Prenatal fluoride exposure, offspring visual acuity and autonomic nervous system function in 6-month-old infants.

BACKGROUND: Prenatal fluoride exposure can have adverse effects on children's development; however, associations with visual and cardiac autonomic nervous system functioning are unknown. We examined associations between prenatal fluoride exposure and visual acuity and heart rate variability (HRV) in 6-month-old infants. METHODS: We used data from Canadian mother-infant pairs participating in the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort. We estimated prenatal fluoride exposure using: i) fluoride concentration in drinking water (mg/L), ii) maternal urinary fluoride adjusted for specific gravity (MUFSG; mg/L) and averaged across pregnancy, and iii) maternal fluoride intake (µg/kg/day) from consumption of water, tea, and coffee, adjusted for maternal body weight (kg). We used multivariable linear regression to examine associations between each measure of fluoride exposure and Teller Acuity Card visual acuity scores (n = 435) and assessed HRV (n = 400) using two measures: root mean square of successive differences (RMSSD) and the standard deviation of N-N intervals (SDNN) measured at 6-months of age. RESULTS: Median (IQR) values for water fluoride, MUFSG, and daily fluoride intake were 0.20 (IQR: 0.13-0.56) mg/L; 0.44 (0.28-0.70) mg/L and 4.82 (2.58-10.83) µg/kg/day, respectively. After adjustment for confounding variables, water fluoride concentration was associated with poorer infant visual acuity (B = -1.51; 95 % CI: -2.14,-0.88) and HRV as indicated by lower RMSSD (B = -1.60; 95 % CI: -2.74,-0.46) but not SDNN. Maternal fluoride intake was also associated with poorer visual acuity (B = -0.82; 95 % CI: -1.35,-0.29) and lower RMSSD (B = -1.22; 95 % CI: -2.15,-0.30). No significant associations were observed between MUFSG and visual acuity or HRV. CONCLUSION: Fluoride in drinking water was associated with reduced visual acuity and alterations in cardiac autonomic function in infancy, adding to the growing body of evidence suggesting fluoride's developmental neurotoxicity.

Cohort profile update: The Canadian Maternal-Infant Research on Environmental Chemicals Child Development study (MIREC-CD PLUS).

BACKGROUND: The pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study was established to determine whether maternal environmental chemical exposures were associated with adverse pregnancy outcomes in 2001 pregnant women. OBJECTIVES: The MIREC-Child Development (CD PLUS) study followed this cohort with the goal of assessing the potential effects of prenatal exposures on anthropometry and neurodevelopment in early childhood. POPULATION: MIREC families with children between the ages of 15 months and 5 years who had agreed to be contacted for future research (n = 1459) were invited to participate in MIREC-CD PLUS which combines data collected from an online Maternal Self-Administered Questionnaire with biomonitoring and neurodevelopment data collected from two in-person visits. PRELIMINARY RESULTS: Between April 2013 and March 2015, 803 children participated in the Biomonitoring visit where we collected anthropometric measures, blood, and urine from the children. The Behavioural Assessment System for Children-2, Behaviour Rating Inventory of Executive Function, MacArthur-Bates Communicative Development Inventories and the Communication subscale of the Adaptive Behaviour Scale from the Bayley Scales of Infant and Toddler Development-III are available on close to 900 children. There were 610 singleton children who completed in-person visits for neurodevelopment assessments including the Social Responsiveness Scale, Wechsler Preschool Primary Scale of Intelligence-III and NEuroPSYchological assessments (NEPSY). Currently, we are following the cohort into early adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). CONCLUSIONS: Data collection for the MIREC-CD PLUS study is complete and analysis of the data continues. We are now extending the follow-up of the cohort into adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). MIREC-CD PLUS is limited by loss to follow-up and the fact that mothers are predominately of higher socioeconomic status and 'White' ethnicity, which limits our generalizability. However, the depth of biomonitoring and clinical measures in MIREC provides a platform to examine associations of prenatal, infancy and childhood exposures with child growth and development.

Folate concentrations and serum perfluoroalkyl and polyfluoroalkyl substance concentrations in adolescents and adults in the USA (National Health and Nutrition Examination Study 2003-16): an observational study.

