Time-specific impact of trace metals on breast density of adolescent girls in Santiago, Chile.

Whether trace metals modify breast density, the strongest predictor for breast cancer, during critical developmental stages such as puberty remains understudied. Our study prospectively evaluated the association between trace metals at Tanner breast stage B1 (n = 291) and at stages both B1 and B4 (n = 253) and breast density at 2 years post-menarche among Chilean girls from the Growth and Obesity Cohort Study. Dual-energy x-ray absorptiometry assessed the volume of dense breast tissue (absolute fibroglandular volume [FGV]) and percent breast density (%FGV). Urine trace metals included arsenic, barium, cadmium, cobalt, cesium, copper, magnesium, manganese, molybdenum, nickel, lead, antimony, selenium, tin, thallium, vanadium, and zinc. At B1, a doubling of thallium concentration resulted in 13.69 cm3 increase in absolute FGV (ß: 13.69, 95% confidence interval [CI]: 2.81, 24.52), while a doubling of lead concentration resulted in a 7.76 cm3 decrease in absolute FGV (ß: -7.76, 95%CI: -14.71, -0.73). At B4, a doubling of barium concentration was associated with a 10.06 cm3 increase (ß: 10.06, 95% CI: 1.44, 18.60), copper concentration with a 12.29 cm3 increase (ß: 12.29, 95% CI: 2.78, 21.56), lead concentration with a 9.86 cm3 increase (ß: 9.86, 95% CI: 0.73, 18.98), antimony concentration with a 12.97 cm3 increase (ß: 12.97, 95% CI: 1.98, 23.79) and vanadium concentration with a 13.14 cm3 increase in absolute FGV (ß: 13.14, 95% CI: 2.73, 23.58). Trace metals may affect pubertal breast density at varying developmental stages with implications for increased susceptibility for breast cancer.

Sex-specific association between prenatal manganese exposure and working memory in school-aged children in Mexico city: An exploratory multi-media approach.

It remains unclear whether manganese (Mn) exposure affects working memory (WM) in a sexually dimorphic manner. Further, no gold standard media exists to measure Mn, suggesting a combined blood and urinary Mn index may better capture the totality of exposure. We investigated the modification effect of child sex on the influence of prenatal Mn exposure on WM in school-age children, exploring two methodological frameworks to integrate exposure estimates across multiple exposure biomarkers. Leveraging the PROGRESS birth cohort in Mexico City, children (N = 559) ages 6-8 completed the between errors and strategy measures of the CANTAB Spatial Working Memory (SWM) task. Mn levels were assayed in blood and urine of mothers during the 2nd and 3rd trimesters and in umbilical cord blood from mothers and children at delivery. Weighted quantile sum regression estimated the association of a multi-media biomarker (MMB) mixture with SWM. We applied a confirmatory factor analysis to similarly quantify a latent blood Mn burden index. We then used an adjusted linear regression to estimate the Mn burden index with SWM measures. Interaction terms were used to estimate the modification effect by child sex for all models. Results showed that the between-errors-specific MMB mixture (i.e., this model demonstrates the impact of the MMB mixture on the between-error scores.) was associated (ß = 6.50, 95% CI: 0.91, 12.08) with fewer between errors for boys and more between errors for girls. The strategy-specific MMB mixture (i.e., this model demonstrates the impact of the MMB mixture on the strategy scores) was associated (ß = -1.36, 95% CI: 2.55, - 0.18) with less efficient strategy performance for boys and more efficient strategy performance for girls. A higher Mn burden index was associated (ß = 0.86, 95% CI: 0.00, 1.72) with more between errors in the overall sample. The vulnerability to prenatal Mn biomarkers on SWM differs in the directionality by child sex. An MMB mixture and composite index of body burden are stronger predictors than a single biomarker for Mn exposure on WM performance.

Epigenome-wide DNA methylation in leukocytes and toenail metals: The normative aging study.

