A Mixed Methods Approach to Understanding the Public Health Impact of a School-Based Citizen Science Program to Reduce Arsenic in Private Well Water.

BACKGROUND: Exposure to arsenic (As) in well water is a well-documented public health issue for Maine and New Hampshire, as well as for other states in the United States and abroad. Arsenic contamination of well water in these locations is primarily attributed to metasedimentary bedrock that leaches As into groundwater. However, As can also enter groundwater reserves from soils contaminated by the historical use of arsenical pesticides. Approximately half of the households in Maine and New Hampshire rely on private wells, many of which have elevated As. Arsenic exposure has been associated with an increased risk of cancer, cardiovascular disease, reduced infection resistance, and lower intelligence quotient in children. Despite these known health impacts, well water testing and treatment are not universal. OBJECTIVES: We have approached the problem of low well water testing rates in Maine and New Hampshire communities by developing the All About Arsenic (AAA) project, which engages secondary school teachers and students as citizen scientists in collecting well water samples for analysis of As and other toxic metals and supports their outreach efforts to their communities. METHODS: We assessed this project's public health impact by analyzing student data relative to existing well water quality datasets in both states. In addition, we surveyed private well owners who contributed well water samples to the project to determine the actions taken to mitigate As in well water. RESULTS: Students collected 3,070 drinking water samples for metals testing, and 752 exceeded New Hampshire's As standard of 5 ppb. The AAA data has more than doubled the amount of information available to public health agencies about well water quality in multiple municipalities across both states. Students also collected information about well types and treatment systems. Their data reveal that some homeowners did not know what type of wells they had or whether they had filtration systems. Those with filtration systems were often unaware of the type of system, what the system was filtering for, or whether the system was designed to remove As. Through interviews with pilot survey participants, we learned that some had begun mitigating their exposure to As and other toxic metals in response to test results from the AAA project. DISCUSSION: A school-based approach to collecting and analyzing private well water samples can successfully reach communities with low testing rates for toxic elements, such as As and other metals. Importantly, information generated through the program can impact household decision-making, and students can influence local and state policymaking by sharing information in their communities. https://doi.org/10.1289/EHP13421.

Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption.

SLC30A10 deficiency is a disease of severe manganese excess attributed to loss of SLC30A10-dependent manganese excretion via the gastrointestinal tract. Patients develop dystonia, cirrhosis, and polycythemia. They are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here we explore the latter observation. Intriguingly, manganese absorption is increased in Slc30a10-deficient mice despite manganese excess. Studies of multiple mouse models indicate that increased dietary manganese absorption reflects two processes: loss of manganese export from enterocytes into the gastrointestinal tract lumen by SLC30A10, and increased absorption of dietary manganese by iron transporters SLC11A2 (DMT1) and SLC40A1 (ferroportin). Our work demonstrates that aberrant absorption contributes prominently to SLC30A10 deficiency and expands our understanding of biological interactions between iron and manganese. Based on these results, we propose a reconsideration of the role of iron transporters in manganese homeostasis is warranted.

Seasonal patterns in trace elements assessed in toenails.

BACKGROUND: Seasonal patterns in measured exposure biomarkers can cause measurement error in epidemiological studies. There is little research about the seasonality of metals and trace elements when assessed in toenail samples. Adjusting for such patterns in models for estimating associations between long-term exposures and health outcomes can potentially improve precision and reduce bias. OBJECTIVES: Assess and describe seasonal patterns in toenail measurements of trace elements. METHODS: The Sister Study enrolled women residing in the US, including Puerto Rico, whose sister had been diagnosed with breast cancer. At the time of enrollment, participants removed nail polish and collected their toenail clippings, which were cleaned before analysis. We considered the following elements: iron, vanadium, aluminum, chromium, manganese, cobalt, nickel, copper, zinc, arsenic, selenium, molybdenum, cadmium, tin, antimony, mercury, and lead. For two subsamples of the cohort, we fit trigonometric regression models with toenail element measures as the outcome, using sine and cosine functions of the collection day (transformed to an angle) to capture seasonal patterns. These models can estimate the amplitude and timing of the peaks in measures. We evaluated the evidence for a seasonal effect by comparing for each measured element the trigonometric model to a model that was constant across time. RESULTS: There was a seasonal trend in toenail element concentration for iron, aluminum, vanadium, chromium, manganese, cobalt, arsenic, molybdenum, cadmium, tin, and lead, all of which peaked near mid-August. Seasonal patterns were concordant across two non-overlapping samples of women, analyzed in different labs. DISCUSSION: Given the evidence supporting seasonal patterns for 11 of the 17 elements measured in toenails, correcting for seasonality of toenail levels of those trace elements in models estimating the association between those exposures and health outcomes is important. The basis for higher concentrations in toenails collected during the summer remains unknown.

