BACKGROUND: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized.
METHODS: In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, urinary metals concentrations during two pregnancy time periods (< 28 weeks and ≥ 28 weeks of gestation) were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. In an exposure-wide association framework, using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, age at pregnancy, race/ethnicity and education. We meta-analyzed across the two cohorts.
RESULTS: In EARLI (n = 170) 17% of children were diagnosed with ASD, and 44% were classified as having non-neurotypical development (Non-TD). In MARBLES (n = 231), 21% were diagnosed with ASD, and 14% classified as Non-TD. During the first and second trimester period (< 28 weeks), having cadmium concentration over the level of detection was associated with 1.69 (1.08, 2.64) times higher risk of ASD, and 1.29 (0.95, 1.75)times higher risk of Non-TD. A doubling of first and second trimester cesium concentration was marginally associated with 1.89 (0.94, 3.80) times higher risk of ASD, and a doubling of third trimester cesium with 1.69 (0.97, 2.95) times higher risk of ASD.
CONCLUSIONS: Exposure in utero to elevated levels of cadmium and cesium, as measured in urine collected during pregnancy, was associated with increased risk of developing ASD.

Polycystic ovary syndrome (PCOS) severely affects women\'s fertility and accompanies serious metabolic disturbances, affecting 5%-20% of women of reproductive age globally. We previously found that exposure to toxic metals in the blood raised the risk of PCOS, but the association between exposure to toxic metals and the risk of PCOS in the follicular fluid, the microenvironment for oocyte growth and development in females, and its effect on metabolism has not been reported. This study aimed to evaluate the associations between the concentrations of cadmium (Cd), mercury (Hg), barium (Ba) and arsenic (As) in FF and the risk of PCOS, and to explore the mediating effect of metabolic markers in FF on the above relationship. We conducted a case-control study, including 557 women with PCOS and 651 controls. Ba, Cd, Hg and As levels in FF were measured by ICP-MS, metabolites levels in FF was measured by LC-MS/MS among 168 participants randomly selected from all the participants. Logistic regression models were used to assess the association of a single metal level with the PCOS risk, and linear regression models were used to assess the relationships of a single metal level with clinical phenotype parameters and metabolites levels. Combined effect of metals mixture levels on the risk of PCOS were assessed via weighted quantile sum (WQS) regression and bayesian kernel machine regression (BKMR). Medication analysis was performed to explore the role of metabolic markers on the relationship of toxic metals levels with the risk of PCOS. The exposure levels of Cd, Hg, Ba and As in FF were all positively and significantly associated with the PCOS risk (with respect to the highest vs. lowest tertile group: OR = 1.57, 95% CI = 1.17 ~ 2.12 for Cd, OR = 1.69, 95% CI = 1.22 ~ 2.34 for Hg, OR = 1.76, 95% CI = 1.32 ~ 2.34 for Ba, OR = 1.42, 95% CI = 1.05 ~ 1.91 for As). In addition, levels of metal mixture also significantly correlated with the risk of PCOS, Cd level contributed most to it. Moreover, we observed significant positive relationships between Cd level and LH (β = 0.048, 95% CI = 0.002 ~ 0.094), T (β = 0.077, 95% CI = 0.029 ~ 0.125) and HOMA-IR value (β = 0.060, 95% CI = 0.012 ~ 0.107), as well as Hg level with LH, FSH/LH ratio and TC. Furthermore, we revealed that estrone sulfate, LysoPE 22:6 and N-Undecanoylglycine were significantly and positively mediating the association between Cd level and the risk of PCOS (with mediated proportion of 0.39, 0.24 and 0.35, respectively), and between Hg level and the risk of PCOS (with mediated proportion of 0.29, 0.20 and 0.46, respectively). These highly expressed metabolites significantly enriched in the fatty acid oxidation, steroid hormone biosynthesis and glycerophospholipids metabolism, which may explain the reason why the levels of Cd and Hg in FF associated with the phenotype of PCOS. Ba and As in FF was not found the above phenomenon. Our results suggested that exposure to multiple toxic metals (Cd, Hg, Ba and As) in FF associated with the increased risk of PCOS, Cd was a major contributor. Levels of Cd and Hg in FF significantly associated with the phenotype of PCOS. The above association may result from that Cd and Hg in FF related with the disturbance of fatty acid oxidation, steroid hormone biosynthesis and the glycerophospholipids metabolism.