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a family of highly fluorinated aliphatic compounds, which are widely used in commercial applications, including food packaging, textiles, and non-stick cookware. Folate might counteract the effects of environmental chemical exposures. We aimed to explore the relationship between blood folate biomarker concentrations and PFAS concentrations. METHODS: This observational study pooled cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2003 to 2016 cycles. NHANES is a population-based national survey that measures the health and nutritional status of the US general population every 2 years by means of questionnaires, physical examination, and biospecimen collection. Folate concentrations in red blood cells and in serum, and perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS) concentrations in serum were examined. We used multivariable regression models to assess the percentage change in serum PFAS concentrations in relation to changes in folate biomarker concentrations. We additionally used models with restricted cubic splines to investigate the shape of these associations. FINDINGS: This study included 2802 adolescents and 9159 adults who had complete data on PFAS concentrations, folate biomarkers, and covariates, were not pregnant, and had never had a cancer diagnosis at the time of the survey. The mean age was 15·4 years (SD 2·3) for adolescents and 45·5 years (17·5) for adults. The proportion of male participants was slightly higher in adolescents (1508 [54%] of 2802 participants) than in adults (3940 [49%] of 9159 participants). We found negative associations between red blood cell folate concentrations and serum concentrations of PFOS (percentage change for a 2·7 fold-increase in folate level -24·36%, 95% CI -33·21 to -14·34) and PFNA (-13·00%, -21·87 to -3·12) in adolescents, and PFOA (-12·45%, -17·28 to -7·35), PFOS (-25·30%, -29·67 to -20·65), PFNA (-21·65%, -26·19 to -16·82), and PFHxS (-11·70%, -17·32 to 5·70) in adults. Associations for serum folate concentrations and PFAS were in line with those found for red blood cell folate levels, although the magnitude of the effects was lower. Restricted cubic spline models suggested linearity of the observed associations, particularly for associations in adults. INTERPRETATION: In this large-scale, nationally representative study, we found consistent inverse associations for most examined serum PFAS compounds in relation to folate concentrations measured in either red blood cells or serum among both adolescents and adults. These findings are supported by mechanistic in-vitro studies that show the potential of PFAS to compete with folate for several transporters implicated in PFAS toxicokinetics. If confirmed in experimental settings, these findings could have important implications for interventions to reduce the accumulated PFAS body burden and mitigate the related adverse health effects. FUNDING: United States National Institute of Environmental Health Sciences.

Diet Quality, Microbial Lignan Metabolites, and Cardiometabolic Health among US Adults.

The gut microbiome has been shown to play a role in the relationship between diet and cardiometabolic health. We sought to examine the degree to which key microbial lignan metabolites are involved in the relationship between diet quality and cardiometabolic health using a multidimensional framework. This analysis was undertaken using cross-sectional data from 4685 US adults (age 43.6 ± 16.5 years; 50.4% female) participating in the National Health and Nutrition Examination Survey for 1999-2010. Dietary data were collected from one to two separate 24-hour dietary recalls and diet quality was characterized using the 2015 Healthy Eating Index. Cardiometabolic health markers included blood lipid profile, glycemic control, adiposity, and blood pressure. Microbial lignan metabolites considered were urinary concentrations of enterolignans, including enterolactone and enterodiol, with higher levels indicating a healthier gut microbial environment. Models were visually examined using a multidimensional approach and statistically analyzed using three-dimensional generalized additive models. There was a significant interactive association between diet quality and microbial lignan metabolites for triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, insulin, oral glucose tolerance, adiposity, systolic blood pressure, and diastolic blood pressure (all p < 0.05). Each of these cardiometabolic health markers displayed an association such that optimal cardiometabolic health was only observed in individuals with both high diet quality and elevated urinary enterolignans. When comparing effect sizes on the multidimensional response surfaces and model selection criteria, the strongest support for a potential moderating relationship of the gut microbiome was observed for fasting triglycerides and oral glucose tolerance. In this study, we revealed interactive associations of diet quality and microbial lignan metabolites with cardiometabolic health markers. These findings suggest that the overall association of diet quality on cardiometabolic health may be affected by the gut microbiome.