Toenail and serum levels as biomarkers of iron status in pre- and postmenopausal women: correlations and stability over eight-year follow-up.

Iron status is often assessed in epidemiologic studies, and toenails offer a convenient alternative to serum because of ease of collection, transport, and storage, and the potential to reflect a longer exposure window. Very few studies have examined the correlation between serum and toenail levels for trace metals. Our aim was to compare iron measures using serum and toenails on both a cross-sectional and longitudinal basis. Using a subset of the US-wide prospective Sister Study cohort, we compared toenail iron measures to serum concentrations for iron, ferritin and percent transferrin saturation. Among 146 women who donated both blood and toenails at baseline, a subsample (59%, n = 86) provided specimens about 8 years later. Cross-sectional analyses included nonparametric Spearman's rank correlations between toenail and serum biomarker levels. We assessed within-woman maintenance of rank across time for the toenail and serum measures and fit mixed effects models to measure change across time in relation to change in menopause status. Spearman correlations at baseline (follow-up) were 0.08 (0.09) for serum iron, 0.08 (0.07) for transferrin saturation, and - 0.09 (- 0.17) for ferritin. The within-woman Spearman correlation for toenail iron between the two time points was higher (0.47, 95% CI 0.30, 0.64) than for serum iron (0.30, 95% CI 0.09, 0.51) and transferrin saturation (0.34, 95% CI 0.15, 0.54), but lower than that for ferritin (0.58, 95% CI 0.43, 0.73). Serum ferritin increased over time while nail iron decreased over time for women who experienced menopause during the 8-years interval. Based on cross-sectional and repeated assessments, our evidence does not support an association between serum biomarkers and toenail iron levels. Toenail iron concentrations did appear to be moderately stable over time but cannot be taken as a proxy for serum iron biomarkers and they may reflect physiologically distinct fates for iron.

Periconceptional and Prenatal Exposure to Metals and Extracellular Vesicle and Particle miRNAs in Human Milk: A Pilot Study.

Human milk is a rich source of microRNAs (miRNAs), which can be transported by extracellular vesicles and particles (EVPs) and are hypothesized to contribute to maternal-offspring communication and child development. Environmental contaminant impacts on EVP miRNAs in human milk are largely unknown. In a pilot study of 54 mother-child pairs from the New Hampshire Birth Cohort Study, we examined relationships between five metals (arsenic, lead, manganese, mercury, and selenium) measured in maternal toenail clippings, reflecting exposures during the periconceptional and prenatal periods, and EVP miRNA levels in human milk. 798 miRNAs were profiled using the NanoString nCounter platform; 200 miRNAs were widely detectable and retained for downstream analyses. Metal-miRNA associations were evaluated using covariate-adjusted robust linear regression models. Arsenic exposure during the periconceptional and prenatal periods was associated with lower total miRNA content in human milk EVPs (PBonferroni < 0.05). When evaluating miRNAs individually, 13 miRNAs were inversely associated with arsenic exposure, two in the periconceptional period and 11 in the prenatal period (PBonferroni < 0.05). Other metal-miRNA associations were not statistically significant after multiple testing correction (PBonferroni ≥ 0.05). Many of the arsenic-associated miRNAs are involved in lactation and have anti-inflammatory properties in the intestine and tumor suppressive functions in breast cells. Our findings raise the possibility that periconceptional and prenatal arsenic exposure may reduce levels of multiple miRNAs in human milk EVPs. However, larger confirmatory studies, which can apply environmental mixture approaches, evaluate potential effect modifiers of these relationships, and examine possible downstream consequences for maternal and child health and breastfeeding outcomes, are needed.