BACKGROUND: Environmental metal exposures have been associated with multiple deleterious health endpoints. DNA methylation (DNAm) may provide insight into the mechanisms underlying these relationships. Toenail metals are non-invasive biomarkers, reflecting a medium-term time exposure window. OBJECTIVES: This study examined variation in leukocyte DNAm and toenail arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg) among elderly men in the Normative Aging Study, a longitudinal cohort. METHODS: We repeatedly collected samples of blood and toenail clippings. We measured DNAm in leukocytes with the Illumina HumanMethylation450 K BeadChip. We first performed median regression to evaluate the effects of each individual toenail metal on DNAm at three levels: individual cytosine-phosphate-guanine (CpG) sites, regions, and pathways. Then, we applied a Bayesian kernel machine regression (BKMR) to assess the joint and individual effects of metal mixtures on DNAm. Significant CpGs were identified using a multiple testing correction based on the independent degrees of freedom approach for correlated outcomes. The approach considers the effective degrees of freedom in the DNAm data using the principal components that explain >95% variation of the data. RESULTS: We included 564 subjects (754 visits) between 1999 and 2013. The numbers of significantly differentially methylated CpG sites, regions, and pathways varied by metals. For example, we found six significant pathways for As, three for Cd, and one for Mn. The As-associated pathways were associated with cancer (e.g., skin cancer) and cardiovascular disease, whereas the Cd-associated pathways were related to lung cancer. Metal mixtures were also associated with 47 significant CpG sites, as well as pathways, mainly related to cancer and cardiovascular disease. CONCLUSIONS: This study provides an approach to understanding the potential epigenetic mechanisms underlying observed relations between toenail metals and adverse health endpoints.

Prenatal Metal Exposures and Associations with Kidney Injury Biomarkers in Children.

Prenatal exposure to arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) may be nephrotoxic, yet limited studies have examined subclinical kidney injury biomarkers in children. We assessed whether metal exposure in the second trimester (2T), a crucial time of kidney development, is associated with altered urine kidney injury and function biomarkers in preadolescent children. Analyses included 494 children participating in a birth cohort study in Mexico City. Concentrations of As, Cd, and Pb were measured from pregnant women in 2T blood and urine, and Hg in urine only. Kidney biomarkers were measured from children in urine at age 8-12 years. We assessed the associations between individual metals and (1) kidney biomarkers using linear regression and (2) a multi-protein kidney mixture using weighted quantile sum (WQS) regression. Associations of separate urine and blood metal mixtures with individual kidney biomarkers were assessed via WQS. Within the multi-protein mixture, the association with increased urinary As was predominated by urine alpha-1-microglobulin (A1M), interferon gamma-induced protein 10 (IP10), and fatty acid binding protein 1; the association with increased urinary Cd was predominated by A1M, clusterin, and albumin. The urine metal mixture was associated with increased albumin (0.23 ng/mL; 95% confidence interval (CI): 0.10, 0.37), IP10 (0.15 ng/mL; 95% CI: 0.02, 0.28), and cystatin C (0.17 ng/mL; 95% CI: 0.04, 0.31); these associations were mainly driven by urinary As and Cd. We observed null associations between prenatal blood or urine metal mixtures and estimated glomerular filtration rate. Higher prenatal urinary metals, individually and as a mixture were associated with altered kidney injury biomarkers in children. Further research and longer participant follow-up are required to ascertain the risk of kidney disease later in life.

Biomarkers of maternal lead exposure during pregnancy using micro-spatial child deciduous dentine measurements.

BACKGROUND: Lead is a toxic chemical of public health concern, however limited biomarkers are able to reconstruct prior lead exposures in early-life when biospecimens are not collected and stored. Although child tooth dentine measurements accurately assess past child perinatal lead exposure, it has not been established if they reflect maternal exposure in pregnancy. AIM: To assess the prenatal relationship between child tooth dentine and maternal blood lead measurements and to estimate maternal lead exposure during the 2nd and 3rd trimesters of pregnancy from weekly child dentine profiles. METHODS: We measured early-life lead exposure in child tooth dentine and maternal blood from 419 child-mother dyads enrolled in the Programming Research in Obesity, Growth, Environment and Social Stress (PROGRESS) cohort. We employed the Super-Learner algorithm to determine the relationship of dentine lead data with maternal blood lead concentrations and to predict maternal lead from child dentine lead data in blinded analyses. We validated and quantified the bias of our results internally. RESULTS: Mothers had moderate blood lead levels (trimesters: 2nd = 29.45 ug/L, 3rd = 31.78 ug/L). Trimester-averaged and weekly child dentine lead measurements were highly correlated with maternal blood levels in the corresponding trimesters. The predicted trimester-specific maternal lead levels were significantly correlated with actual measured blood values (trimesters: 2nd = 0.83; 3rd = 0.88). Biomarkers of maternal lead exposure discriminated women highly exposed to lead (>mean) with 85 % and 96 % specificity in the 2nd and 3rd trimesters, respectively, with 80 % sensitivity. DISCUSSION: Weekly child dentine lead levels can serve as biomarkers of past child and maternal lead exposures during pregnancy.

Racial/ethnic and neighborhood disparities in metals exposure during pregnancy in the Northeastern United States.

