Associations of Trimester-Specific Exposure to Perchlorate, Thiocyanate, and Nitrate with Childhood Neurodevelopment: A Birth Cohort Study in China.

Studies about the impacts of maternal exposure to perchlorate, thiocyanate, and nitrate on offspring neurodevelopment are scarce. Based on a birth cohort in China, 1,028 mothers provided urine samples at three trimesters for determination of the three target analytes, and their offspring neurodevelopment was evaluated at 2 years old. Associations of maternal exposure to the three chemicals with offspring neurodevelopment were estimated using three statistical methods. Trimester-specific analyses using generalized estimating equation models showed that double increment of thiocyanate and nitrate during the first trimester was associated with 1.56 (95% CI: -2.82, -0.30) and 1.22 (-2.40, -0.03) point decreases in the offspring mental development index (MDI), respectively. Weighted quantile sum (WQS) regression analyses showed that the mixture exposure at the first and second trimesters was negatively associated with the offspring MDI (ß = -2.39, 95% CI: -3.85, -0.93; ß = -1.75, 95% CI: -3.04, -0.47, respectively) and thiocyanate contributed the most to the association (65.0 and 91.6%, respectively). Bayesian kernel machine regression analyses suggested an inverted U-shape relationship of maternal urinary thiocyanate with the offspring MDI. These findings suggested that prenatal exposure to the three chemicals (at current levels), especially thiocyanate and nitrate, may impair neurodevelopment. Early pregnancy seems to be the sensitive window.

Prenatal and early postnatal exposure to ambient particulate matter and early childhood neurodevelopment: A birth cohort study.

Adverse impacts of prenatal or postnatal ambient particulate matter exposure have been identified on offspring neurodevelopment. However, it is unclear whether the effect in the two exposure periods is different for early childhood neurodevelopment. This study aimed to evaluate and compare the associations of prenatal and early postnatal exposure to ambient particulate matter with offspring neurodevelopment at 2 years of age and to identify which period was more sensitive to the effects of ambient particulate matter on offspring neurodevelopment. A total of 1331 mother-child pairs from a birth cohort were included in this study from October 2013 to September 2014 in Wuhan, China. The concentrations of ambient daily fine particulate matter (PM2.5) and particulate matter less than 10 µm in aerodynamic diameter (PM10) at each participant's home address during pregnancy and the first two years after birth were estimated by land-use regression models (LUR). Offspring neurodevelopment was measured by the Chinese revision of Bayley Scale of Infant Development (BSID-CR) for each child at 2 years of age. Mental developmental index (MDI) and psychomotor developmental index (PDI) from the BSID-CR were used as outcome variables. A generalized estimating equation (GEE) model was used to estimate the associations of prenatal and postnatal PM2.5 and PM10 exposure with offspring neurodevelopment. After adjusting for potential confounders, we found that both prenatal and early postnatal exposure to PM2.5 and PM10 were associated with decreased offspring MDI and PDI scores. Compared with prenatal exposure, the associations of early postnatal exposure to PM2.5 and PM10 with offspring MDI and PDI were stronger. This study indicates that exposure to ambient particulate matters, mainly during early postnatal period and to a lesser extent prenatally, is associated with impaired offspring neurodevelopment.

Composition and consistence of the bacterial microbiome in upper, middle and lower esophagus before and after Lugol's iodine staining in the esophagus cancer screening.

BACKGROUND: Esophageal bacteria, as the integral composition of human ecosystem, have been reported to be associated with esophageal lesions. However, few studies focus on microbial compositions in different esophageal segments, especially after Lugol's iodine staining (LIS) in the endoscopic examination for the screening of esophageal cancer. We aim to investigate the composition of the bacterial microbiome in upper, middle and lower esophagus and if LIS would affect the detection of bacteria. METHODS: A total of 141 fasting samples including the upper, middle and lower esophagus from 27 participants were collected by brushing the mucosal surface of the esophagus before (Eso) and after (Lug) LIS. Bacterial V3-V4 region of 16S rRNA gene was amplified and sequenced by Illumina's sequencing platform. RESULTS: The top six abundant bacterial phyla taxa among three locations from both Eso and Lug groups were Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, Fusobacteria and TM7. In terms of genera, the bacterium in three locations from two groups was all characterized by a highest relative abundance of Streptococcus. Bacteria diversity and the relative abundance between Eso and Lug were comparable (p > .05). Bacteria diversity was consistent in different esophageal locations within the individual. CONCLUSION: The bacterial microbiome in healthy esophagus are highly diverse and consistent even among three physiological sites at all clades. Lugol's iodine staining would not change local microenvironment in term of microbial composition. These findings provide an essential baseline for future studies investigating local and systemic bacterial microbiome and esophageal diseases.

