in SS LepR mutant rats versus SS rats, and chronic treatment with abatacept significantly reduced these renal abnormalities in SS LepR mutant rats. These data suggest that renal T-cell activation contributes to the early progression of renal injury associated with prepubertal obesity.

Predicting Redox Conditions in Groundwater at a National Scale Using Random Forest Classification.

Redox conditions in groundwater may markedly affect the fate and transport of nutrients, volatile organic compounds, and trace metals, with significant implications for human health. While many local assessments of redox conditions have been made, the spatial variability of redox reaction rates makes the determination of redox conditions at regional or national scales problematic. In this study, redox conditions in groundwater were predicted for the contiguous United States using random forest classification by relating measured water quality data from over 30,000 wells to natural and anthropogenic factors. The model correctly predicted the oxic/suboxic classification for 78 and 79% of the samples in the out-of-bag and hold-out data sets, respectively. Variables describing geology, hydrology, soil properties, and hydrologic position were among the most important factors affecting the likelihood of oxic conditions in groundwater. Important model variables tended to relate to aquifer recharge, groundwater travel time, or prevalence of electron donors, which are key drivers of redox conditions in groundwater. Partial dependence plots suggested that the likelihood of oxic conditions in groundwater decreased sharply as streams were approached and gradually as the depth below the water table increased. The probability of oxic groundwater increased as base flow index values increased, likely due to the prevalence of well-drained soils and geologic materials in high base flow index areas. The likelihood of oxic conditions increased as topographic wetness index (TWI) values decreased. High topographic wetness index values occur in areas with a propensity for standing water and overland flow, conditions that limit the delivery of dissolved oxygen to groundwater by recharge; higher TWI values also tend to occur in discharge areas, which may contain groundwater with long travel times. A second model was developed to predict the probability of elevated manganese (Mn) concentrations in groundwater (i.e., ≥50 µg/L). The Mn model relied on many of the same variables as the oxic/suboxic model and may be used to identify areas where Mn-reducing conditions occur and where there is an increased risk to domestic water supplies due to high Mn concentrations. Model predictions of redox conditions in groundwater produced in this study may help identify regions of the country with elevated groundwater vulnerability and stream vulnerability to groundwater-derived contaminants.

Metformin reduces insulin resistance and attenuates progressive renal injury in prepubertal obese Dahl salt-sensitive rats.

Prepubertal obesity is currently an epidemic and is considered as a major risk factor for renal injury. Previous studies have demonstrated that insulin resistance contributes to renal injury in obesity, independent of diabetes. However, studies examining the relationship between insulin resistance and renal injury in obese children are lacking. Recently, we reported that progressive renal injury in Dahl salt-sensitive (SS) leptin receptor mutant (SSLepRmutant) rats was associated with insulin resistance before puberty. Therefore, the aim of the present study was to examine whether decreasing insulin resistance with metformin will reduce renal injury in SSLepRmutant rats. Four-wk-old SS and SSLepRmutant rats were separated into the following two groups: 1) vehicle and 2) metformin (300 mg/kg/day) via chow diet for 4 wk. Chronic administration of metformin markedly reduced insulin resistance and dyslipidemia in SSLepRmutant rats. We did not detect any differences in mean arterial pressure between vehicle and metformin-treated SS and SSLepRmutant rats. Proteinuria was significantly greater in SSLepRmutant rats versus SS rats throughout the study, and metformin administration significantly reduced proteinuria in SSLepRmutant rats. At the end of the protocol, metformin prevented the renal hyperfiltration observed in SSLepRmutant rats versus SS rats. Glomerular and tubular injury and renal inflammation and fibrosis were significantly higher in vehicle-treated SSLepRmutant rats versus SS rats, and metformin reduced these parameters in SSLepRmutant rats. These data suggest that reducing insulin resistance with metformin prevents renal hyperfiltration and progressive renal injury in SSLepRmutant rats before puberty and may be therapeutically useful in managing renal injury during prepubertal obesity.NEW & NOTEWORTHY Childhood/prepubertal obesity is a public health concern that is associated with early signs of proteinuria. Insulin resistance has been described in obese children. However, studies investigating the role of insulin resistance during childhood obesity-associated renal injury are limited. This study provides evidence of an early relationship between insulin resistance and renal injury in a rat model of prepubertal obesity. These data also suggest that reducing insulin resistance with metformin may be renoprotective in obese children.

Perfluoroalkyl and Polyfluoroalkyl Substances in Groundwater Used as a Source of Drinking Water in the Eastern United States.