Despite the unequal burden of environmental exposures borne by racially minoritized communities, these groups are often underrepresented in public health research. Here, we examined racial/ethnic disparities in exposure to metals among a multi-ethnic sample of pregnant women. The sample included women enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort (N = 382). Urinary metal concentrations (arsenic [As], barium [Ba], cadmium [Cd], cesium [Cs], chromium [Cr], lead [Pb], antimony [Sb]) were measured during mid-pregnancy and information on individual- and neighborhood-level characteristics was ascertained during an in-person interview and from publicly available databases, respectively. Linear regression was used to examine individual and neighborhood characteristics in relation to metal concentrations. Black/Black-Hispanic women had Cd, Cr, Pb, and Sb levels that were 142.0%, 10.9%, 35.0%, and 32.1% higher than White, non-Hispanic women, respectively. Likewise, White-Hispanic women had corresponding levels that were 141.5%, 108.2%, 59.9%, and 38.3% higher. These same metals were also higher among women residing in areas with higher crime, higher diversity, lower educational attainment, lower household income, and higher poverty. Significant disparities in exposure to metals exist and may be driven by neighborhood-level factors. Exposure to metals for pregnant women can be especially harmful. Understanding exposure inequalities and identifying factors that increase risk can help inform targeted public health interventions.

Early childhood fluoride exposure and preadolescent kidney function.

BACKGROUND: Early-life renal maturation is susceptible to nephrotoxic environmental chemicals. Given the widespread consumption of fluoride and the global obesity epidemic, our main aim was to determine whether childhood fluoride exposure adversely affects kidney function in preadolescence, and if adiposity status modifies this association. METHODS: Our study included 438 children from the PROGRESS cohort. Urinary fluoride (uF) was assessed at age 4 by diffusion analysis; outcomes studied included estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), selected kidney proteins and blood pressure measured at age 8-12 years. We modeled the relationship between uF and outcomes, and adjusted for body mass index (BMI), age, sex, and socioeconomic status. RESULTS: The median uF concentration was 0.67 µg/mL. We observed null associations between 4-year uF and preadolescent eGFR, although effect estimates were in the expected inverse direction. A single unit increase in ln-transformed uF was associated with a 2.2 mL/min decrease in cystatin C-based eGFR (95% CI: 5.8, 1.4; p = 0.23). We observed no evidence of sex-specific effects or effect modification by BMI status. Although uF was not associated with BMI, among children with obesity, we observed an inverse association (ß: 4.8; 95% CI: 10.2, 0.6; p = 0.08) between uF and eGFR. CONCLUSIONS: Low-level fluoride exposure in early childhood was not associated with renal function in preadolescence. However, given the adverse outcomes of chronic fluoride consumption it is possible that the preadolescent age was too young to observe any effects. Longitudinal follow-up in this cohort and others is an important next step.

Metal mixtures are associated with increased anxiety during pregnancy.

BACKGROUND: Exposure to low-dose toxic metals in the environment is ubiquitous. Several murine studies have shown metals induce anxiety-like behaviors, and mechanistic research supports that metals disrupt neurotransmitter signaling systems implicated in the pathophysiology of anxiety. In this study, we extend prior research by examining joint exposure to six metals in relation to maternal anxiety symptoms during pregnancy. METHODS: The sample includes 380 participants enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) pregnancy cohort. Spot urine was collected during pregnancy (mean ± standard deviation: 31.1 ± 6.1 weeks), and concentrations of six metals (barium [Ba], cadmium [Cd], chromium [Cr], cesium [Cs], lead [Pb], antimony [Sb]) were measured by Inductively Coupled Plasma - Mass Spectrometry. Trait anxiety symptoms were measured during pregnancy using a short version of the Spielberger State Trait Anxiety Inventory (STAI-T) and information on covariates was collected by questionnaire. We used weighted quantile sum (WQS) regression as the primary modeling approach to examine metals, treated as a mixture, in relation to higher (≥20) vs. lower anxiety symptoms while adjusting for urinary creatinine and key sociodemographic variables. RESULTS: The sample is socioeconomically and racially/ethnically diverse. Urinary metal concentrations were log-normally distributed and 25% of the sample had an STAI-T score ≥20. Joint exposure to metals was associated with elevated anxiety symptoms (ORWQS = 1.56, 95% CI: 1.24, 1.96); Cd (61.8%), Cr (14.7%), and Cs (12.7%) contributed the greatest weight to the mixture effect. CONCLUSION: Exposure to metals in the environment may be associated with anxiety symptoms during pregnancy. This is a public health concern, as anxiety disorders are highly prevalent and associated with significant co-morbidities, especially during pregnancy when both the mother and developing fetus are susceptible to adverse health outcomes.