Environmental perchlorate, thiocyanate, and nitrate exposures and bone mineral density: a national cross-sectional study in the US adults.

Associations of perchlorate, thiocyanate, and nitrate exposures with bone mineral density (BMD) in adults have not previously been studied. This study aimed to estimate the associations of individual and concurrent exposure of the three chemicals with adult BMD. Based on National Health and Nutrition Examination Survey (NHANES, 2011-2018), 1618 non-pregnant adults (age ≥ 20 years and 47.0% female) were included in this study. Survey-weighted linear regression models were used to estimate individual urinary perchlorate, thiocyanate, and nitrate concentrations with lumbar spine BMD and total BMD in adults. Then, weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models were conducted to evaluate associations of co-occurrence of the three chemicals with adult BMD. In all participants, nitrate exposure was inversely associated with lumbar spine BMD (ß = - 0.054, 95%CI: - 0.097, - 0.010). In stratification analyses, significant inverse associations were observed in female and participants older than 40 years old. In WQS regressions, significant negative associations of the weighted sum of the three chemicals with total and lumbar spine BMD (ß = - 0.014, 95%CI: - 0.021, - 0.007; ß = - 0.011, 95%CI: - 0.019, - 0.004, respectively) were found, and the dominant contributor was nitrate. In the BKMR models, non-linear dose-response associations of nitrate exposure with lumbar spine and total BMD were observed. These findings suggested that environmental perchlorate, thiocyanate, and nitrate exposure may reduce adult BMD and nitrate is the main contributor.

Urinary perchlorate, thiocyanate, and nitrate and their associated risk factors among Chinese pregnant women.

Perchlorate, nitrate, and thiocyanate are well-known inhibitors of iodide uptake and thyroid-disrupting chemicals. Widespread human exposure to them has been identified, whereas studies on their internal exposure levels among Chinese pregnant women are scarce and factors associated with them are not well recognized. The objective of this study is to determine their levels and identify the associated factors among pregnant women (n = 1120), based on a prospective birth cohort in Wuhan, central China, using repeated urine samples of three trimesters. Urinary perchlorate, thiocyanate, and nitrate were 100% detected in the samples, and specific gravity-adjusted median concentrations of them in all the samples were 12.6 ng/mL, 367 ng/mL, and 63.7 µg/mL, respectively. Their concentrations were weakly-to-moderately correlated with each other, with Spearman correlation coefficients ranging from 0.27 to 0.54. Poor reproducibility were observed for the three analytes over the three trimesters, with intraclass correlation coefficient of 0.07, 0.19, 0.04 for perchlorate, thiocyanate, and nitrate, respectively. The women who were overweight or used tap water as drinking water had significantly higher perchlorate concentrations, while those with excessive gestational weight gain had significantly higher thiocyanate concentrations (p < 0.05). The women with a college degree or above had lower nitrate concentrations (p < 0.05). Meanwhile, the median concentration of perchlorate in urine samples collected in spring, thiocyanate in those collected in winter, and nitrate in those collected in autumn, was significantly higher compared to their median concentrations in the samples collected in other three seasons (p < 0.05), respectively. Urinary perchlorate and nitrate concentrations of pregnant women in this study were higher than the concentrations of pregnant women in other countries, while thiocyanate concentrations were lower than that of most other countries. This study suggested potential covariates for future epidemiological analyses.

Exposure to multiple neonicotinoid insecticides, oxidative stress, and gestational diabetes mellitus: Association and potential mediation analyses.