Human placental microRNAs dysregulated by cadmium exposure predict neurobehavioral outcomes at birth.

BACKGROUND: Prenatal cadmium (Cd) exposure has been implicated in both placental toxicity and adverse neurobehavioral outcomes. Placental microRNAs (miRNAs) may function to developmentally program adverse pregnancy and newborn health outcomes in response to gestational Cd exposure. METHODS: In a subset of the Rhode Island Child Health Study (RICHS, n = 115) and the New Hampshire Birth Cohort Study (NHBCS, = 281), we used small RNA sequencing and trace metal analysis to identify Cd-associated expression of placental miRNAs using negative binomial generalized linear models. We predicted mRNAs targeted by Cd-associated miRNAs and relate them to neurobehavioral outcomes at birth through the integration of transcriptomic data and summary scores from the NICU Network Neurobehavioral Scale (NNNS). RESULTS: Placental Cd concentrations are significantly associated with the expression level of five placental miRNAs in NHBCS, with similar effect sizes in RICHS. These miRNA target genes overrepresented in nervous system development, and their expression is correlated with NNNS metrics suggestive of atypical neurobehavioral outcomes at birth. CONCLUSIONS: Gestational Cd exposure is associated with the expression of placental miRNAs. Predicted targets of these miRNAs are involved in nervous system development and may also regulate placental physiology, allowing their dysregulation to modify developmental programming of early life health outcomes. IMPACT: This research aims to address the poor understanding of the molecular mechanisms governing adverse pregnancy and newborn health outcomes in response to Gestational cadmium (Cd) exposure. Our results outline a robust relationship between Cd-associated placental microRNA expression and NICU Network Neurobehavioral Scales (NNNS) at birth indicative of atypical neurobehavior. This study utilized healthy mother-infant cohorts to describe the role of Cd-associated dysregulation of placental microRNAs as a potential mechanism by which adverse neurobehavioral outcomes are developmentally programmed.

Adaptive-mixture-categorization (AMC)-based g-computation and its application to trace element mixtures and bladder cancer risk.

Several new statistical methods have been developed to identify the overall impact of an exposure mixture on health outcomes. Weighted quantile sum (WQS) regression assigns the joint mixture effect weights to indicate the overall association of multiple exposures, and quantile-based g-computation is a generalized version of WQS without the restriction of directional homogeneity. This paper proposes an adaptive-mixture-categorization (AMC)-based g-computation approach that combines g-computation with an optimal exposure categorization search using the F statistic. AMC-based g-computation reduces variance within each category and retains the variance between categories to build more powerful predictors. In a simulation study, the performance of association analysis was improved using categorizing by AMC compared with quantiles. We applied this method to assess the association between a mixture of 12 trace element concentrations measured from toenails and the risk of non-muscle invasive bladder cancer. Our findings suggested that medium-level (116.7-145.5 µg/g) vs. low-level (39.5-116.2 µg/g) of toenail zinc had a statistically significant positive association with bladder cancer risk.

Molecular MRI quantification of extracellular aldehyde pairs for early detection of liver fibrogenesis and response to treatment.

Liver fibrosis plays a critical role in the evolution of most chronic liver diseases and is characterized by a buildup of extracellular matrix, which can progress to cirrhosis, hepatocellular carcinoma, liver failure, or death. Now, there are no noninvasive methods available to accurately assess disease activity (fibrogenesis) to sensitively detect early onset of fibrosis or to detect early response to treatment. Here, we hypothesized that extracellular allysine aldehyde (LysAld) pairs formed by collagen oxidation during active fibrosis could be a target for assessing fibrogenesis with a molecular probe. We showed that molecular magnetic resonance imaging (MRI) using an extracellular probe targeting these LysAld pairs acts as a noninvasive biomarker of fibrogenesis and demonstrated its high sensitivity and specificity in detecting fibrogenesis in toxin- and dietary-induced mouse models, a cholestasis rat model of liver fibrogenesis, and in human fibrotic liver tissues. Quantitative molecular MRI was highly correlated with fibrogenesis markers and enabled noninvasive detection of early onset fibrosis and response to antifibrotic treatment, showing high potential for clinical translation.