Prenatal lead exposure and childhood lung function: Influence of maternal cortisol and child sex.

INTRODUCTION: Maternal hypothalamic-pituitary-adrenal (HPA) axis disruption in pregnancy may contribute to the programming of childhood respiratory disease and may modify the effect of chemical toxins, like lead (Pb), on lung development. Child sex may further modify these effects. We sought to prospectively examine associations between maternal HPA axis disruption, prenatal Pb and childhood lung function and explore potential effect modification by maternal cortisol and child sex on the association between prenatal Pb and lung function outcomes. MATERIALS AND METHODS: Analyses included 222 mothers and children enrolled in a longitudinal birth cohort study in Mexico City. Maternal diurnal salivary cortisol was assessed in pregnancy; cortisol awakening response (CAR) and diurnal slope were calculated. Blood Pb was measured during the second trimester of pregnancy. Post-bronchodilator lung function was tested at ages 8-11 years. Associations were modeled using generalized linear models with interaction terms, adjusting for covariates. RESULTS: A higher (flatter) diurnal slope was associated with lower FEV1/FVC ratio (ß: 0.433, 95%CI [-0.766, -0.101]). We did not find any main effect associations between prenatal Pb and lung function outcomes. We report an interaction between Pb and cortisol in relation to FEV1/FVC and FEF25-75% (pinteraction<0.05 for all). Higher prenatal Pb was associated with reduced FEV1/FVC only in children whose mothers had a high CAR. Higher prenatal Pb was also associated with reduced FEV1/FVC and FEF25-75% in mothers with a flatter diurnal slope. A 3-way interaction between prenatal Pb, CAR and sex on FEV1/FVC, indicated that boys born to women with high CAR and higher prenatal Pb levels had lower FEV1/FVC ratios (pinteraction = 0.067). CONCLUSIONS: Associations between prenatal Pb and childhood lung function were modified by disrupted maternal cortisol in pregnancy and child sex. These findings underscore the need to consider complex interactions to fully elucidate effects of prenatal Pb exposure on childhood lung function.

Association between prenatal metal exposure and adverse respiratory symptoms in childhood.

INTRODUCTION: Manganese and lead have been cross-sectionally associated with adverse respiratory outcomes in childhood but there is limited data on their combined effects starting in utero. We examined associations between in utero exposure to metals and childhood respiratory symptoms. METHODS: We assessed 633 mother-child dyads enrolled in the Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) birth cohort in Mexico City. Blood manganese (BMn) and lead (BPb) were measured in mothers at 2nd and 3rd trimester. Ever wheeze, current wheeze and asthma diagnosis were ascertained at 4-5 and 6-7 year visits through the International Study of Asthma and Allergies in Childhood survey. Logistic mixed model regression was used to assess the association between prenatal metals and respiratory outcomes in children across the 4-5 and 6-7 year visits. Covariates included mother's age, education and asthma, environmental tobacco smoke, child's sex and assessment time. RESULTS: In adjusted models, higher 2nd trimester BPb had a significant association with elevated odds of ever wheeze (Odds Ratio (OR): 1.97, 95% CI: 1.05, 3.67). BMn at 2nd trimester was associated with decreased (OR: 0.06, 95% CI: 0.01, 0.35) odds of current wheeze. We did not find any statistically significant associations with 3rd trimester blood metals. CONCLUSION: Prenatal exposure to Pb was associated with higher odds of ever wheeze while Mn was negatively associated with odds of current wheeze. These findings underscore the need to consider prenatal metal exposure, including low exposure levels, in the study of adverse respiratory outcomes.

Lead exposure and serum metabolite profiles in pregnant women in Mexico City.