Association between toxic metals, vitamin D and preterm birth in the Maternal-Infant research on environmental chemicals study.

BACKGROUND: Toxic metals, like lead, are risk factors for preterm birth (PTB), but few studies have examined low levels found in most Canadians. Vitamin D, which may have antioxidant activity, protects against PTB. OBJECTIVES: In this study, we investigated the impact of toxic metals (lead, mercury, cadmium and arsenic) on PTB and examined if maternal plasma vitamin D concentrations modify these associations. METHODS: We investigated whether concentrations of metals in whole blood measured in early and late pregnancy were associated with PTB (<37 weeks) and spontaneous PTB in 1851 live births from the Maternal-Infant Research on Environmental Chemicals Study using discrete time survival analysis. We also investigated whether the risk of PTB was modified by first-trimester plasma 25-hydroxyvitamin D (25OHD) concentrations. RESULTS: Of 1851 live births, 6.1% (n = 113) were PTBs and 4.9% (n = 89) were spontaneous PTB. A 1 µg/dL increase in blood lead concentrations during pregnancy was associated with an increased risk of PTB (relative risk [RR] 1.48, 95% confidence interval [CI] 1.00, 2.20) and spontaneous PTB (RR 1.71, 95% CI 1.13, 2.60). The risk was higher in women with insufficient vitamin D concentrations (25OHD <50 nmol/L) for both PTB (RR 2.42, 95% CI 1.01, 5.79) and spontaneous PTB (RR 3.04, 95% CI 1.15, 8.04). However, an interaction on the additive scale was not present. Arsenic was associated with a higher risk of PTB (RR 1.10, 95% CI 1.02, 1.19) and spontaneous PTB (RR 1.11, 95% CI 1.03, 1.20) per 1 µg/L. CONCLUSIONS: Gestational exposure to low levels of lead and arsenic may increase the risk of PTB and spontaneous PTB; individuals with insufficient vitamin D may be more susceptible to the adverse effects of lead. Given our relatively small number of cases, we encourage testing of this hypothesis in other cohorts, especially those with vitamin D-deficient populations.

Palaeolithic diet score and risk of breast cancer among postmenopausal women overall and by hormone receptor and histologic subtypes.

BACKGROUND: The Palaeolithic diet (PD) has gained popularity globally. There is emerging evidence of its putative health benefits as short-term effects on chronic diseases have been reported. We evaluated the association between long-term adherence to the PD and breast cancer (BC) risk among postmenopausal women. METHODS: 65,574 women from the Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale (E3N) cohort were followed from 1993 to 2014. Incident BC cases were identified and validated. The PD score was calculated using dietary intake self-reported at baseline (1993) and follow-up (2005) or baseline only if censored before follow-up. Multivariable Cox proportional hazards regression models were used to estimate BC hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Over a mean follow-up of 20 years, 3968 incident BC cases occurred. An increase of 1 standard deviation in the PD score was associated with an 8% lower BC risk, fully-adjusted model: HR1-SD 0.92, 95% CI; 0.89, 0.95. Compared to women with low adherence to the PD, women with high adherence had a 17% lower BC risk, HRQ5 vs Q1 0.83, 95% CI; 0.75, 0.92, Ptrend < 0.01. When considering BC subtypes, we observed the same pattern of association (Pheterogeneity > 0.10 for all). CONCLUSIONS: High adherence to a PD characterised by fruit, vegetables, nuts, fish, and lean meat and limited in dairy, grains, legumes, refined sugar, and alcohol was associated with a lower BC risk. The lack of heterogeneity according to BC subtypes could indicate the involvement of non-hormonal mechanisms. The protocol is registered at clinicaltrials.gov as NCT03285230. REGISTRY: The protocol is registered at clinicaltrials.gov as NCT03285230.

Reducing the complexity of high-dimensional environmental data: An analytical framework using LASSO with considerations of confounding for statistical inference.