In 2019, 254 samples were collected from five aquifer systems to evaluate perfluoroalkyl and polyfluoroalkyl substance (PFAS) occurrence in groundwater used as a source of drinking water in the eastern United States. The samples were analyzed for 24 PFAS, major ions, nutrients, trace elements, dissolved organic carbon (DOC), volatile organic compounds (VOCs), pharmaceuticals, and tritium. Fourteen of the 24 PFAS were detected in groundwater, with 60 and 20% of public-supply and domestic wells, respectively, containing at least one PFAS detection. Concentrations of tritium, chloride, sulfate, DOC, and manganese + iron; percent urban land use within 500 m of the wells; and VOC and pharmaceutical detection frequencies were significantly higher in samples containing PFAS detections than in samples with no detections. Boosted regression tree models that consider 57 chemical and land-use variables show that tritium concentration, distance to the nearest fire-training area, percentage of urban land use, and DOC and VOC concentrations are the top five predictors of PFAS detections, consistent with the hydrologic position, geochemistry, and land use being important controls on PFAS occurrence in groundwater. Model results indicate that it may be possible to predict PFAS detections in groundwater using existing data sources.

Populations using public-supply groundwater in the conterminous U.S. 2010; Identifying the wells, hydrogeologic regions, and hydrogeologic mapping units.

Most Americans receive their drinking water from publicly supplied sources, a large portion of it from groundwater. Mapping these populations consistently and at a high resolution is important for understanding where the resource is used and needs to be protected. The results show that 269 million people are supplied by public supply, 107 million are supplied by groundwater and 162 million are supplied by surface water. The population using public supply drinking water was mapped in two ways: the census enhanced method (CEM) evenly distributes the population across populated census blocks, and the urban land-use enhanced method (ULUEM) distributes the population only to certain urban land use designations. In addition, a two-dimensional polygon dataset was created for the conterminous U.S. that identifies 177 unique Hydrogeologic Mapping Units (HMUs) with similar hydrogeologic characteristics. The HMUs do not overlap, but they can delineate areas where stacked hydrogeologic regions (HRs) contribute drinking water from below the surface. HRs are waterbearing geologic regions identified as either a principal aquifers (PA) or secondary hydrogeologic regions (SHR). Within each HMU, the wells were used to determine the proportion of each HR that is providing groundwater to the HMU. In 63% of the HMUs, a single HR is providing water to the public supply wells located within it, while the rest of the HMUs show that the wells are tapping up to a maximum of four stacked HRs. In total, groundwater from 108 HRs provide drinking water for public supply, six of which provide more than 50% of the groundwater used for public supply drinking water. The aquifer serving the largest number of equivalent people (>17 million) is the glacial aquifer. The HR providing the greatest number of people per km2 is the Biscayne aquifer in Florida at nearly 453 people per km2.

Interferon γ neutralization reduces blood pressure, uterine artery resistance index, and placental oxidative stress in placental ischemic rats.

Preeclampsia (PE) is characterized by maternal hypertension, intrauterine growth restriction, and increased cytolytic natural killer cells (cNKs), which secrete interferon γ (IFNγ). However, the precise role of IFNγ in contributing to PE pathophysiology remains unclear. Using the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia, we tested the hypothesis that neutralization of IFNγ in RUPPs will decrease placental reactive oxygen species (ROS) and improve vascular function resulting in decreased MAP and improved fetal growth. On gestation day (GD) 14, the RUPP procedure was performed and on GDs 15 and 18, a subset of normal pregnant rats (NP) and RUPP rats were injected with 10 µg/kg of an anti-rat IFNγ monoclonal antibody. On GD 18, uterine artery resistance index (UARI) was measured via Doppler ultrasound and on GD 19, mean arterial pressure (MAP) was measured, animals were euthanized, and blood and tissues were collected for analysis. Increased MAP was observed in RUPP rats compared with NP and was reduced in RUPP + anti-IFNγ. Placental ROS was also increased in RUPP rats compared with NP rats and was normalized in RUPP + anti-IFNγ. Fetal and placental weights were reduced in RUPP rats, but were not improved following anti-IFNγ treatment. However, UARI was elevated in RUPP compared with NP rats and was reduced in RUPP + anti-IFNγ. In conclusion, we observed that IFNγ neutralization reduced MAP, UARI, and placental ROS in RUPP recipients. These data suggest that IFNγ is a potential mechanism by which cNKs contribute to PE pathophysiology and may represent a therapeutic target to improve maternal outcomes in PE.

Status and trends of orthophosphate concentrations in groundwater used for public supply in California.