The potential involvement of inhaled iron (Fe) in the neurotoxic effects of ultrafine particulate matter air pollution exposure on brain development in mice.

BACKGROUND: Air pollution has been associated with neurodevelopmental disorders in epidemiological studies. In our studies in mice, developmental exposures to ambient ultrafine particulate (UFP) matter either postnatally or gestationally results in neurotoxic consequences that include brain metal dyshomeostasis, including significant increases in brain Fe. Since Fe is redox active and neurotoxic to brain in excess, this study examined the extent to which postnatal Fe inhalation exposure, might contribute to the observed neurotoxicity of UFPs. Mice were exposed to 1 µg/m3 Fe oxide nanoparticles alone, or in conjunction with sulfur dioxide (Fe (1 µg/m3) + SO2 (SO2 at 1.31 mg/m3, 500 ppb) from postnatal days 4-7 and 10-13 for 4 h/day. RESULTS: Overarching results included the observations that Fe + SO2 produced greater neurotoxicity than did Fe alone, that females appeared to show greater vulnerability to these exposures than did males, and that profiles of effects differed by sex. Consistent with metal dyshomeostasis, both Fe only and Fe + SO2 exposures altered correlations of Fe and of sulfur (S) with other metals in a sex and tissue-specific manner. Specifically, altered metal levels in lung, but particularly in frontal cortex were found, with reductions produced by Fe in females, but increases produced by Fe + SO2 in males. At PND14, marked changes in brain frontal cortex and striatal neurotransmitter systems were observed, particularly in response to combined Fe + SO2 as compared to Fe only, in glutamatergic and dopaminergic functions that were of opposite directions by sex. Changes in markers of trans-sulfuration in frontal cortex likewise differed in females as compared to males. Residual neurotransmitter changes were limited at PND60. Increases in serum glutathione and Il-1a were female-specific effects of combined Fe + SO2. CONCLUSIONS: Collectively, these findings suggest a role for the Fe contamination in air pollution in the observed neurotoxicity of ambient UFPs and that such involvement may be different by chemical mixture. Translation of such results to humans requires verification, and, if found, would suggest a need for regulation of Fe in air for public health protection.

Infant infections, respiratory symptoms, and allergy in relation to timing of rice cereal introduction in a United States cohort.

Rice products marketed in the USA, including baby rice cereal, contain inorganic arsenic, a putative immunotoxin. We sought to determine whether the timing of introduction of rice cereal in the first year of life influences occurrence of infections, respiratory symptoms, and allergy. Among 572 infants from the New Hampshire Birth Cohort Study, we used generalized estimating equation, adjusted for maternal smoking during pregnancy, marital status, education attainment, pre-pregnancy body mass index, maternal age at enrollment, infant birth weight, and breastfeeding history. Among 572 infants, each month earlier of introduction to rice cereal was associated with increased risks of subsequent upper respiratory tract infections (relative risk, RR = 1.04; 95% CI: 1.00-1.09); lower respiratory tract infections (RR = 1.19; 95% CI: 1.02-1.39); acute respiratory symptoms including wheeze, difficulty breathing, and cough (RR = 1.10; 95% CI: 1.00-1.22); fever requiring a prescription medicine (RR = 1.22; 95% CI: 1.02-1.45) and allergy diagnosed by a physician (RR = 1.20; 95% CI: 1.06-1.36). No clear associations were observed with gastrointestinal symptoms. Our findings suggest that introduction of rice cereal earlier may influence infants' susceptibility to respiratory infections and allergy.

Distribution and accumulation of mercury in pot-grown African rice cultivars (Oryza glaberrima Steud. and Oryza sativa L.) determined via LA-ICP-MS.

