Ethical dimensions of clinical data sharing by US healthcare organizations for purposes beyond direct patient care: Interviews with healthcare leaders.

OBJECTIVES: Empirically investigate current practices and analyze ethical dimensions of clinical data sharing by healthcare organizations for uses other than treatment, payment, and operations. Make recommendations to inform research and policy for healthcare organizations to protect patients' privacy and autonomy when sharing data with unrelated third parties. METHODS: Semi-structured interviews and surveys involving 24 informatics leaders from 22 US healthcare organizations, accompanied by thematic and ethical analyses. RESULTS: We found considerable heterogeneity across organizations in policies and practices. Respondents understood "data sharing" and "research" in very different ways. Their interpretations of these terms ranged from making data available for academic and public health uses, and to HIEs; to selling data for corporate research, to contracting with aggregators for future resale or use. The nine interview themes were that healthcare organizations: (1) share clinical data with many types of organizations, (2) have a variety of motivations for sharing data, (3) do not make data sharing policies readily available, (4) have widely varying data sharing approval processes, (5) most commonly rely on HIPAA de-identification to protect privacy, (6) were concerned about clinical data use by electronic health record vendors, (7) lacked data sharing transparency to the general public, (8) allowed individual patients little control over sharing of their data, and (9) had not yet changed data sharing practices within the year following the US Supreme Court 2022 decision denying rights to abortion. CONCLUSIONS: Our analysis identified gaps between ethical principles and healthcare organizations' data sharing policies and practices. To better align clinical data sharing practices with patient expectations and biomedical ethical principles, we recommend: updating HIPAA, including re-identification and upstream sharing restrictions in data sharing contracts, better coordination across data sharing approval processes, fuller transparency and opt-out options for patients, and accountability for data sharing and consequent harms.

A National Simulation-Based Study of Pediatric Critical Care Transport Teams Performance.

OBJECTIVES: To assess pediatric critical care transport (CCT) teams' performance in a simulated environment and to explore the impact of team and center characteristics on performance. STUDY DESIGN: This observational, multi-center, simulation-based study enlisted a national cohort of pediatric transport centers. Teams participated in three scenarios: non-accidental abusive head injury (NAT), sepsis, and cardiac arrest. The primary outcome was teams' simulation performance score. Secondary outcomes were associations between performance, center and team characteristics. RESULTS: We recruited 78 transport teams with 196 members from 12 CCT centers. Scores on performance measures that were developed were 89% (IQR 78-100) for NAT, 63.3% (IQR 45.5-81.8) for sepsis, and 86.6% (IQR 66.6-93.3) for cardiac arrest. In multivariable analysis, overall performance was higher for teams including a respiratory therapist (RT; (0.5 points [95% CI: 0.13, 0.86]) or paramedic (0.49 points [95% CI: 0.1, 0.88]) and dedicated pediatric teams (0.37 points [95% 0.06, 0.68]). Each year increase in program age was associated with an increase of 0.04 points (95% CI: 0.02, 0.06). CONCLUSIONS: Dedicated pediatric teams, inclusion of RTs and paramedics, and center age were associated with higher simulation scores for pediatric CCT teams. These insights can guide efforts to enhance the quality of care for children during interfacility transports.

Accelerated Longitudinal Glycemic Changes in Relation to Urinary Toxic/Essential Metals and Metal Mixtures Among Mexican Americans Living in Starr County, Texas.