Phosphorus is a necessary nutrient for all organisms. However excessive phosphorus can cause eutrophication in surface water. Groundwater can be an important nonpoint contributor of phosphorus to surface water bodies. Most groundwater phosphorus is in the form of orthophosphate and orthophosphate concentrations in California groundwater vary temporally and geographically. This study quantifies orthophosphate concentrations in water samples from public supply wells in California, evaluates temporal trends (both step and monotonic trends) in orthophosphate concentration for different areas of the state, and explores potential explanatory factors for the trends observed. Orthophosphate concentrations are low in 42 percent of the groundwater used for public supply in California, moderate in 43 percent, and high in 15 percent of this groundwater relative to reference conditions and a goal expressed by the USEPA for streams overlying the aquifers. The findings also suggest that orthophosphate concentrations increased in approximately one-third of this groundwater during the study period (2000 to 2018). The timing of orthophosphate increases observed in time-series evaluations coincided approximately with the timing of increases observed in step-trend evaluations, with both suggesting that the increasing trend occurred mostly before 2011. Principal component analysis (PCA) of the statewide dataset indicates that orthophosphate concentrations are antithetically related to dissolved oxygen (DO), and weakly associated with boron, arsenic, and fluoride. Step trend and time-series trend analyses using PCA were inconclusive.

Fluoride occurrence in United States groundwater.

Data from 38,105 wells were used to characterize fluoride (F) occurrence in untreated United States (U.S.) groundwater. For domestic wells (n = 11,032), water from which is generally not purposely fluoridated or monitored for quality, 10.9% of the samples have F concentrations >0.7 mg/L (U.S. Public Health Service recommended optimal F concentration in drinking water for preventing tooth decay) (87% are <0.7 mg/L); 2.6% have F > 2 mg/L (EPA Secondary Maximum Contaminant Level, SMCL); and 0.6% have F > 4 mg/L (EPA MCL). The data indicate the biggest concern with F in domestic wells at the national scale could be one of under consumption of F with respect to the oral-health benchmark (0.7 mg/L). Elevated F concentrations relative to the SMCL and MCL are regionally important, particularly in the western U.S. Statistical comparisons of potentially important controlling factors in four F-concentration categories (<0.1-0.7 mg/L; >0.7-2 mg/L; >2-4 mg/L; >4 mg/L) at the national scale indicate the highest F-concentration category is associated with groundwater that has significantly greater pH values, TDS and alkalinity concentrations, and well depths, and lower Ca/Na ratios and mean annual precipitation, than the lowest F-concentration category. The relative importance of the controlling factors appears to be regionally variable. Three case studies illustrate the spatial variability in controlling factors using groundwater-age (groundwater residence time), water-isotope (evaporative concentration), and water-temperature (geothermal processes) data. Populations potentially served by domestic wells with F concentrations <0.7, >0.7, >2, and >4 mg/L are estimated to be ~28,200,000, ~3,110,000; ~522,000; and ~172,000 people, respectively, in 40 principal aquifers with at least 25 F analyses per aquifer.

Estimating domestic well locations and populations served in the contiguous U.S. for years 2000 and 2010.

Domestic wells provide drinking water supply for approximately 40 million people in the United States. Knowing the location of these wells, and the populations they serve, is important for identifying heavily used aquifers, locations susceptible to contamination, and populations potentially impacted by poor-quality groundwater. The 1990 census was the last nationally consistent survey of a home's source of water, and has not been surveyed since. This paper presents a method for projecting the population dependent on domestic wells for years after 1990, using information from the 1990 census along with population data from subsequent censuses. The method is based on the "domestic ratio" at the census block-group level, defined here as the number of households dependent on domestic wells divided by the total population. Analysis of 1990 data (>220,000 block-groups) indicates that the domestic ratio is a function of the household density. As household density increases, the domestic ratio decreases, once a household density threshold is met. The 1990 data were used to develop a relationship between household density and the domestic ratio. The fitted model, along with household density data from 2000 and 2010, was used to estimate domestic ratios for each decadal year. In turn, the number of households dependent on domestic wells was estimated at the block-group level for 2000 and 2010. High-resolution census-block population data were used to refine the spatial distribution of domestic-well usage and to convert the data into population numbers. The results are presented in two downloadable raster datasets for each decadal year. It is estimated that the total population using domestic-well water in the contiguous U.S. increased 1.5% from 1990 to 2000 to a total of 37.25 million people and increased slightly from 2000 to 2010 to 37.29 million people.

Secondary Hydrogeologic Regions of the Conterminous United States.