BACKGROUND: Manganese (Mn) is an essential micronutrient as well as a well-established neurotoxicant. Occupational and environmental exposures may bypass homeostatic regulation and lead to increased systemic Mn levels. Translocation of ultrafine ambient airborne particles via nasal neuronal pathway to olfactory bulb and tract may be an important pathway by which Mn enters the central nervous system.
OBJECTIVE: To measure olfactory tract/bulb tissue metal concentrations in Mn-exposed and non-exposed mineworkers.
METHODS: Using inductively coupled plasma-mass spectrometry (ICP-MS), we measured and compared tissue metal concentrations in unilateral olfactory tracts/bulbs of 24 Mn-exposed and 17 non-exposed South African mineworkers. We used linear regression to investigate the association between cumulative Mn exposures and olfactory tract/bulb Mn concentration.
RESULTS: The difference in mean olfactory tract/bulb Mn concentrations between Mn-exposed and non-Mn exposed mineworkers was 0.16 µg/g (95% CI -0.11, 0.42); but decreased to 0.09 µg/g (95% CI 0.004, 0.18) after exclusion of one influential observation. Olfactory tract/bulb metal concentration and cumulative Mn exposure suggested there may be a positive association; for each mg Mn/m3-year there was a 0.05 µg/g (95% CI 0.01, 0.08) greater olfactory tract/bulb Mn concentration overall, but -0.003 (95% CI -0.02, 0.02) when excluding the three influential observations. Recency of Mn exposure was not associated with olfactory tract/bulb Mn concentration.
CONCLUSIONS: Our findings suggest that Mn-exposed mineworkers might have higher olfactory tract/bulb tissue Mn concentrations than non-Mn exposed mineworkers, and that concentrations might depend more on cumulative dose than recency of exposure.

UNASSIGNED: Autism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized.
UNASSIGNED: In Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, maternal urinary metals concentrations at two time points during pregnancy were measured using inductively coupled plasma mass spectrometry. At age three, clinicians assessed ASD with DSM-5 criteria. Using multivariable log binomial regression, we examined each metal for association with ASD status, adjusting for gestational age at urine sampling, child sex, maternal age, and maternal education, and meta-analyzed across the two cohorts.
UNASSIGNED: In EARLI (n=170) 17.6% of children were diagnosed with ASD, and an additional 43.5% were classified as having other non-neurotypical development (Non-TD). In MARBLES (n=156), 22.7% were diagnosed with ASD, while an additional 11.5% had Non-TD. In earlier pregnancy metals measures, having cadmium concentration over the level of detection was associated with 1.78 (1.19, 2.67) times higher risk of ASD, and 1.43 (1.06, 1.92) times higher risk of Non-TD. A doubling of early pregnancy cesium concentration was marginally associated with 1.81 (0.95, 3.42) times higher risk of ASD, and 1.58 (0.95, 2.63) times higher risk of Non-TD.
UNASSIGNED: Exposure in utero to elevated levels of cadmium and cesium, as measured in maternal urine collected during pregnancy, was associated with increased risk of developing ASD.

The impact of exposure to metals on chronic kidney disease (CKD) has only been investigated in two-way or single metal interactions in previous studies. We investigated the associations between five single metals in blood and their mixed exposure and CKD by using the machine learning approach. Relevant data were extracted from the National Health and Nutrition Examination Survey (NHANES 2011-2020), and the level of five metals in blood detected by inductively coupled plasma mass spectrometry was considered as exposures, namely, cadmium (Cd), lead (Pb), total mercury (Hg), manganese (Mn), and selenium (Se). The correlations between individual metal and metal mixtures and CKD were then evaluated by survey-multivariable logistic regression (SMLR), generalized weighted quantile sum (WQS), and Bayesian kernel machine regression (BKMR). Altogether, our study included 12,412 participants representing 572.6 million non-institutionalized US adults. Several single metals with the high quartile of exposure showed a positive association with the CKD ratio including Cd [(AOR = 1.873, 95% CI: 1.537, 2.284), Q4], Pb [(AOR = 1.559, 95% CI: 1.295, 1.880), Q4], and total Hg [(AOR = 1.169, 95% CI: 1.018, 1.343), Q2], while Mn [(AOR = 0.796, 95% CI: 0.684, 0.927), Q2] and Se [(AOR = 0.805, 95% CI: 0.664, 0.976), Q4] were negatively associated with the CKD ratio. In light of the positive fit of the WQS regression model, a significantly positive correlation was found between mixed metals and CKD (AOR = 1.373, 95% CI: 1.224, 1.539) after full covariate adjustment, and a similar finding was also detected in the BKMR model. Our study revealed that each single metal including Cd, Pb, and total Hg might have a positive association with CKD while this association was negative for both Mn and Se. The five metals might have a positive joint effect on CKD.