OBJECTIVE: Metal and metalloid exposures (hereafter "metals") are associated with adverse health outcomes, including type 2 diabetes; however, previous studies were largely cross- sectional or underpowered. Furthermore, underserved racial/ethnic groups are underrepresented in environmental health research despite having higher rates of type 2 diabetes and a greater risk of metal exposures. Consequently, we evaluated continuous glycemic traits in relation to baseline urinary toxic metal, essential metal, and metal mixtures in a cohort of Mexican American adults. RESEARCH DESIGN AND METHODS: A total of 510 participants were selected based upon self-reported diabetes status and followed over 3 years. Urinary metals were assessed at baseline. Linear mixed-effects models were used to estimate per-month changes in hemoglobin A1c, fasting plasma glucose, and postload glucose in relation to urinary metal levels. Multiple statistical approaches were used to assess the associations between glycemic traits and metal mixtures. RESULTS: After adjustment, higher urinary levels of arsenic, selenium, copper, molybdenum, nickel, and tin were associated with faster increases in measures of glycemia. The toxic metal mixture composed of arsenic, lead, cadmium, nickel, and tin was associated with faster increases in postload glucose. Using postload glucose criteria, highest versus lowest arsenic was predicted to accelerate conversion of normoglycemia to prediabetes and diabetes by 23 and 65 months, respectively. CONCLUSIONS: In this underrepresented, high-risk Mexican American population, exposure to toxic metals and alterations in essential metal homeostasis were associated with faster increases in glycemia over time that may accelerate type 2 diabetes development.

Ethical and Regulatory Perspectives on Generative Artificial Intelligence in Pathology.

CONTEXT.­: Technology companies and research groups are increasingly exploring applications of generative artificial intelligence (GenAI) in pathology and laboratory medicine. Although GenAI holds considerable promise, it also introduces novel risks for patients, communities, professionals, and the scientific process. OBJECTIVE.­: To summarize the current frameworks for the ethical development and management of GenAI within health care settings. DATA SOURCES.­: The analysis draws from scientific journals, organizational websites, and recent guidelines on artificial intelligence ethics and regulation. CONCLUSIONS.­: The literature on the ethical management of artificial intelligence in medicine is extensive but is still in its nascent stages because of the evolving nature of the technology. Effective and ethical integration of GenAI requires robust processes and shared accountability among technology vendors, health care organizations, regulatory bodies, medical professionals, and professional societies. As the technology continues to develop, a multifaceted ecosystem of safety mechanisms and ethical oversight is crucial to maximize benefits and mitigate risks.

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.

Predictors of Toxic Metal/Metalloid Exposures Among Mexican Americans in Starr County, Texas.

BACKGROUND: Arsenic, cadmium, and lead are toxic elements that widely contaminate our environment. These toxicants are associated with acute and chronic health problems, and evidence suggests that minority communities, including Hispanic/Latino Americans, are disproportionately exposed. Few studies have assessed culturally specific predictors of exposure to understand the potential drivers of racial/ethnic exposure disparities. OBJECTIVE: We sought to evaluate acculturation measures as predictors of metal/metalloid (hereafter "metal") concentrations among Mexican American adults to illuminate potential exposure sources that may be targeted for interventions. METHODS: As part of a longitudinal cohort, 510 adults, aged 35 to 69 years, underwent baseline interview, physical examination, and urine sample collection. Self-reported acculturation was assessed across various domains using the Short Acculturation Scale for Hispanics (SASH). Multivariable linear regression was used to assess associations between acculturation and urinary concentrations of arsenic, cadmium, and lead. Ordinal logistic regression was utilized to assess associations between acculturation and a metal mixture score. Lastly, best subset selection was used to build a prediction model for each toxic metal with a combination of the acculturation predictors. RESULTS: After adjustment, immigration factors were positively associated with arsenic and lead concentrations. For lead alone, English language and American media and food preferences were associated with lower levels. Immigration and parental heritage from Mexico were positively associated with the metal mixture, while preferences for English language, media, and food were negatively associated. CONCLUSION: Acculturation-related predictors of exposure provide information about potential sources of toxic metals, including international travel, foods, and consumer products. The findings in this research study provide information to empower future efforts to identify and address specific acculturation-associated toxicant exposures in order to promote health equity through clinical guidance, patient education, and public policy.

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.

Exposure to metal mixtures and telomere length in Bangladeshi children.