There is limited information concerning the distribution of mercury in rice, particularly in African rice. The objective was to compare the distribution of total mercury (THg) and methylmercury (MeHg) in African rice (Oryza glaberrima Steud.) and Asian rice (O. sativa L.). It is hypothesized that increased mineral accumulation and greater stress tolerance in O. glaberrima will affect the uptake and distribution of THg and MeHg, compared to O. sativa. Rice varieties from the Republic of Mali, including O. glaberrima (n =1) and O. sativa (n = 2), were cultivated in a greenhouse, in mercury-spiked soil (50 mg/kg) (n =3 replicates/variety). THg and MeHg concentrations were analyzed in the grain (brown rice), and the THg distribution was analyzed using laser ablation inductively coupled-plasma mass spectrometry (LA-ICP-MS). THg and MeHg concentrations did not differ between O. glaberrima and O. sativa grain. However, in both O. sativa varieties, THg was highly concentrated in the scutellum, which surrounds the embryo and is removed during polishing. Conversely, in O. glaberrima grain, THg was widely distributed throughout the endosperm, the edible portion of the grain. Differences in the THg distribution in O. glaberrima grain, compared to O. sativa, may elevate the risk of mercury exposure through ingestion of polished rice. The novelty of this study includes the investigation of a less-studied rice species (O. glaberrima), the use of a highly sensitive elemental imaging technique (LA-ICP-MS), and its finding of a different grain THg distribution in O. glaberrima than has been observed in O. sativa.

Human health risk from consumption of aquatic species in arsenic-contaminated shallow urban lakes.

Arsenic (As) causes cancer and non-cancer health effects in humans. Previous research revealed As concentrations over 200 µg g-1 in lake sediments in the south-central Puget Sound region affected by the former ASARCO copper smelter in Ruston, WA, and significant bioaccumulation of As in plankton in shallow lakes. Enhanced uptake occurs during summertime stratification and near-bottom anoxia when As is mobilized from sediments. Periodic mixing events in shallow lakes allow dissolved As to mix into oxygenated waters and littoral zones where biota reside. We quantify As concentrations and associated health risks in human-consumed tissues of sunfish [pumpkinseed (Lepomis gibbosus) and bluegill (Lepomis macrochirus)], crayfish [signal (Pacifastacus leniusculus) and red swamp (Procambarus clarkii)], and snails [Chinese mystery (Bellamya chinensis)] from lakes representing a gradient of As contamination and differing mixing regimes. In three shallow lakes with a range of arsenic in profundal sediments (20 to 206 µg As g-1), mean arsenic concentrations ranged from 2.9 to 46.4 µg g-1 in snails, 2.6 to 13.9 µg g-1 in crayfish, and 0.07 to 0.61 µg g-1 in sunfish. Comparatively, organisms in the deep, contaminated lake (208 µg g-1 in profundal sediments) averaged 11.8 µg g-1 in snails and 0.06 µg g-1 in sunfish. Using inorganic As concentrations, we calculated that consuming aquatic species from the most As-contaminated shallow lake resulted in 4-10 times greater health risks compared to the deep lake with the same arsenic concentrations in profundal sediments. We show that dynamics in shallow, polymictic lakes can result in greater As bioavailability compared to deeper, seasonally stratified lakes. Arsenic in oxygenated waters and littoral sediments was more indicative of exposure to aquatic species than profundal sediments, and therefore we recommend that sampling methods focus on these shallow zones to better indicate the potential for uptake into organisms and human health risk.

Toenail metal concentrations and age at menopause: A prospective study.