As the most extensively used insecticides worldwide, neonicotinoid insecticides (NNIs) have received a growing global concern over their adverse health effects. This study aimed to assess the associations of urinary concentrations of NNIs in early pregnancy with gestational diabetes mellitus (GDM) and the mediation roles of oxidative DNA damage, RNA damage, and lipid peroxidation in the associations. With a prospective nested case-control study, 519 GDM cases and 519 controls were matched on the infant's sex and maternal age. Urinary biomarkers of NNIs exposure and oxidative stress were measured in early pregnancy. We estimated the associations of single and the mixture of NNIs and their metabolites with GDM by conditional logistic regression and quantile g-computation models, respectively. The mediating roles of oxidative stress were evaluated by the structural equation model. The odds of GDM significantly increased by 15 %, 18 %, 26 %, 42 %, 49 %, and 13 % in each unit increment of ln-transformed concentrations of urinary imidacloprid (IMI), imidacloprid-olefin (IMI-olefin), desnitro-imidacloprid (DN-IMI), thiamethoxam (THM), clothianidin, and desmethyl-clothianidin, respectively. Exposure to the mixture of NNIs was associated with increased odds of GDM (adjusted OR: 1.76; 95 %CI: 1.45, 2.13). Advanced maternal age enhanced the associations of 5-hydroxy-IMI, DN-IMI, and IMI-olefin with GDM (P < 0.05), and being overweight/obese before pregnancy strengthened the effects of IMI, IMI-olefin, and THM on GDM (P < 0.05). In the association of NNIs exposure and GDM, the proportions mediated by oxidative DNA damage, RNA damage, and overall oxidative stress were 9.8 %, 11.8 %, and 14.5 %, respectively (P < 0.05). Exposure to individual NNIs and a mixture of NNIs were associated with GDM, and maternal age and pre-pregnancy BMI may modify the association. The possible mechanism underlying the association between NNIs and GDM may involve oxidative damage to nucleic acids.

Associations of Gestational Diabetes Mellitus and Excessive Gestational Weight Gain with Offspring Obesity Risk.

OBJECTIVE: Gestational diabetes mellitus (GDM) and gestational weight gain (GWG) are important risk factors that are known to affect offspring growth, but these outcomes are inconsistent and it remains unknown if both risk factors have a synergetic effect on early childhood growth. The present study aimed to conduct offspring body mass index-for-age Z-scores (BMIZ) trajectories and to evaluate the independent and interactive effect of the status of GDM and excessive GWG on the risks of overweight/obesity from birth to 24 months of age. METHODS: A total of 7949 mother-child pairs were enrolled in this study. The weight and length of children were measured at birth, 6, 12, and 24 months of age to calculate BMIZ. RESULTS: The status of GDM was positively associated with offspring BMIZ and risk of macrosomia at birth but was not associated with offspring BMIZ or the risks of overweight/obesity at 6, 12, and 24 months of age. In contrast, excessive GWG was positively linked to offspring BMIZ, the stable high BMIZ trajectory pattern, and risks of overweight/obesity in the first 24 months of age. These two risk factors also had a significant synergistic effect on macrosomia at birth, but the interactive effect was only significant in boys during the follow-up years in the sex-stratified analyses. CONCLUSION: The maternal GWG was a more pronounced predictor than GDM with relation to BMIZ and risk of overweight/obesity in early childhood. The interactive effect between these risk factors on offspring overweight/obesity may vary by sex.

Urinary paracetamol (4-acetaminophenol) and its isomer 2-acetaminophenol of Chinese pregnant women: Exposure characteristics and association with oxidative stress biomarkers.