PURPOSE: Frameworks for selecting exposures in high-dimensional environmental datasets, while considering confounding, are lacking. We present a two-step approach for exposure selection with subsequent confounder adjustment for statistical inference. METHODS: We measured cognitive ability in 338 children using the Woodcock-Muñoz General Intellectual Ability (GIA) score, and potential associated features across several environmental domains. Initially, 111 variables theoretically associated with GIA score were introduced into a Least Absolute Shrinkage and Selection Operator (LASSO) in a 50% feature selection subsample. Effect estimates for selected features were subsequently modeled in linear regressions in a 50% inference (hold out) subsample, first adjusting for sex and age and later for covariates selected via directed acyclic graphs (DAGs). All models were adjusted for clustering by school. RESULTS: Of the 15 LASSO selected variables, eleven were not associated with GIA score following our inference modeling approach. Four variables were associated with GIA scores, including: serum ferritin adjusted for inflammation (inversely), mother's IQ (positively), father's education (positively), and hours per day the child works on homework (positively). Serum ferritin was not in the expected direction. CONCLUSIONS: Our two-step approach moves high-dimensional feature selection a step further by incorporating DAG-based confounder adjustment for statistical inference.

Exposure to perfluoroalkyl substances and women's fertility outcomes in a Singaporean population-based preconception cohort.

OBJECTIVES: Experimental models have demonstrated a link between exposure to perfluoroalkyl substances (PFAS) and decreased fertility and fecundability; however, human studies are scarce. We assessed the associations between preconception plasma PFAS concentrations and fertility outcomes in women. METHODS: In a case-control study nested within the population-based Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO), we measured PFAS in plasma collected in 2015-2017 from 382 women of reproductive age trying to conceive. Using Cox proportional hazards regression (fecundability ratios [FRs]) and logistic regression (odds ratios [ORs]) models, we assessed the associations of individual PFAS with time-to-pregnancy (TTP), and the likelihoods of clinical pregnancy and live birth, respectively, over one year of follow-up, adjusting for analytical batch, age, education, ethnicity, and parity. We used Bayesian weighted quantile sum (BWQS) regression to assess the associations of the PFAS mixture with fertility outcomes. RESULTS: We found a 5-10 % reduction in fecundability per quartile increase of exposure to individual PFAS (FRs [95 % CIs] for clinical pregnancy = 0.90 [0.82, 0.98] for PFDA; 0.88 [0.79, 0.99] for PFOS; 0.95 [0.86, 1.06] for PFOA; 0.92 [0.84, 1.00] for PFHpA). We observed similar decreased odds of clinical pregnancy (ORs [95 % CIs] = 0.74 [0.56, 0.98] for PFDA; 0.76 [0.53, 1.09] for PFOS; 0.83 [0.59, 1.17] for PFOA; 0.92 [0.70, 1.22] for PFHpA) and live birth per quartile increases of individual PFAS and the PFAS mixture (ORs [95 % CIs] = 0.61 [0.37, 1.02] for clinical pregnancy, and 0.66 [0.40, 1.07] for live birth). Within the PFAS mixture, PFDA followed by PFOS, PFOA, and PFHpA were the biggest contributors to these associations. We found no evidence of association for PFHxS, PFNA, and PFHpS and the fertility outcomes examined. CONCLUSIONS: Higher PFAS exposures may be associated with decreased fertility in women. The potential impact of ubiquitous PFAS exposures on infertility mechanisms requires further investigation.

Associations with Blood Lead and Urinary Cadmium Concentrations in Relation to Mortality in the US Population: A Causal Survival Analysis with G-Computation.

Using the parametric g-formula, we estimated the 27-year risk of all-cause and specific causes of mortality under different potential interventions for blood lead (BLLs) and urinary cadmium (UCd) levels. We used data on 14,311 adults aged ≥20 years enrolled in the NHANES-III between 1988 and 1994 and followed up through 31 Dec 31 2015. Time and cause of death were determined from the National Death Index records. We used the parametric g-formula with pooled logistic regression models to estimate the relative and absolute risk of all-cause, cardiovascular, and cancer mortality under different potential threshold interventions for BLLs and UCd concentrations. Median follow-up was 22.5 years. A total of 5167 (36%) participants died by the end of the study, including 1550 from cardiovascular diseases and 1135 from cancer. Increases in BLLs and creatinine-corrected UCd levels from the 5th to the 95th percentiles were associated with risk differences of 4.17% (1.54 to 8.77) and 6.22% (4.51 to 12.00) for all-cause mortality, 1.52% (0.09 to 3.74) and 1.06% (-0.57 to 3.50) for cardiovascular disease mortality, and 1.32% (-0.09 to 3.67) and 0.64% (-0.98 to 2.80) for cancer mortality, respectively. Interventions to reduce historical exposures to lead and cadmium may have prevented premature deaths, especially from cardiovascular disease.