BACKGROUND: Menopause timing is related to cancer, cardiovascular disease, and mortality. Lead has been associated with an earlier age at menopause, but no study has considered exposure to other metals or multiple metals simultaneously. METHODS: At baseline, we measured toenail concentrations of 16 metals for 903 premenopausal women in the Sister Study (2003-2009). Age at menopause was ascertained through follow-up questionnaires. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between individual metals and age at menopause. We used quantile-g-computation to examine the association between age at menopause and the joint effect of a simultaneous increase in (1) all metals and for subgroups of metals categorized as (2) essential or (3) non-essential. RESULTS: For individual metals, we observed negligible associations except for an interquartile range increase in lead which was modestly associated with an earlier age at menopause (HR = 1.03, 95% CI = 1.01, 1.05). In the mixture analyses, a quartile increase in all metals was associated with a later age at menopause (HR = 0.81, 95% CI = 0.64, 1.02). The metals with the largest negative contributions (i.e., associated with a later age at menopause) were chromium and nickel. The joint effect for the essential metals remained inverse (HR = 0.83, 95% CI = 0.64, 1.07), but was attenuated for nonessential metals (HR = 0.98, 95% CI = 0.76, 1.24). CONCLUSIONS: Although no individual metal was strongly associated with age at menopause, our joint effect analysis suggests that having low levels of essential metals could be associated with an earlier age at menopause.

Placental lncRNA expression associated with placental cadmium concentrations and birth weight.

Heavy metal exposures, such as cadmium, can have negative effects on infant birth weight (BW)-among other developmental outcomes-with placental dysfunction potentially playing a role in these effects. In this study, we examined how differential placental expression of long non-coding RNAs (lncRNAs) may be associated with cadmium levels in placenta and whether differences in the expression of those lncRNAs were associated with fetal growth. In the Rhode Island Child Health Study, we used data from Illumina HiSeq whole transcriptome RNA sequencing (n = 199) to examine association between lncRNA expression and measures of infant BW as well as placental cadmium concentrations controlled for appropriate covariates. Of the 1191 lncRNAs sequenced, 46 demonstrated associations (q < 0.05) with BW in models controlling for infant sex, maternal age, BMI, maternal education, and smoking during pregnancy. Furthermore, four of these transcripts were associated with placental cadmium concentrations, with MIR22HG and ERVH48-1 demonstrating increases in expression associated with increasing cadmium exposure and elevated odds of small for gestational age birth, while AC114763.2 and LINC02595 demonstrated reduced expression associated with cadmium, but elevated odds of large for gestational age birth with increasing expression. We identified relationships between lncRNA expression with both placental cadmium concentrations and BW. This study provides evidence that disrupted placental expression of lncRNAs may be a part of cadmium's mechanisms of reproductive toxicity.

Keratinous biomarker of mercury exposure associated with amyotrophic lateral sclerosis risk in a nationwide U.S. study.

Objective: The majority of cases of the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) are of unknown etiology. A proportion of these cases are likely to be attributable to contaminant exposures, although the specific environmental etiology of ALS remains largely a mystery. Certain forms of the neurotoxic metal mercury readily cross into the central nervous system. Fish is a dietary source of methylmercury, but also of beneficial components, such as omega-3 polyunsaturated fatty acids. Prior work using clinic-based studies of toenails and hair as keratinous biomarkers of exposure suggest elevated mercury levels in ALS patients compared with controls. We sought to validate this relationship in a U.S. case-control comparison of mercury levels in nail clippings. Methods: We performed trace element analysis using inductively coupled plasma mass spectrometry (ICP-MS) on the nail clippings of n = 70 female, geographically representative ALS patients from the National ALS Biorepository and compared them to n = 210 age-matched controls from a set of n = 1216 nationally distributed controls from the Sister and Two Sister Studies. Results: Compared to the lowest quartile of nail mercury, moderate levels were associated with decreased risk of ALS (P = 4.18e-6). However, the odds of having nail mercury levels above the 90th percentile were 2.3-fold higher among ALS patients compared with controls (odds ratio (OR) = 2.3, 95% confidence interval 1.10-4.58, adjusted for age and smoking status). Conclusion: This finding suggests that excessive mercury exposure may be associated with the neurodegenerative health of aging populations.

Addressing K/L-edge overlap in elemental analysis from micro-X-ray fluorescence: bioimaging of tungsten and zinc in bone tissue using synchrotron radiation and laser ablation inductively coupled plasma mass spectrometry.