N-Acetyl-4-aminophenol (NA4AP, paracetamol/acetaminophen), a widely used pharmaceutical, is ubiquitous in urine samples of general population, raising concern about human health risks; oxidative stress is considered to be a mechanism for its toxicities. N-Acetyl-2-aminophenol (NA2AP) is an isomer of NA4AP; until now, few studies characterized exposure characteristics of NA4AP and NA2AP in pregnant women. In this work, NA4AP and NA2AP concentrations in urine samples (n = 2124) collected at three different trimesters were measured to examine their internal body burden among Chinese pregnant women (n = 708) and their associations with three oxidative stress biomarkers (OSBs, 8-OHG, 8-OHdG, and HNE-MA). NA4AP was detected in 100% of the urine samples (median concentration: 7.96 ng/mL); NA2AP was detected in 94.9% of them (median: 3.05 ng/mL). The intraclass correlation coefficients of their concentrations across three trimesters were poor (<0.4); correlations of NA4AP and NA2AP were weak (r: 0.15-0.23). Pregnant women who had higher household income or urine samples provided in summer (vs. winter) had higher concentrations of NA4AP. Pregnant women who had a college degree or above (vs. less than a high school education) had higher concentrations of NA2AP but urine samples provided in summer (vs. winter) had lower concentrations of NA2AP. The 95th percentile estimated daily intake of NA4AP (2,331 ng/kg-bw/d) based on averaged concentrations of the three trimesters was 40 times lower than the cRfD for NA4AP (2.33 vs. 93 µg/kg-bw/d). Urinary concentrations of NA4AP and NA2AP were associated with higher levels of the selected OSBs. For example, an interquartile range increase in NA4AP was associated with a 26.5% (95% CI: 23.6-29.6%) increase in 8-OHG, a 27.5% (95% CI: 23.8-31.3%) increase in 8-OHdG, and a 33.4% (95% CI: 24.7-42.7%) increase in HNE-MA (p < 0.05). This is the first study to measure their concentrations repeatedly over three trimesters, examine their exposure characteristics, and reveal their associations with the selected OSBs in pregnant women. Further studies are needed to identify non-intentional exposure sources of NA4AP, NA2AP, and another isomer of them (i.e., N-acetyl-3-aminophenol), as well as more health risks related to their exposure.

Sex-specific associations of early postnatal blood copper levels with neurodevelopment at 2 years of age.

Copper (Cu) is an essential trace element; however, it can be harmful in excess. Previous studies have shown that prenatal Cu levels may affect childhood neurodevelopment; however, studies focused on early postnatal Cu levels are limited. We studied 843 children born in Wuhan City and investigated the associations between early life Cu levels and neurodevelopment in 2-year-old children. Blood samples collected from children at 12 and 24 months of age were used to analyze Cu levels. Neurodevelopment was scored using the Bayley Scale of Children at 24 months of age. We found that a higher Cu level at 12 months of age was positively associated with mental development index (MDI) in boys (ß = 6.75, 95 %CI: 1.12, 12.38). Further non-linear analysis showed an inverted U-shape association between Cu level at 20 months and PDI in boys, indicating that Cu levels may have an optimal concentration for neurodevelopment (p for overall association = 0.01, p for non-linear association < 0.01). In addition, all meaningful results mentioned above were observed only in boys, and a statistically significant sex-related modifying effect was observed (p < 0.05). In conclusion, this study repeated measures early life Cu levels and suggested sex-specific associations between early life Cu levels and neurodevelopment in 2-year-old children.

Prenatal exposure to organochlorine pesticides and infant growth: A longitudinal study.

BACKGROUND: The association between exposure to organochlorine pesticides (OCPs) and infant growth has been reported contradictorily in previous studies. Few studies have investigated the effects of prenatal exposure to OCPs on infant growth assessed longitudinally at multiple time points. OBJECTIVES: The purpose of the study was to examine the associations between prenatal exposure to OCPs and infant growth at birth, 6, 12 and 24 months of age, and further to explore the potential sex-specific effects. METHODS: The study population included 1039 mother-infant pairs who participated in a birth cohort study in Wuhan, China. The weight, length and body mass index (BMI) z-score of infants were measured and calculated at birth, 6, 12 and 24 months of age. The overweight status was defined as BMI z-score ≥ 85th percentile according to the standard of World Health Organization. The concentrations of OCPs were measured in cord serum, including hexachlorocyclohexanes (HCHs, consisted of α-HCH, ß-HCH, and γ-HCH), p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) and its metabolites: p,p'-dichlorodiphenyldichloroethane (p,p'-DDD), and p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE). Generalized linear models were applied to estimate the associations of cord OCPs with infant growth parameters. A group-based semiparametric mixture model was used to estimate growth patterns of infants. Linear-mixed growth curve models were used to examine relationships between predicted growth trajectories and prenatal exposure to OCPs. Weighted quantile sum regression (WQSR) analyses were used to estimate the mixture effects of OCPs on infant growth. RESULTS: Higher cord serum ß-HCH concentrations were associated with higher BMI z-score at 12 [ß = 0.07, 95%CI: 0.01, 0.13] and 24 months of age [ß = 0.08, 95% CI: 0.02, 0.14]. Similar patterns were observed for relationships of γ-HCH [ß = 0.04, 95%CI: 0.01, 0.07] and p,p'-DDT [ß = 0.03, 95% CI: 0.00, 0.06] with BMI z-score at 6 and 12 months of age, respectively. However, higher cord serum p,p'-DDE concentrations were associated with a reduction of BMI z-score at 6 months of age [ß = -0.07, 95% CI: -0.12, -0.01]. Cord serum ß-HCH was also positively associated with the risk of overweight at 12 months of age [RR = 1.16, 95% CI (1.02, 1.33), for the medium vs the lowest tertile]. Among girls, the effects of ß-HCH on BMI z-score and overweight status were stronger than boys at 12 and 24 months of age. No statistically significant relationships of other OCPs with infant growth were observed. CONCLUSIONS: Prenatal exposure to ß-HCH was associated with increased BMI z-score and higher risk of overweight status in infants especially at 12 and 24 months of age, which seemed to be stronger in girls.