Telomere length is associated with chronic diseases and in younger populations, may represent a biomarker of disease susceptibility. As growing evidence suggests that environmental factors, including metals, may impact telomere length, we investigated the association between 17 metals measured in toenail samples and leukocyte relative telomere length (RTL), among 472 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort. In single exposure linear regression models, a doubling of arsenic (As) and mercury (Hg) (µg/g) were associated with a -0.21 (95%CI: -0.032, -0.010; p=0.0005) and -0.017 (95%CI: -0.029, -0.004; p=0.006) difference in RTL, respectively. In Bayesian Kernel Machine Regression (BKMR) mixture models, the overall metal mixture was inversely associated with RTL (P-for-trend <0.001). Negative associations with RTL were observed with both log2-As and log2-Hg, while an inverted U-shaped association was observed for log2-zinc (Zn) with RTL. We found little evidence of interaction among metals. Sex-stratification identified stronger associations of the overall mixture and log2-As with RTL among females, compared to males. Our study suggests that As and Hg may independently influence RTL in mid-childhood. Further studies are needed to investigate potential long-term impacts of metal-associated telomere shortening in childhood on health outcomes in adult life.

Deciduous teeth from the New Hampshire birth cohort study: Early life environmental and dietary predictors of dentin elements.

BACKGROUND: Sparse research exists on predictors of element concentrations measured in deciduous teeth. OBJECTIVE: To estimate associations between maternal/child characteristics, elements measured in home tap water during pregnancy and element concentrations in the dentin of shed deciduous teeth. METHODS: Our analysis included 152 pregnant person-infant dyads followed from the second trimester through the end of the first postnatal year from the New Hampshire Birth Cohort Study. During pregnancy and early infancy, we collected dietary and sociodemographic information via surveys, measured elements in home tap water, and later collected naturally exfoliated teeth from child participants. We measured longitudinal deposition of elements in dentin using LA-ICP-MS. Multivariable linear mixed models were used to estimate associations between predictors and dentin element concentrations. RESULTS: We measured 12 elements in dentin including those previously reported (Ba, Mn, Pb, Sr, Zn) and less frequently reported (Al, As, Cd, Cu, Hg, Li, and W). A doubling of Pb or Sr concentrations in water was associated with higher dentin Pb or Sr respectively in prenatally formed [9% (95%CI: 3%, 15%); 3% (1%, 6%)] and postnatally formed [10% (2%, 19%); 6% (2%, 10%)] dentin. Formula feeding from birth to 6 weeks or 6 weeks to 4 months was associated with higher element concentrations in postnatal dentin within the given time period as compared to exclusive human milk feeding: Sr: 6 weeks: 61% (36%, 90%) and 4 months: 85% (54%, 121%); Ba: 6 weeks: 35% (3.3%, 77%) and 4 months: 42% (10%, 83%); and Li: 6 weeks: 61% (33%, 95%) and 4 months: 58% (31%, 90%). SIGNIFICANCE: These findings offer insights into predictors of dentin elements and potential confounders in exposure-health outcome relationships during critical developmental periods.

A new mRNA structure prediction based approach to identifying improved signal peptides for bone morphogenetic protein 2.

BACKGROUND: Signal peptide (SP) engineering has proven able to improve production of many proteins yet is a laborious process that still relies on trial and error. mRNA structure around the translational start site is important in translation initiation and has rarely been considered in this context, with recent improvements in in silico mRNA structure potentially rendering it a useful predictive tool for SP selection. Here we attempt to create a method to systematically screen candidate signal peptide sequences in silico based on both their nucleotide and amino acid sequences. Several recently released computational tools were used to predict signal peptide activity (SignalP), localization target (DeepLoc) and predicted mRNA structure (MXFold2). The method was tested with Bone Morphogenetic Protein 2 (BMP2), an osteogenic growth factor used clinically for bone regeneration. It was hoped more effective BMP2 SPs could improve BMP2-based gene therapies and reduce the cost of recombinant BMP2 production. RESULTS: Amino acid sequence analysis indicated 2,611 SPs from the TGF-ß superfamily were predicted to function when attached to BMP2. mRNA structure prediction indicated structures at the translational start site were likely highly variable. The five sequences with the most accessible translational start sites, a codon optimized BMP2 SP variant and the well-established hIL2 SP sequence were taken forward to in vitro testing. The top five candidates showed non-significant improvements in BMP2 secretion in HEK293T cells. All showed reductions in secretion versus the native sequence in C2C12 cells, with several showing large and significant decreases. None of the tested sequences were able to increase alkaline phosphatase activity above background in C2C12s. The codon optimized control sequence and hIL2 SP showed reasonable activity in HEK293T but very poor activity in C2C12. CONCLUSIONS: These results support the use of peptide sequence based in silico tools for basic predictions around signal peptide activity in a synthetic biology context. However, mRNA structure prediction requires improvement before it can produce reliable predictions for this application. The poor activity of the codon optimized BMP2 SP variant in C2C12 emphasizes the importance of codon choice, mRNA structure, and cellular context for SP activity.