Synchrotron radiation micro-X-ray fluorescence (SR-µXRF) is a powerful elemental mapping technique that has been used to map tungsten and zinc distribution in bone tissue. However, the heterogeneity of the bone samples along with overlap of the tungsten L-edge with the zinc K-edge signals complicates SR-µXRF data analysis, introduces minor artefacts into the resulting element maps, and decreases image sensitivity and resolution. To confirm and more carefully delineate these SR-µXRF results, we have employed laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to untangle the problem created by the K/L-edge overlap of the tungsten/zinc pair. While the overall elemental distribution results are consistent between the two techniques, LA-ICP-MS provides significantly higher sensitivity and image resolution compared with SR-µXRF measurements in bone. These improvements reveal tissue-specific distribution patterns of tungsten and zinc in bone, not observed using SR-µXRF. We conclude that probing elemental distribution in bone is best achieved using LA-ICP-MS, though SR-µXRF retains the advantage of being a non-destructive method with the capability of being paired with X-ray techniques, which determine speciation in situ. Since tungsten is an emerging contaminant recently found to accumulate in bone, accurately determining its distribution and speciation in situ is essential for directing toxicological studies and informing treatment regimes. Graphical abstract Tungsten and zinc localization and uptake in mouse femurs were imaged by synchrotron radiation, left, and by laser ablation ICP-MS, right. The increased resolution of the LA-ICP-MS technique resolves the problem of the overlap in tungsten's L-edge and zinc's K-edge.

Maternal urinary cadmium, glucose intolerance and gestational diabetes in the New Hampshire Birth Cohort Study.

BACKGROUND: Exposure to cadmium may contribute to the risk of gestational diabetes mellitus (GDM) and glucose intolerance during pregnancy. METHODS: We examined 917 women enrolled from 2009 to 2017 in the New Hampshire Birth Cohort Study. Lifestyle, diet, demographic factors and pregnancy outcomes were collected by questionnaire and medical record review. Cadmium concentrations were measured in urine samples collected at 24-28 weeks gestation. Women were classified as normal (n = 815), glucose intolerant (n = 86), or GDM (n = 16) based on clinical data (i.e., glucose challenge test, oral glucose challenge test). We calculated odds ratios (OR) and 95% confidence intervals (CI), adjusting for potential confounders, using multinomial logistic regression to examine disease severity (normal, glucose intolerant, GDM) and logistic regression to examine the combined outcome of gestational hyperglycemia. RESULTS: Little to no association was observed for glucose intolerance (OR = 1.11, 95%CI 0.85-1.45) or GDM (OR = 0.86, 95% CI 0.51-1.44) with a doubling of urinary cadmium as compared to normal women. The combined outcome of gestational hyperglycemia yielded similar results (OR = 1.07, 95% CI 0.84-1.35). However, when stratified by pre-pregnancy body mass index (BMI), there was a slight association with the combined outcome in normal weight women (OR = 1.32, 95% CI 0.88-1.98) and no association in the overweight or obese women. This positive association remained in restricted analyses of only women with no exposure to smoking during pregnancy and those who had never smoked. CONCLUSIONS: Cadmium exposure was suggestively associated with increased risk of gestational hyperglycemia among women not already at increased risk of GDM due to being overweight or obese; however, associations of cadmium with gestational hyperglycemia were not statistically significant.

Validity of retrospective occupational exposure estimates of lead and manganese in a case-control study.

OBJECTIVES: The validity of surrogate measures of retrospective occupational exposure in population-based epidemiological studies has rarely been evaluated. Using toenail samples as bioindicators of exposure, we assessed whether work tasks and expert assessments of occupational metal exposure obtained from personal interviews were associated with lead and manganese concentrations. METHODS: We selected 609 controls from a case-control study of bladder cancer in New England who had held a job for ≥1 year 8-24 months prior to toenail collection. We evaluated associations between toenail metal concentrations and five tasks extracted from occupational questionnaires (grinding, painting, soldering, welding, working near engines) using linear regression models. For 139 subjects, we also evaluated associations between the toenail concentrations and exposure estimates from three experts. RESULTS: We observed a 1.9-fold increase (95% CI 1.4 to 2.5) in toenail lead concentrations with painting and 1.4-fold increase (95% CI 1.1 to 1.7) in manganese concentrations with working around engines and handling fuel. We observed significant trends with increasing frequency of both activities. For lead, significant trends were observed with the ratings from all three experts. Their average ratings showed the strongest association, with subjects rated as possibly or probably exposed to lead having concentrations that were 2.0 and 2.5 times higher, respectively, than in unexposed subjects (ptrend <0.001). Expert estimates were only weakly associated with manganese toenail concentrations. CONCLUSIONS: Our findings support the ability of experts to identify broad contrasts in previous occupational exposure to lead. The stronger associations with task frequency and expert assessments support using refined exposure characterisation whenever possible.