Prenatal and childhood chlordecone exposure, cognitive abilities and problem behaviors in 7-year-old children: the TIMOUN mother-child cohort in Guadeloupe.

BACKGROUND: Chlordecone is a highly persistent organochlorine insecticide that was intensively used in banana fields in the French West Indies, resulting in a widespread contamination. Neurotoxicity of acute exposures in adults is well recognized, and empirical data suggests that prenatal exposure affects visual and fine motor developments during infancy and childhood, with greater susceptibility in boys. OBJECTIVE: To assess the associations between pre- and postnatal exposures to chlordecone and cognitive and behavioral functions in school-aged children from Guadeloupe. METHODS: We examined 576 children from the TIMOUN mother-child cohort in Guadeloupe at 7 years of age. Concentrations of chlordecone and other environmental contaminants were measured in cord- and children's blood at age 7 years. Cognitive abilities of children were assessed with the Wechsler Intelligence Scale for Children-IV (WISC-IV), and externalizing and internalizing problem behaviors documented with the Strengths and Difficulties Questionnaire (SDQ) completed by the child's mother. We estimated covariate-adjusted associations between cord- and 7-years chlordecone concentrations and child outcomes using structural equations modeling, and tested effect modification by sex. RESULTS: Geometric means of blood chlordecone concentrations were 0.13 µg/L in cord blood and 0.06 µg/L in children's blood at age 7 years. A twofold increase in cord blood concentrations was associated with 0.05 standard deviation (SD) (95% Confidence Interval [CI]: 0.0, 0.10) higher internalizing problem scores, whereas 7-years chlordecone concentrations were associated with lower Full-Scale IQ scores (FSIQ) and greater externalized behavioral problem scores. A twofold increase in 7-year chlordecone concentrations was associated with a decrease of 0.67 point (95% CI: -1.13, -0.22) on FSIQ and an increase of 0.04 SD (95% CI: 0.0, 0.07) on externalizing problems. These associations with Cognitive abilities were driven by decreases in perceptive reasoning, working memory and verbal comprehension. Associations between 7-year exposure and perceptive reasoning, working memory, and the FSIQ were stronger in boys, whereas cord blood and child blood associations with internalizing problems were stronger in girls. CONCLUSIONS: These results suggests that cognitive abilities and externalizing behavior problems at school age are impaired by childhood, but not in utero, exposure to chlordecone, and that prenatal exposure is related to greater internalizing behavioral problems.

Association between urinary phthalate biomarker concentrations and adiposity among postmenopausal women.

BACKGROUND: Obesity is a leading risk factor for chronic diseases, potentially related to excess abdominal adiposity. Phthalates are environmental chemicals that have been suggested to act as obesogens, driving obesity risk. For the associations between phthalates and adiposity, prior studies have focused primarily on body mass index. We hypothesize that more refined measures of adiposity and fat distribution may provide greater insights into these associations given the role of central adiposity in chronic disease risk. OBJECTIVES: To evaluate associations between urinary phthalate biomarkers and both visceral and subcutaneous adipose tissue (VAT and SAT) among postmenopausal women enrolled in the Women's Health Initiative (WHI). METHODS: We included 1125 WHI participants with available, coincident measurements of urinary phthalate biomarkers (baseline, year 3) and VAT and SAT (baseline, year 3, year 6). VAT and SAT measurements were estimated from DXA scans. Multilevel mixed-effects models estimated the prospective associations between urinary phthalate biomarkers at baseline and VAT and SAT three years later. RESULTS: In multivariable adjusted models, we observed positive associations between some phthalate biomarkers, including the sum of di-isobutyl phthalate (ΣDiBP) biomarkers, MCNP, and ΣDEHP, with VAT three years later. For example, we observed positive associations between concentrations of ΣDiBP and VAT (Q4 vs Q1 ß = 7.15, 95% CI -1.76-16.06; Q3 vs Q1 ß = 10.94, 95% CI 3.55-18.33). Associations were generally attenuated but remained significant after additional adjustment for SAT. MBzP was positively associated with SAT. Other phthalate biomarkers investigated (MEP, MCOP, MCPP, ΣDBP) were not significantly associated with VAT or SAT. DISCUSSION: Based on robust measures of adiposity, this study provides supportive evidence that higher urinary concentrations of select phthalate compounds were associated with higher VAT levels over time in postmenopausal women. Efforts to replicate these findings are needed.