Impacts of Ambient Fine Particulate Matter on Blood Pressure Pattern and Hypertensive Disorders of Pregnancy: Evidence From the Wuhan Cohort Study.

[Figure: see text].

Preconceptional and the first trimester exposure to PM2.5 and offspring neurodevelopment at 24 months of age: Examining mediation by maternal thyroid hormones in a birth cohort study.

Prenatal fine particulate matter (PM2.5) exposure has been associated with impaired offspring neurodevelopment; however, the association of PM2.5 exposure during preconception with offspring's neurodevelopment and factors responsible for this association are still unclear. This study estimated the associations of PM2.5 exposure during preconception and the first trimester with offspring neurodevelopment and evaluated whether maternal thyroid hormones mediate these associations. We recruited 1329 mother-child pairs between 2013 and 2015 in Wuhan, China. PM2.5 exposure levels of each woman during the 3 months preconception and the first trimester were estimated using land-use regression models. Offspring neurodevelopment characterized by mental developmental index (MDI) and psychomotor developmental index (PDI) were measured at 24 months of age. Maternal serum levels of free thyroxine (FT3), free triiodothyronine (FT4), and thyroid-stimulating hormone (TSH) during early pregnancy were measured of a subset of the 1329 women (551 women). Generalized estimation equation and general linear regression models were used to estimate the associations between maternal PM2.5 exposure, thyroid hormones, and offspring neurodevelopment. After adjusting for potential confounders, we found that either among all participants or the subset, PM2.5 exposure during preconception and the first trimester was negatively associated with offspring PDI. Double increment in the first trimester PM2.5 exposure was significantly associated with 3.43 and 6.48 points decrease in offspring MDI. In the subset, each doubling of PM2.5 exposure during preconception and the first trimester was significantly associated with 7.93 and 8.02 points decrease in maternal FT4 level, respectively. Increased maternal FT4, in turn, was associated with increased PDI (ß = 16.69, 95% CI: 5.39, 27.99). About 7.7% (95% CI: 2.0%-19.4%) and 8.6% (95% CI: 3.0%, 22.1%) of the effect of PM2.5 exposure during preconception on offspring PDI was mediated through maternal FT4 and the FT4/FT3 ratio, respectively.

Associations of urine metals and metal mixtures during pregnancy with cord serum vitamin D Levels: A prospective cohort study with repeated measurements of maternal urinary metal concentrations.