Maternal exposure to metals may pose a risk to the health of newborns, however, the underlying mechanisms remain ambiguous. Herein, we aimed to investigate the influence of metals exposure on birth outcomes and reveal the importance of metabolites in the exposure-outcomes association by using metabolomics methods.
In our study, 292 mother-pairs were included who were recruited from the affiliated hospitals of Nanjing Medical University between 2006 and 2011. We measured fifteen metals (mercury, lead, vanadium, arsenic, zinc, cadmium, rubidium, copper, cobalt, iron, molybdenum, strontium, thallium, magnesium and calcium) and metabolites in maternal second trimester serums by using inductively coupled plasma mass spectrometry and ultra-high performance liquid chromatography high resolution accurate mass spectrometry, respectively. A multi-step statistical analysis strategy including exposome-wide association study (ExWAS) model, variable selection models and multiple-exposure models were performed to systematically appraise the associations of individual and mixed metals exposure with birth outcomes. Furthermore, differential metabolites that associated with metals exposure and birth outcomes were identified using linear regression models.
Metal\'s levels in maternal serums ranged from 0.05 μg/L to 1864.76 μg/L. In the ExWAS model, maternal exposure to arsenic was negatively associated with birth weight (β = 188.83; 95% CI: -368.27, -9.39), while maternal mercury exposure showed a positive association (β = 533.65; 95%CI: 179.40, 887.90) with birth weight. Moreover, each unit increase in mercury (1 ng/mL-log transformed) was associated with a 1.82 week-increase (95%CI: 0.85, 2.79) in gestational age. These findings were subsequently validated by variable selection models and multiple exposure models. Metabolomic analysis further revealed the significant role of 3-methyladenine in the relationship between arsenic exposure and birth weight.
This study provides new epidemiological evidence indicating the associations of metals exposure and neonatal birth outcomes, and emphasizes the potential role of metabolite biomarkers and their importance in monitoring adverse birth outcomes.

Native American communities suffer disproportionately from elevated metal exposures and increased risk for cardiovascular diseases and diabetes. DNA methylation is a sensitive biomarker of aging-related processes and novel epigenetic-based \"clocks\" can be used to estimate accelerated biological aging that may underlie increased risk. Metals alter DNA methylation, yet little is known about their individual and combined impact on epigenetic age acceleration. Our objective was to investigate the associations of metals on several DNA methylation-based aging measures in the Strong Heart Study (SHS) cohort.
Blood DNA methylation data from 2,301 SHS participants was used to calculate age acceleration of epigenetic clocks (PhenoAge, GrimAge, DunedinPACE, Hannum, Horvath). Urinary metals [arsenic (As), cadmium (Cd), tungsten (W), zinc (Zn), selenium (Se), molybdenum (Mo)] were creatinine-adjusted and categorized into quartiles. We examined associations of individual metals through linear regression models and used Bayesian Kernel Machine Regression (BKMR) for the impact of the total metal mixture on epigenetic age acceleration.
The mixture of nonessential metals (W, As, Cd) was associated with greater GrimAge acceleration and DunedinPACE, while the essential metal mixture (Se, Zn, Mo) was associated with lower epigenetic age acceleration. Cd was associated with increased epigenetic age acceleration across all clocks and BKMR analysis suggested nonlinear associations between Se and DunedinPACE, GrimAge, and PhenoAge acceleration. No interactions between individual metals were observed. The associations between Cd, Zn, and epigenetic age acceleration were greater in never smokers in comparison to current/former smokers.
Nonessential metals were positively associated with greater epigenetic age acceleration, with strongest associations observed between Cd and DunedinPACE and GrimAge acceleration. In contrast, essential metals were associated with lower epigenetic aging. Examining the influence of metal mixtures on epigenetic age acceleration can provide insight into metals and aging-related diseases.