BACKGROUND: Lead (Pb) exposure is a global health hazard causing a wide range of adverse health outcomes. Yet, the mechanisms of Pb toxicology remain incompletely understood, especially during pregnancy. To uncover biological pathways impacted by Pb exposure, this study investigated serum metabolomic profiles during the third trimester of pregnancy that are associated with blood Pb and bone Pb. METHODS: We used data and specimens from 99 women enrolled in the Programming Research in Obesity, Growth, Environment, and Social Stressors birth cohort in Mexico City. Maternal Pb exposure was measured in whole blood samples from the third trimester of pregnancy and in the tibia and patella bones at 1 month postpartum. Third-trimester serum samples underwent metabolomic analysis; metabolites were identified based on matching to an in-house analytical standard library. A metabolome-wide association study was performed using multiple linear regression models. Class- and pathway-based enrichment analyses were also conducted. RESULTS: The median (interquartile range) blood Pb concentration was 2.9 (2.6) µg/dL. Median bone Pb, measured in the tibia and patella, were 2.5 (7.3) µg/g and 3.6 (9.5) µg/g, respectively. Of 215 total metabolites identified in serum, 31 were associated with blood Pb (p < 0.05). Class enrichment analysis identified significant overrepresentation of metabolites classified as fatty acids and conjugates, amino acids and peptides, and purines. Tibia and patella Pb were associated with 14 and 8 metabolites, respectively (p < 0.05). Comparing results from bone and blood Pb, glycochenodeoxycholic acid, glycocholic acid, and 1-arachidonoylglycerol were positively associated with blood Pb and tibia Pb, and 7-methylguanine was negatively associated with blood Pb and patella Pb. One metabolite, 5-aminopentanoic acid, was negatively associated with all three Pb measures. CONCLUSIONS: This study identified serum metabolites in pregnant women associated with Pb measured in blood and bone. These findings provide insights on the metabolic profile around Pb exposure in pregnancy and information to guide mechanistic studies of toxicological effects for mothers and children.

Prospective Associations of Early Pregnancy Metal Mixtures with Mitochondria DNA Copy Number and Telomere Length in Maternal and Cord Blood.

BACKGROUND: Metal exposure during pregnancy influences maternal and child health. Oxidative stress and inflammation may mediate adverse effects of heavy metals, whereas essential metals may act as antioxidants. Mitochondrial DNA is a prime target for metal-induced oxidative damage. Telomere dysfunction is attributed to imbalances between reactive oxidant species and antioxidants. OBJECTIVES: We evaluated individual and joint associations of prenatal metals with mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) in maternal and cord blood as biomarkers of inflammation and oxidative stress. METHODS: We measured six nonessential metals (arsenic, barium, cadmium, cesium, lead, mercury) and four essential metals (magnesium, manganese, selenium, zinc) in first-trimester maternal red blood cells in Project Viva, a U.S. prebirth cohort. We measured relative mtDNAcn (n=898) and TL (n=893) in second-trimester maternal blood and mtDNAcn (n=419) and TL (n=408) in cord blood. We used multivariable linear regression and quantile g-computation to estimate associations between prenatal metals and the biomarkers. We used generalized additive models and Bayesian kernel machine regression to examine nonlinearity and interactions. RESULTS: A 2-fold increase in maternal magnesium was associated with lower maternal [ß=-0.07, 95% confidence interval (CI): -0.10, -0.01] and cord blood (ß=-0.08, 95% CI: -0.20, -0.01) mtDNAcn. Lead was associated with higher maternal mtDNAcn (ß=0.04, 95% CI: 0.01, 0.06). Selenium was associated with longer cord blood TL (ß=0.30, 95% CI: 0.01 0.50). An association was observed between the nonessential metal mixture and higher maternal mtDNAcn (ß=0.04, 95% CI: 0.01, 0.07). There was a nonlinear relationship between cord blood mtDNAcn and magnesium; maternal mtDNAcn and barium, lead, and mercury; and maternal TL and barium. DISCUSSION: Maternal exposure to metals such as lead, magnesium, and selenium was associated with mtDNAcn and TL in maternal second trimester and cord blood. Future work will evaluate whether these biomarkers are associated with child health. https://doi.org/10.1289/EHP9294.

Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals.

BACKGROUND: Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6-10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR < 0.05), and for DMRs using comb-p (Sidak p < 0.05). Covariates included biologically relevant variables and estimated cell-type composition. We also performed sex-stratified analyses. RESULTS: Pb was associated with decreased methylation of cg20608990 (CASP8) (FDR = 0.04), and Mn was associated with increased methylation of cg02042823 (A2BP1) in cord blood (FDR = 9.73 × 10-6). Both associations remained significant but attenuated in blood DNAm collected at mid-childhood (p < 0.01). Two and nine Mn-associated DMPs were identified in male and female infants, respectively (FDR < 0.05), with two and six persisting in mid-childhood (p < 0.05). All metals except Ba and Pb were associated with ≥ 1 DMR among all infants (Sidak p < 0.05). Overlapping DMRs annotated to genes in the human leukocyte antigen (HLA) region were identified for Cr, Cs, Cu, Hg, Mg, and Mn. CONCLUSIONS: Prenatal metal exposure is associated with DNAm, including DMRs annotated to genes involved in neurodevelopment. Future research is needed to determine if DNAm partially explains the relationship between prenatal metal exposures and health outcomes.