Placental Expression of Imprinted Genes, Overall and in Sex-Specific Patterns, Associated with Placental Cadmium Concentrations and Birth Size.

BACKGROUND: Prenatal cadmium (Cd) exposure has been recognized to restrict growth, and male and female fetuses may have differential susceptibility to the developmental toxicity of Cd. Imprinted genes, which exhibit monoallelic expression based on parent of origin, are highly expressed in placental tissues. The function of these genes is particularly critical to fetal growth and development, and some are expressed in sex-specific patterns. OBJECTIVES: We aimed to examine whether prenatal Cd associates with the expression of imprinted placental genes, overall or in fetal sex-specific patterns, across two independent epidemiologic studies. METHODS: We tested for Cd­sex interactions in association with gene expression, then regressed the placental expression levels of 74 putative imprinted genes on placental log-Cd concentrations while adjusting for maternal age, sex, smoking history, and educational attainment. These models were performed within study- and sex-specific strata in the New Hampshire Birth Cohort Study (NHBCS; [Formula: see text]) and the Rhode Island Child Health Study (RICHS; [Formula: see text]). We then used fixed-effects models to estimate the sex-specific and overall associations across strata and then examine heterogeneity in the associations by fetal sex. RESULTS: We observed that higher Cd concentrations were associated with higher expression of distal-less homeobox 5 (DLX5) ([Formula: see text]), and lower expression of h19 imprinted maternally expressed transcript (H19) ([Formula: see text]) and necdin, MAGE family member (NDN) ([Formula: see text]) across study and sex-specific strata, while three other genes [carboxypeptidase A4 (CPA4), growth factor receptor bound protein 10 (GRB10), and integrin-linked kinase (ILK)] were significantly associated with Cd concentrations, but only among female placenta ([Formula: see text]). Additionally, the expression of DLX5, H19, and NDN, the most statistically significant Cd-associated genes, were also associated with standardized birth weight z-scores. DISCUSSION: The differential regulation of a set of imprinted genes, particularly DLX5, H19, and NDN, in association with prenatal Cd exposure may be involved in overall developmental toxicity, and some imprinted genes may respond to Cd exposure in a manner that is specific to infant gender. https://doi.org/10.1289/EHP4264.

Toenail-Based Metal Concentrations and Young-Onset Breast Cancer.

Several metals have carcinogenic properties, but their associations with breast cancer are not established. We studied cadmium, a metalloestrogen, and 9 other metals-arsenic, cobalt, chromium, copper, mercury, molybdenum, lead, tin, and vanadium--in relation to young-onset breast cancer (diagnosis age <50 years), which tends to be more aggressive than and have a different risk profile from later-onset disease. Recent metal exposure was measured by assessing element concentrations, via inductively coupled plasma mass spectrometry, in toenail clippings of 1,217 disease-discordant sister pairs in the US-based Sister (2003-2009) and Two Sister (2008-2010) studies. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. After correcting for differential calendar time of sample collection, no statistically significant associations were observed between any metals and breast cancer. Vanadium had the largest odds ratio (for fourth vs. first quartile, odds ratio = 1.36, 95% confidence interval: 0.84, 2.21; P for trend = 0.17). Cadmium was associated with a small increase in risk, with no evidence of a dose-response relationship (for fourth vs. first quartile, odds ratio = 1.15, 95% confidence interval: 0.82, 1.60; P for trend = 0.67). Positive associations between urinary cadmium concentrations and breast cancer have been reported in case-control studies, but we observed no such association between young-onset breast cancer and toenail concentrations of any assessed metals.