The U.S. Geological Survey (USGS) previously identified and mapped 62 Principal Aquifers (PAs) in the U.S., with 57 located in the conterminous states. Areas outside of PAs, which account for about 40% of the conterminous U.S., were collectively identified as "other rocks." This paper, for the first time, subdivides this large area into internally-consistent features, defined here as Secondary Hydrogeologic Regions (SHRs). SHRs are areas of other rock within which the rocks or deposits are of comparable age, lithology, geologic or physiographic setting, and relationship to the presence or absence of underling PAs or overlying glacial deposits. A total of 69 SHRs were identified. The number and size of SHRs identified in this paper are comparable to the number and size of PAs previously identified by the USGS. From a two-dimensional perspective, SHRs are complementary to PAs, mapped only where the PAs were not identified on the USGS PA map and not mapped where the PAs were identified. SHRs generally consist of low permeability rocks or deposits, but can include locally productive aquifers. The two maps, taken together, provide a comprehensive, national-scale hydrogeologic framework for assessing and understanding groundwater systems.

Elevated Manganese Concentrations in United States Groundwater, Role of Land Surface-Soil-Aquifer Connections.

Chemical data from 43 334 wells were used to examine the role of land surface-soil-aquifer connections in producing elevated manganese concentrations (>300 µg/L) in United States (U.S.) groundwater. Elevated concentrations of manganese and dissolved organic carbon (DOC) in groundwater are associated with shallow, anoxic water tables and soils enriched in organic carbon, suggesting soil-derived DOC supports manganese reduction and mobilization in shallow groundwater. Manganese and DOC concentrations are higher near rivers than farther from rivers, suggesting river-derived DOC also supports manganese mobilization. Anthropogenic nitrogen may also affect manganese concentrations in groundwater. In parts of the northeastern U.S. containing poorly buffered soils, ∼40% of the samples with elevated manganese concentrations have pH values < 6 and elevated concentrations of nitrate relative to samples with pH ≥ 6, suggesting acidic recharge produced by the oxidation of ammonium in fertilizer helps mobilize manganese. An estimated 2.6 million people potentially consume groundwater with elevated manganese concentrations, the highest densities of which occur near rivers and in areas with organic carbon rich soil. Results from this study indicate land surface-soil-aquifer connections play an important role in producing elevated manganese concentrations in groundwater used for human consumption.

Domestic well locations and populations served in the contiguous U.S.: 1990.

We estimate the location and population served by domestic wells in the contiguous United States in two ways: (1) the "Block Group Method" or BGM, uses data from the 1990 census, and (2) the "Road-Enhanced Method" or REM, refines the locations by using a buffer expansion and shrinkage technique along roadways to define areas where domestic wells exist. The fundamental assumption is that houses (and therefore domestic wells) are located near a named road. The results are presented as two nationally-consistent domestic-well population datasets. While both methods can be considered valid, the REM map is more precise in locating domestic wells; the REM map has a smaller amount of spatial bias (Type 1 and Type 2 errors nearly equal vs biased in Type 1), total error (10.9% vs 23.7%), and distance error (2.0km vs 2.7km), when comparing the REM and BGM maps to a calibration map in California. However, the BGM map is more inclusive of all potential locations for domestic wells. Independent domestic well datasets from the USGS, and the States of MN, NV, and TX show that the BGM captures about 5 to 10% more wells than the REM. One key difference between the BGM and the REM is the mapping of low density areas. The REM reduces areas mapped as low density by 57%, concentrating populations into denser regions. Therefore, if one is trying to capture all of the potential areas of domestic-well usage, then the BGM map may be more applicable. If location is more imperative, then the REM map is better at identifying areas of the landscape with the highest probability of finding a domestic well. Depending on the purpose of a study, a combination of both maps can be used.

Metrics for Assessing the Quality of Groundwater Used for Public Supply, CA, USA: Equivalent-Population and Area.

Data from 11,000 public supply wells in 87 study areas were used to assess the quality of nearly all of the groundwater used for public supply in California. Two metrics were developed for quantifying groundwater quality: area with high concentrations (km(2) or proportion) and equivalent-population relying upon groundwater with high concentrations (number of people or proportion). Concentrations are considered high if they are above a human-health benchmark. When expressed as proportions, the metrics are area-weighted and population-weighted detection frequencies. On a statewide-scale, about 20% of the groundwater used for public supply has high concentrations for one or more constituents (23% by area and 18% by equivalent-population). On the basis of both area and equivalent-population, trace elements are more prevalent at high concentrations than either nitrate or organic compounds at the statewide-scale, in eight of nine hydrogeologic provinces, and in about three-quarters of the study areas. At a statewide-scale, nitrate is more prevalent than organic compounds based on area, but not on the basis of equivalent-population. The approach developed for this paper, unlike many studies, recognizes the importance of appropriately weighting information when changing scales, and is broadly applicable to other areas.