Nephrotoxic Metal Mixtures and Preadolescent Kidney Function.

Exposure to metals including lead (Pb), cadmium (Cd), and arsenic (As), may impair kidney function as individual toxicants or in mixtures. However, no single medium is ideal to study multiple metals simultaneously. We hypothesized that multi-media biomarkers (MMBs), integrated indices combining information across biomarkers, are informative of adverse kidney function. Levels of Pb, Cd, and As were quantified in blood and urine in 4-6-year-old Mexican children (n = 300) in the PROGRESS longitudinal cohort study. We estimated the mixture effects of these metals, using weighted quantile sum regression (WQS) applied to urine biomarkers (Umix), blood biomarkers (Bmix), and MMBs, on the cystatin C-based estimated glomerular filtration rate (eGFR) and serum cystatin C assessed at 8-10 years of age, adjusted for covariates. Quartile increases in Umix and the MMB mixture were associated with 2.5% (95%CI: 0.1, 5.0) and 3.0% (95%CI: 0.2, 5.7) increased eGFR and -2.6% (95% CI: -5.1%, -0.1%) and -3.3% (95% CI: -6.5%, -0.1%) decreased cystatin C, respectively. Weights indicate that the strongest contributors to the associations with eGFR and serum cystatin C were Cd and Pb, respectively. MMBs detected mixture effects distinct from associations with individual metals or media-type, highlighting the benefits of incorporating information from multiple exposure media in mixtures analyses.

Hair mercury levels, intake of omega-3 fatty acids and ovarian reserve among women attending a fertility center.

OBJECTIVE: To investigate the association of hair mercury (Hg) levels with antral follicle count (AFC), as a marker of ovarian reserve, and evaluate whether this relationship differed among women with high vs. low total intake of long chain omega-3 polyunsaturated fatty acids (n3PUFA) from foods and supplements. DESIGN: We included 353 women attending an academic fertility center (2007-2019) who had data on hair Hg levels, total n3PUFA intake, and AFC. METHODS: Hair Hg levels were assessed using a Direct Mercury Analyser, total n3PUFA intake was estimated using an extensively validated food frequency questionnaire, and AFC was assessed by transvaginal ultrasonography. Poisson regression models adjusted for potential confounders were used to evaluate the association of hair Hg levels (divided into tertiles, and as above vs below EPA reference (1 ppm)) with AFC. Associations were also evaluated after stratification by median n3PUFA intake (≤0.124% vs. >0.125% calories/week). RESULTS: Women's median hair Hg level was 0.60 ppm (range = 0.001-8.60 ppm), with more than 30% > 1 ppm (EPA reference level). Hair Hg was positively related to AFC after adjusting for age, BMI, smoking status, infertility diagnosis, and alcohol intake. However, associations became attenuated after adjustment for intake of total n3PUFA. The positive associations of hair Hg and AFC were observed only among women above the median total n3PUFA intake. Specifically, women who consumed >0.125% calories/week of total n3PUFA had mean AFCs of 11.9, 13.2 and 14.1, respectively, across increasing tertiles of hair Hg (p,trend = 0.004). Similar results were found when hair Hg was divided above vs below EPA reference (mean AFC = 12.7 vs. 14.1, p = 0.008). CONCLUSIONS: In these women, positive associations of hair Hg with AFC may be reflective of beneficial effects of n3PUFA on ovarian reserve rather than a beneficial effect of Hg per se. Our findings highlight the importance of considering diet when exploring Hg effects on women's reproductive health in urban settings.

Co-exposure to manganese and lead and pediatric neurocognition in East Liverpool, Ohio.

Exposure to metal mixtures may lead to health impacts greater than the effects associated with singular exposures. Two common childhood environmental exposures, manganese (Mn) and lead (Pb), are associated with similar adverse neurodevelopmental effects; however, the effects surrounding concurrent exposure to both metals remain unclear. We study the impact of joint exposure to Mn and Pb on cognitive performance in school-aged children participating in the Communities Actively Researching Exposure Study (CARES) based in East Liverpool, Ohio. Blood Pb levels were measured for each child (geometric mean (GM) = 1.13 µg/dL, range 0.30 µg/dL - 6.64 µg/dL). Mn was measured in participant blood, hair, and toenails with GMs of 10.1 µg/L, 360 ng/g, 0.974 µg/g, respectively. Trained team members administered the Wechsler Intelligence Scale for Children-IV (WISC-IV) to assess intelligence quotient (IQ). The WISC-IV provides scores for Full Scale IQ, Perceptual Reasoning, Processing Speed, Working Memory, and Verbal Comprehension. Interactions between blood Pb and all Mn biomarkers were tested in linear models adjusted for child sex, household income, and serum cotinine. Separate regression models were run for each of the Mn biomarkers. The cohort was comprised of 106 children with a mean age of 8.4 years. Interactions between blood Pb and hair Mn were significant (p < 0.05) for four out of the five IQ domains. The effect of blood Pb on IQ was more pronounced at higher levels of hair and toenail Mn. No significant associations were observed when characterizing the main effect of Mn using blood. Uncovering the health impacts associated with exposure mixtures is critical to understanding the impact of real-life conditions. Our findings suggest that joint exposure to Mn and Pb may produce heightened neurocognitive impacts even at blood Pb levels below the CDC reference concentration of 5 µg/dL.