Fish intake and mercury exposure in young children.

Fish consumption is one of the main sources of mercury (Hg) exposure, but few studies have examined Hg exposure from fish consumption among children. This study aimed to assess the frequency of fish intake and associations with Hg and other element concentrations among 700 three-year-old children from the New Hampshire Birth Cohort Study. Usual fish intake was derived from a validated food frequency questionnaire (Block Questionnaire for ages 2-7) and toenail element concentrations were determined using ICP-MS. Multiple linear regression analysis was used to assess the association between fish intake and toenail element concentrations. A mixture analysis, using Weighted quantile sum (WQS) regression, was used to estimate the relative contribution of fish consumption to element exposures. Twenty-three percent of children were reported to consume at least one fish meal/week on average during the previous 6 months. In adjusted linear regression models, children with any type of fish consumption versus no consumption had 108% (95% confidence interval (CI: 68%, 153%)) higher toenail Hg concentrations. To a lesser extent, children consuming "other fish (not fried) including tuna" and "fried fish or fish sticks" had 120% (95% CI: 82%, 164%), and 23% (95% CI: 2%, 51%) higher toenail concentrations, respectively, than those consuming no fish. Using WQS regression, Hg was the element most strongly related to fish consumption. Fish intake among young children was related to Hg exposure even at low levels of consumption. Future studies will need to determine the health consequences of this exposure.

Associations of Perinatal Metal and Metalloid Exposures with Early Child Behavioral Development Over Time in the New Hampshire Birth Cohort Study.

Research on the neurodevelopmental effects of metal(loid)s has focused mainly on outcomes assessed at one time point, even though brain development progresses over time. We investigated biomarkers of perinatal exposure to metals and changes in child behavior over time. We followed 268 participants from the prospective New Hampshire Birth Cohort Study between birth and age 5 years. We measured arsenic (As), copper (Cu), manganese (Mn), lead (Pb), selenium (Se), and zinc (Zn) in toenails from 6-week-old infants. The Behavioral Symptoms Index (BSI), externalizing, and internalizing symptoms were assessed using the Behavior Assessment System for Children, 2nd edition (BASC-2) at ages 3 and 5 years. Multivariable linear regression was used to estimate associations of metals with behavior change, calculated as the difference in symptom raw scores between 3 and 5 years, in addition to the associations for symptom scores at 3 and 5 years separately. Sex-specific associations were also explored using stratified models and a sex-metal interaction term. Adjusted associations of metals and change in behavior varied by exposure and outcome. Each 1 µg/g increase in ln toenail Cu was associated with improved behavior between 3 and 5 years [BSI: ß = - 3.88 (95%CI: - 7.12, - 0.64); Externalizing problems: ß = - 2.20 (95%CI: - 4.07, - 0.33)]. Increasing Zn was associated with increased externalizing behavior over time (ß = 3.42 (95%CI: 0.60, 6.25). Sex-stratified analyses suggested more pronounced associations among boys compared to girls. Perinatal exposure to metals may alter behavioral development between ages 3 and 5 years. Findings support the need for more research on associations between metals and neurodevelopment over longer time periods.

Integrative Co-Registration of Elemental Imaging and Histopathology for Enhanced Spatial Multimodal Analysis of Tissue Sections through TRACE.