Sampling of the nasal epithelial lining fluid is a potential method to assess exposure to air pollution within the respiratory tract among high risk populations. We investigated associations of short- and long-term particulate matter exposure (PM) and pollution-related metals in the nasal fluid of people with chronic obstructive pulmonary disease (COPD). This study included 20 participants with moderate-to-severe COPD from a larger study who measured long-term personal exposure to PM2.5 using portable air monitors and short-term PM2.5 and black carbon (BC) using in-home samplers for the seven days preceding nasal fluid collection. Nasal fluid was sampled from both nares by nasosorption, and inductively coupled plasma mass spectrometry was used to determine the concentration of metals with major airborne sources. Correlations of selected elements (Fe, Ba, Ni, Pb, V, Zn, Cu) were determined within the nasal fluid. Associations between personal long-term PM2.5 and seven day home PM2.5 and BC exposure and nasal fluid metal concentrations were determined by linear regression. Within nasal fluid samples, concentrations of vanadium and nickel (r = 0.8) and lead and zinc (r = 0.7) were correlated. Seven day and long-term PM2.5 exposure were both associated with higher levels of copper, lead, and vanadium in the nasal fluid. BC exposure was associated with higher levels of nickel in the nasal fluid. Levels of certain metals in the nasal fluid may serve as biomarkers of air pollution exposure in the upper respiratory tract.

Aging is related to a progressive decline in physiological functions and is affected by environmental factors. Metal exposures are linked with many health effects, but have poorly understood associations with aging. In this study, a total of 33,916 participants from the Dongfeng-Tongji cohort were included to establish biological age (BA) predictors by using recent advanced algorithms, Klemera and Doubal method (KDM) and Mahalanobis distance. Two biological aging indexes (BAIs), recorded as KDM-accel [the residual from regressing KDM-BA on chronological age] and physiological dysregulation (PD), were separately defined and tested on their associations with mortality by using Cox proportional hazard models. Among 3320 subjects with laboratory determinations of 23 metals in plasma, the individual and overall associations between these metals and BAIs were evaluated by using multiple-linear regression and weighted quantile sum (WQS) models. Both BAIs were prospectively associated with all-cause mortality among the whole participants [KDM-accel: HR(95%CI) = 1.23(1.18, 1.29); PD: HR(95%CI) = 1.37(1.31, 1.42)]. Each 1-unit increment in ln-transformed strontium and molybdenum were cross-sectionally associated with a separate 0.71- and 0.34-year increase in KDM-accel, and each 1 % increment in copper, rubidium, strontium, cobalt was cross-sectionally associated with a separate 0.10 %, 0.10 %, 0.09 %, 0.02 % increase in PD (all FDR < 0.05). The WQS models observed mixture effects of multi-metals on aging, with a 0.20-year increase in KDM-accel and a 0.04 % increase in PD for each quartile increase in ln-transformed concentrations of all metals [KDM-accel: β(95%CI) = 0.20(0.08, 0.32); PD: β(95%CI) = 0.04(0.02, 0.06)]. Our findings revealed that plasma strontium, molybdenum, copper, rubidium and cobalt were associated with accelerated aging. Multi-metals exposure showed mixture effects on the aging process, which highlights potential preventative interventions.

Environmental exposures to agrochemicals and nutritional factors may be associated with Parkinson\'s Disease (PD). None of the studies to date has examined the combined effects of diet and agricultural chemical exposure together. To address these research gaps, we aimed to assess the association of nutritional factors and agrochemical exposure with the risk of PD. A hospital-based case-control study was conducted. Multivariable logistic regressions were used to estimate the association of nutritional and agrochemical exposures with PD, adjusting for gender, age, socio-economic status, head injury, family history, smoking, metals exposure, and α-synuclein gene polymorphism. Weighted Quantile Sum (WQS) regression was applied to examine the effect of dietary components as a mixture. We recruited 347 cases and 389 controls. Parent history of PD (OR = 4.15, 95%CI: 2.10, 8.20), metals exposure (OR = 2.50, 95%CI: 1.61-3.89), SNCA rs356219 polymorphism (OR = 1.39, 95%CI: 1.04-1.87 for TC vs. TT; OR = 2.17, 95%CI: 1.43-3.28 for CC vs. TT), agrochemical exposures (OR = 2.11, 95%CI: 1.41-3.16), and being born in the Brescia province (OR = 1.83, 95%CI: 1.17-2.90) were significantly associated with PD. Conversely, fish intake and coffee consumption had a protective effect. The study confirmed the role of environmental exposures in the genesis of PD. Fish intake and coffee consumption are protective factors even when agricultural chemical exposures exist. Genetic factors and metals exposure were confirmed as risk factors for PD.