Early pregnancy exposure to metal mixture and birth outcomes - A prospective study in Project Viva.

BACKGROUND: Prenatal exposure to metals has been individually associated with birth outcomes. However, little is known about the effect of metal mixture, particularly at low exposure levels. OBJECTIVES: To estimate individual and joint effects of metal mixture components on birth outcomes. METHODS: We used data from 1,391 mother-infant pairs in Project Viva (1999-2002). We measured 11 metals in maternal 1st trimester erythrocyte; abstracted birth weight from medical records; calculated gestational age from last menstrual period or ultrasound; and obtained birth length (n = 729) and head circumference (n = 791) from research measurements. We estimated individual and joint effects of metals using multivariable linear and Bayesian kernel machine regressions. RESULTS: In both single metal and metal mixture analyses, exposure to higher concentrations of arsenic was associated with lower birth weight in males, zinc with higher head circumference in females, and manganese with higher birth length in sex-combined analysis. We also observed sex-specific metal interactions with birth outcomes. Arsenic and manganese showed a synergistic association with birth weight in males, in whom an interquartile range (IQR) increase in arsenic was associated with 25.3 g (95% CI: -79.9, 29.3), 47.9 g (95% CI: -98.0, 2.1), and 72.2 g (95% CI: -129.8, -14.7) lower birth weight when manganese concentrations were at 25th, 50th, and 75th percentiles, respectively. Lead and zinc showed an antagonistic association with head circumference in males, where an IQR increase in lead was associated with 0.18 cm (95% CI: -0.35, -0.02), 0.10 cm (95% CI: -0.25, 0.04), 0.03 cm (95% CI: -0.2, 0.14) smaller head circumference when zinc concentrations were at 25th, 50th, and 75th percentiles, respectively. Exposure to higher concentrations of arsenic was also associated with lower gestational age in males when concentrations of manganese and lead were higher. DISCUSSION: Maternal erythrocyte concentrations of arsenic, manganese, lead, and zinc were individually and interactively associated with birth outcomes. The associations varied by infant sex and exposure level of other mixture components.

Prenatal exposure to a mixture of elements and neurobehavioral outcomes in mid-childhood: Results from Project Viva.

BACKGROUND: Lead (Pb), manganese (Mn), selenium (Se) and methylmercury (MeHg) can be neurotoxic individually, despite Mn and Se also being essential elements. Little is known about the joint effects of essential and non-essential elements on neurobehavior, particularly for prenatal exposures. OBJECTIVES: To evaluate associations of prenatal exposure to multiple elements with executive function and neurobehavior in children. METHODS: Participants included 1009 mother-child pairs from the Project Viva pre-birth cohort. We estimated maternal erythrocyte Pb, Mn, Se, and Hg concentrations prenatally. In 6-11-year old children (median 7.6 years), parents and teachers rated children's executive function-related behaviors using the Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite score and behavioral difficulties using the Strengths and Difficulties Questionnaire (SDQ) total difficulties score. We evaluated associations of element mixtures with neurobehavior using Bayesian kernel machine regression (BKMR), multivariable linear regression, and quantile g-computation. RESULTS: Median erythrocyte Pb, Mn, Se, and Hg concentrations were 1.1 µg/dL, 33.1 µg/L, 204.5 ng/mL, and 3.1 ng/g, respectively. Findings from BKMR and quantile g-computation models both showed worse (higher) parent-rated BRIEF and SDQ z-scores with higher concentrations of the mixture, although estimates were imprecise. When remaining elements were set at their median within BKMR models, increases in Pb and Se from the 25th to 75th percentile of exposure distributions were associated with 0.08 (95% CI: 0.02, 0.19) and 0.07 (95% CI: 0.03, 0.16) standard deviation increases in parent-rated BRIEF scores, and 0.08 (95% CI: 0.02, 0.17) and 0.05 (95% CI: 0.03, 0.13) standard deviation increases in SDQ scores, respectively. There was no evidence of element interactions. DISCUSSION: Although associations were small in magnitude, we found a trend of worsening neurobehavioral ratings with increasing prenatal exposure to an element mixture. However, we may be observing a limited range of dose-dependent impacts given the levels of exposure within our population.