Summary: Elemental imaging provides detailed profiling of metal bioaccumulation, offering more precision than bulk analysis by targeting specific tissue areas. However, accurately identifying comparable tissue regions from elemental maps is challenging, requiring the integration of hematoxylin and eosin (H&E) slides for effective comparison. Facilitating the streamlined co-registration of Whole Slide Images (WSI) and elemental maps, TRACE enhances the analysis of tissue regions and elemental abundance in various pathological conditions. Through an interactive containerized web application, TRACE features real-time annotation editing, advanced statistical tools, and data export, supporting comprehensive spatial analysis. Notably, it allows for comparison of elemental abundances across annotated tissue structures and enables integration with other spatial data types through WSI co-registration. Availability and Implementation: Available on the following platforms- GitHub: jlevy44/trace_app , PyPI: trace_app , Docker: joshualevy44/trace_app , Singularity: joshualevy44/trace_app . Contact: joshua.levy@cshs.org. Supplementary information: Supplementary data are available.

Lead exposure across the life course and age at death.

BACKGROUND: Lead (Pb) exposure has been associated with an increased risk of all-cause mortality, even at low levels. Little is known about how the timing of Pb exposure throughout life may influence these relationships. Quantifying the amount of Pb present in various tissues of the body provides measurements of exposure from different periods of life. These include bone, tooth enamel, which is the hard outer layer of the crown, and tooth cementum, which is the calcified connective tissue covering the tooth root. The purpose of the study was to examine Pb exposure at multiple periods throughout life, including childhood (enamel), adulthood (cementum), and later life (bone), and to estimate their associations with age at death. METHODS: 208 skeleton donors (born 1910-1960) from an ongoing case-control study were included in this study. Pb was measured in tibia (shin), bone using X-Ray Florescence and in teeth using Laser-Ablation Inductively Coupled Plasma Mass Spectroscopy. After excluding unusually high measurements (>2sd), this resulted in a final sample of 111 with all exposure measures. Correlations across measures were determined using partial Spearman correlations. Associations between Pb exposure and age at death were estimated using Multivariable Linear Regression. RESULTS: Pb measures across exposure periods were all significantly correlated, with the highest correlation between cementum and tibia measures (r = 0.61). Donors were largely female (63.0 %), White (97.3 %), and attended some college (49.5 %). Single exposure models found that higher tooth cementum Pb (-1.27; 95 % CI: -2.48, -0.06) and tibia bone Pb (-0.91; 95 % CI: -1.67, -0.15) were significantly associated with an earlier age at death. When considered simultaneously, only cementum Pb remained significant (-1.51; 95 % CI: -2.92, -0.11). Secondary analyses suggest that the outer cementum Pb may be especially associated with an earlier age at death. CONCLUSION: Results suggest that higher Pb exposure is associated with an earlier age at death, with adulthood as the life period of most relevance. Additional studies using Pb exposure measures from different life stages should be conducted.

Urinary biomarkers of exposure to toxic and essential elements: A comparison of infants fed with human milk or formula.

Background: Early-life exposure to nonessential (toxic) and essential trace elements can influence child development. Although infant formula powders and the water used to reconstitute them can contain higher concentrations of many elements compared with human milk, the influence of feeding mode on reliable biomarkers of infant exposure has rarely been demonstrated. Methods: We evaluated associations between urinary biomarkers and feeding mode (exclusively human milk, exclusively formula, or combination-fed) for four toxic (arsenic, cadmium, nickel, and uranium) and three essential elements (cobalt, molybdenum, and selenium) using general linear models. Results: A total of 462 participants from the rural New Hampshire Birth Cohort Study were on average 6 weeks old between July 2012 and March 2019 and had urine samples, 3-day food diaries, and relevant covariate data available. In adjusted models, urinary arsenic was 5.15 (95% confidence interval = 4.04, 6.58), molybdenum was 19.02 (14.13-25.59), and selenium was 1.51 (1.35-1.68) times higher in infants fed exclusively with formula compared with infants fed exclusively with human milk. By contrast, urinary uranium was 0.59 (0.46-0.75) and cobalt was 0.78 (0.65-0.95) times lower with formula feeding than human milk feeding. Conclusion: Our findings suggest that infant exposure to several potentially toxic elements varies by feeding mode, as concentrations of reliable urinary biomarkers were higher with formula or human milk, depending on the element. Importantly, exposure to arsenic increased with household tap water arsenic regardless of feeding mode, suggesting that all infants could be at risk in populations with high concentrations of arsenic in drinking water.