Dietary patterns and urinary phthalate exposure among postmenopausal women of the Women's Health Initiative.

BACKGROUND: Phthalates are endocrine-disrupting chemicals linked to a higher risk of numerous chronic health outcomes. Diet is a primary source of exposure, but prior studies exploring associations between dietary patterns and phthalate exposure are limited. OBJECTIVES: We evaluated the associations between dietary patterns and urinary phthalate biomarkers among a subset of postmenopausal women participating in the Women's Health Initiative (WHI). METHODS: We included WHI participants selected for a nested case-control study of phthalates and breast cancer (N = 1240). Dietary intake was measured via self-administered food frequency questionnaires at baseline and year-3. We used these data to calculate scores for alignment with the Dietary Approach to Stop Hypertension (DASH), alternative Mediterranean (aMed), and Dietary Inflammatory Index (DII) diets. We measured 13 phthalate metabolites and creatinine in 2-3 urine samples per participant collected over 3-years when all participants were cancer-free. We fit multivariable generalized estimating equation models to estimate the cross-sectional associations. RESULTS: DASH and aMed dietary scores were inversely associated with the sum of di(2-Ethylhexyl) phthalate (-6.48%, 95% CI -9.84, -3.00; -5.23%, 95% CI -8.73, -1.60) and DII score was positively associated (9.00%, 95% CI 5.04, 13.11). DASH and aMed scores were also inversely associated with mono benzyl phthalate and mono-3-carboxypropyl phthalate. DII scores were positively associated with mono benzyl phthalate and the sum of di-n-butyl phthalate. DISCUSSION: Higher dietary alignment with DASH and aMed dietary patterns were significantly associated with lower concentrations of certain phthalate biomarkers, while an inflammatory diet pattern was associated with higher phthalate biomarker concentrations. These findings suggest that dietary patterns high in fruits, vegetables, and low-fat foods and low in processed foods may be useful in avoiding exposure to phthalates.

Effects of Lifetime Exposures to Environmental Contaminants on the Adult Gut Microbiome.

Emerging experimental evidence indicates that toxicant-induced alterations in gut microbiota composition and activity may affect host homeostasis. However, data from human studies are scarce; to our knowledge, no previous studies have quantified the association of lifetime exposure to environmental chemicals, across multiple time points, with the composition of the adult gut microbiome. Here we studied 124 individuals born in the Faroe Islands in 1986-1987 who were followed approximately every seven years from birth through age 28 years. Organochlorine compounds, including polychlorinated biphenyls (PCBs) and pesticides, perfluoroalkyl substances (PFAS), and mercury (Hg), were measured in cord blood and longitudinally in participants' blood. At age 28, the gut microbiome was assessed using shotgun metagenomic sequencing. Historical contaminant exposures had little direct effect on the adult gut microbiome, while a small number of fastidious anaerobes were weakly linked to recent PFAS/PFOS exposures at age 28. In this cohort, our findings suggest no lasting effects of early life exposures on adult gut microbial composition, but proximal exposures may contribute to gut microbiome alterations. The methods developed and used for this investigation may help in future identification of small but lasting impacts of environmental toxicant exposure on the gut microbiome.

Potential benefits of joint hypothetical interventions on diet, lead, and cadmium on mortality in US adults.