Early pregnancy essential and non-essential metal mixtures and gestational glucose concentrations in the 2nd trimester: Results from project viva.

Metals are involved in glucose metabolism, and some may alter glycemic regulation. However, joint effects of essential and non-essential metals on glucose concentrations during pregnancy are unclear. This study explored the joint associations of pregnancy exposures to essential (copper, magnesium, manganese, selenium, zinc) and non-essential (arsenic, barium, cadmium, cesium, lead, mercury) metals with gestational glucose concentrations using 1,311 women enrolled 1999-2002 in Project Viva, a Boston, MA-area pregnancy cohort. The study measured erythrocyte metal concentrations from 1st trimester blood samples and used glucose concentrations measured 1 h after non-fasting 50-gram glucose challenge tests (GCT) from clinical gestational diabetes screening at 26-28 weeks gestation. Bayesian Kernel Machine Regression (BKMR) and quantile-based g-computation were applied to model the associations of metal mixtures-including their interactions-with glucose concentrations post-GCT. We tested for reproducibility of BKMR results using generalized additive models. The BKMR model showed an inverse U-shaped association for barium and a linear inverse association for mercury. Specifically, estimated mean glucose concentrations were highest around 75th percentile of barium concentrations [2.1 (95% confidence interval: -0.2, 4.4) mg/dL higher comparing to the 25th percentile], and each interquartile range increase of erythrocyte mercury was associated with 1.9 mg/dL lower mean glucose concentrations (95% credible interval: -4.2, 0.4). Quantile g-computation showed joint associations of all metals, essential-metals, and non-essential metals on gestational glucose concentrations were all null, however, we observed evidences of interaction for barium and lead. Overall, we found early pregnancy barium and mercury erythrocytic concentrations were associated with altered post-load glucose concentrations in later pregnancy, with potential interactions between barium and lead.

Diet and erythrocyte metal concentrations in early pregnancy-cross-sectional analysis in Project Viva.

BACKGROUND: Dietary sources of metals are not well established among pregnant women in the United States. OBJECTIVE: We aimed to perform a diet-wide association study (DWAS) of metals during the first trimester of pregnancy. METHODS: In early pregnancy (11.3 ± 2.8 weeks of gestation), 1196 women from Project Viva (recruited 1999-2002 in eastern Massachusetts) completed a validated FFQ (135 food items) and underwent measurements of erythrocyte metals [arsenic (As), barium, cadmium, cesium (Cs), copper, mercury (Hg), magnesium, manganese, lead (Pb), selenium (Se), zinc]. The DWAS involved a systematic evaluation and visualization of all bivariate relations for each food-metal combination. For dietary items with strong associations with erythrocyte metals, we applied targeted maximum likelihood estimations and substitution models to evaluate how hypothetical dietary interventions would influence metals' concentrations. RESULTS: Participants' mean ± SD age was 32.5 ± 4.5 y and prepregnancy BMI was 24.8 ± 5.4 kg/m2; they were mostly white (75.9%), college graduates (72.4%), married or cohabitating (94.6%), had a household income >$70,000/y (63.5%), and had never smoked (67.1%). Compared with other US-based cohorts, the overall diet quality of participants was above average, and concentrations of erythrocyte metals were lower. The DWAS identified significant associations of several food items with As, Hg, Pb, Cs, and Se; for example, As was higher for each SD increment in fresh fruit (11.5%; 95% CI: 4.9%, 18.4%), white rice (17.9%; 95% CI: 9.4%, 26.9%), and seafood (50.9%; 95% CI: 42.8%, 59.3%). Following the guidelines for pregnant women to consume ≤3 servings/wk of seafood was associated with lower As (-0.55 ng/g; 95% CI: -0.82, -0.28 ng/g) and lower Hg (-2.67 ng/g; 95% CI: -3.55, -1.80 ng/g). Substituting white rice with bread, pasta, tortilla, and potato was also associated with lower As (35%-50%) and Hg (35%-70%). CONCLUSIONS: Our DWAS provides a systematic evaluation of diet-metals relations. Prenatal diet may be an important source of exposures to metals.