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.

Quantified retrospective biomonitoring of fetal and infant elemental exposure using LA-ICP-MS analysis of deciduous dentin in three contrasting human cohorts.

BACKGROUND: Spatial elemental analysis of deciduous tooth dentin combined with odontochronological estimates can provide an early life (in utero to ~2 years of age) history of inorganic element exposure and status. OBJECTIVE: To demonstrate the importance of data normalization to a certified reference material to enable between-study comparisons, using populations with assumed contrasting elemental exposures. METHODS: We used laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) of dentin to derive a history of elemental composition from three distinct cohort studies: a present day rural cohort, (the New Hampshire Birth Cohort Study (NHBCS; N = 154)), an historical cohort from an urban area (1958-1970), (the St. Louis Baby Tooth Study (SLBT; N = 78)), and a present-day Nigerian cohort established to study maternal HIV transmission (Dental caries and its association with Oral Microbiomes and HIV in young children-Nigeria (DOMHaIN; N = 31)). RESULTS: We report Li, Al, Mn, Cu, Zn, Sr, Ba and Pb concentrations (µg/g) and qualitatively examine As, Cd and Hg across all three cohorts. Rates of detection were highest, both overall and for each cohort individually, for Zn, Sr, Ba and Li. Zinc was detected in 100% of samples and was stably present in teeth at a concentration range of 64 - 86 µg/g. Mercury, As and Cd detection rates were the lowest, and had high variability within individual ablated spots. We found the highest concentrations of Pb in the pre- and postnatal dentin of the SLBT cohort, consistent with the prevalent use of Pb as an additive to gasoline prior to 1975. The characteristic decline in Mn after the second trimester was observed in all cohorts. IMPACT: Spatially resolved elemental analysis of deciduous teeth combined with methods for estimating crown formation times can be used to reconstruct an early-life history of elemental exposure inaccessible via other biomarkers. Quantification of data into absolute values using an external standard reference material has not been conducted since 2012, preventing comparison between studies, a common and highly informative component of epidemiology. We demonstrate, with three contrasting populations, that absolute quantification produces data with the lowest variability, compares well with available data and recommends that future tooth biomarker studies report data in this way.

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.

The contributions of neonatal inhalation of copper to air pollution-induced neurodevelopmental outcomes in mice.

Exposures to ambient ultrafine particle (UFP) air pollution (AP) during the early postnatal period in mice (equivalent to human third trimester brain development) produce male-biased changes in brain structure, including ventriculomegaly, reduced brain myelination, alterations in neurotransmitters and glial activation, as well as impulsive-like behavioral characteristics, all of which are also features characteristic of male-biased neurodevelopmental disorders (NDDs). The purpose of this study was to ascertain the extent to which inhaled Cu, a common contaminant of AP that is also dysregulated across multiple NDDs, might contribute to these phenotypes. For this purpose, C57BL/6J mice were exposed from postnatal days 4-7 and 10-13 for 4 hr/day to inhaled copper oxide (CuxOy) nanoparticles at an environmentally relevant concentration averaging 171.9 ng/m3. Changes in brain metal homeostasis and neurotransmitter levels were determined following termination of exposure (postnatal day 14), while behavioral changes were assessed in adulthood. CuxOy inhalation modified cortical metal homeostasis and produced male-biased disruption of striatal neurotransmitters, with marked increases in dopaminergic function, as well as excitatory/inhibitory imbalance and reductions in serotonergic function. Impulsive-like behaviors in a fixed ratio (FR) waiting-for-reward schedule and a fixed interval (FI) schedule of food reward occurred in both sexes, but more prominently in males, effects which could not be attributed to altered locomotor activity or short-term memory. Inhaled Cu as from AP exposures, at environmentally relevant levels experienced during development, may contribute to impaired brain function, as shown by its ability to disrupt brain metal homeostasis and striatal neurotransmission. In addition, its ability to evoke impulsive-like behavior, particularly in male offspring, may be related to striatal dopaminergic dysfunction that is known to mediate such behaviors. As such, regulation of air Cu levels may be protective of public health.

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.