BACKGROUND: Vitamin D deficiency has been associated with the increased risk of many diseases, especially during early life. Exposure to some toxic metals may decrease vitamin D levels in adults and children in previous studies. However, less is known about the associations of maternal metals exposure during pregnancy with newborns' vitamin D status. OBJECTIVE: We conducted a prospective cohort study to investigate the relationships between urine metals and metal mixtures during pregnancy and newborns' vitamin D status. METHODS: Urine samples of 598 pregnant women were collected in each trimester and cord blood samples of newborns were collected at delivery. The concentrations of 20 metals in urine and 25-hydroxyvitamin D [25(OH)D] in cord serum were quantified. Generalized linear models were used to estimate the associations between individual metals and cord serum total 25(OH)D. We applied Bayesian Kernel Machine Regression (BKMR) to evaluate the mixture and interaction effects of urine metals. RESULTS: In individual metals analyses, we reported that a double increase in urine vanadium (V), cobalt (Co), and thallium (Tl) throughout pregnancy was associated with a 9.91% [95% confidence interval (CI): -18.58%, -0.30%], 11.42% (95% CI: -17.73%, -4.63%), and 12.64% (95% CI: -21.44%, -2.86%) decrease in cord serum total 25(OH)D, respectively. Exposures to the three metals during the whole pregnancy were also correlated to increased odds for newborns' vitamin D deficiency (<20 ng/mL) [odds ratio (95% CI): 1.80 (1.05, 3.10) for V, 1.88 (1.25, 2.82) for Co, and 1.90 (1.07, 3.38) for Tl]. BKMR analyses revealed a negative influence of metal mixtures (V+Co+Tl) on neonatal vitamin D status, as well as potential synergism between V and Co and between V and Tl. CONCLUSIONS: Our study provides evidence of negative impacts of maternal exposure to V, Co, and Tl during pregnancy on cord serum vitamin D levels at delivery. Potential synergism between V and Co and between V and Tl existed in their associations with cord serum total 25(OH)D.

Association between exposure to per- and polyfluoroalkyl substances and blood glucose in pregnant women.

Increasing evidence shows that exposure to per- and polyfluoroalkyl substances (PFASs), common and persistent anthropogenic pollutants, may affect glucose homeostasis. However, data is limited for pregnant women, and it is less clear how novel fluorinated pollutants affect glucose homeostasis during pregnancy. Our goal was to investigate the relationships of exposure to13 PFASs including some novel fluorinated pollutants with blood glucose in 874 Chinese pregnant women from the general population. We measured blood glucose following an oral glucose tolerance test (OGTT) in the second trimester and quantified PFAS concentrations in umbilical cord blood. The associations of PFAS exposure with fasting, 1-h OGTT and 2-h OGTT glucose were examined using the general linear regression model. For every doubling of perfluorobutane sulfonate (PFBS), a short-chain PFAS, the 1-h and 2-h OGTT blood glucose increased 0.09 mmol/L (ß = 0.09, 95%CI: 0.02, 0.17) and 0.07 mmol/L (ß = 0.07, 95%CI: 0.01, 0.13), respectively. In addition, perfluoroheptanoate (PFHpA), an alternative of perfluorooctanoate (PFOA), was positively associated with fasting glucose (ß = 0.07, 95%CI: 0.02, 0.13; high vs low). Higher levels of PFAS exposure were related to increased blood glucose in pregnant women, indicating PFAS exposure may impair glucose homeostasis during pregnancy.

Prenatal and postnatal cadmium exposure and cellular immune responses among pre-school children.

BACKGROUND: Experimental studies have demonstrated that cadmium exposure induces alterations on immune function, but epidemiological evidence is lacking. OBJECTIVE: To examine the associations between prenatal and postnatal cadmium exposure and cellular immune responses among pre-school children. METHODS: Pre-school aged children (n = 407) were followed from a prospective birth cohort study in Wuhan, China. Maternal urinary and children's plasma cadmium concentrations were measured as biomarkers of prenatal and postnatal cadmium exposure, respectively. Children's cellular immune responses were assessed by peripheral blood T lymphocyte subsets and plasma cytokines. Multivariable adjusted models were applied to estimate the associations of prenatal and postnatal cadmium exposure with T lymphocyte subsets and cytokines, and the effect modification by child gender were also examined. RESULTS: Maternal urinary cadmium was associated with reduced absolute counts of CD3+CD4+ cells (-12.45%; 95% CI: -23.74%, 0.40% for the highest vs. lowest quartile; p for trend = 0.045). Inverse associations of maternal urinary cadmium with %CD3+CD4+ cells and CD4+/CD8+ ratio were only observed among females (both p-interaction < 0.050); whereas an inverse association with absolute counts of CD3+CD8+ cells was only observed among males (p-interaction = 0.057). Positive associations of maternal urinary cadmium with %CD3+CD4+ cells, interleukin-4 (IL-4), and IL-6 were only observed among females, although there were no significant interactions. We observed no clear associations of children's plasma cadmium with T lymphocyte subsets and cytokines. CONCLUSION: Prenatal but not postnatal cadmium exposure was associated with sex-specific alterations on children's cellular immune responses.