BACKGROUND: Previous studies reported associations between high blood lead levels (BLLs) and urinary cadmium (UCd) concentrations and all-cause and cause-specific mortality. It is hypothesized that these associations are mediated by inflammation; therefore, adherence to an anti-inflammatory diet may mitigate these effects. We sought to estimate the potential effects of joint hypothetical interventions on metals levels and adherence to an anti-inflammatory diet or fruits and vegetables (FV) intake on the expected mortality distributions. METHODS: We used data on 14,311 adults aged ≥ 20 years enrolled in the NHANES-III between 1988 and 1994 and followed up through Dec 31, 2015. We estimated daily FV servings and adherence to the dietary inflammatory index at baseline using 24-hour dietary recalls. Mortality was determined from the National Death Index records. We used the parametric g-formula with pooled logistic regression models to estimate the absolute risk of all-cause, cardiovascular, and cancer mortality under different hypothetical interventions compared to the natural course (no intervention). RESULTS: Overall, we observed a decreased mortality risk when intervening to lower metals levels or increasing adherence to an anti-inflammatory diet or the daily FV servings. The joint intervention to lower BLLs and UCd and increase the adherence to the anti-inflammatory diet had the strongest impact on cancer mortality risk (risk difference [RD] = -1.50% (-2.52% to -0.62%)) compared to the joint intervention only on metals levels RD= -0.97% (-1.89 to 0.70). The same pattern of associations was observed for the joint intervention to lower both metals and increased daily FV servings and cardiovascular diseases mortality risk. CONCLUSION: Higher diet quality may constitute a complementary approach to the interventions to reduce exposures to cadmium and lead to further minimize their effects on mortality. A paradigm shift is required from a pollutant-focused only to a combination with a human-focused approach for primary prevention against these metals.

Association between serum per- and polyfluoroalkyl substances concentrations and common cold among children and adolescents in the United States.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) exert immunosuppressive effects in experimental animals. Few epidemiologic studies investigated PFAS exposure and immune-related clinical outcomes such as common cold, especially during childhood when the immune system is developing. METHODS: This study used data from the National Health and Nutrition Examination Survey and included 517 children 3-11 years (2013-2014 cycle) and 2732 adolescents 12-19 years (2003-2016 cycles). Serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS) were quantified. Common cold was self-reported by the participant or parent as having a head cold or chest cold in the last month. Multivariable logistic regression models were applied to examine the covariate-adjusted odds ratios (ORs) between individual PFAS concentrations and common cold incidence in the past month. The joint effect of PFAS mixtures was evaluated using Probit Bayesian Kernel Machine Regression (BKMR). RESULTS: A doubling of serum PFHxS concentration was associated with a 31% higher odds (OR = 1.31, 95% CI: 1.06, 1.62) of common cold among children. Serum PFNA (OR = 1.36, 95% CI: 0.93, 1.98) and PFOA (OR = 1.32, 95% CI: 0.67, 2.62) concentrations were also related to common cold among children, as were serum PFOS concentrations among adolescents (OR = 1.13, 95% CI: 0.96, 1.32). ORs were higher in male than female children and adolescents. BKMR showed a clear increasing trend of common cold estimates across quantiles of the total PFAS mixture concentration among children, while no obvious pattern emerged in adolescents. DISCUSSION: Among children in the United States, serum concentrations of PFAS mixtures, especially PFHxS and PFNA, were associated with higher odds of common cold. Among adolescents, PFOS was associated with increased common cold in the last month. This study contributes to the existing evidence supporting the immunotoxicity of PFAS in childhood and adolescence.

Associations between household air pollution and early child development among children aged 36-59 months in Bangladesh.

BACKGROUND: Household air pollution (HAP) from solid fuel use (SFU) for cooking may impact child health in low-resources countries. This study examined the associations between HAP and early childhood development (ECD) outcomes among children under 5 years of age in Bangladesh and explored potential effect modification by sex and urbanicity. METHODS: The study sample consisted of 9395 children aged 36-59 months in the households from the Bangladesh Multiple Indicator Cluster Survey 2019. SFU and levels of exposure to SFU (unexposed, moderately exposed and highly exposed) were used as proxies of HAP exposure. We estimated the covariate-adjusted prevalence ratios (aPRs) and 95% CIs for the associations between HAP and ECD outcomes using multilevel mixed-effects Poisson regression models with a robust variance estimator. RESULTS: 81.4% of children were exposed to SFU, and the prevalence of developmental delay (in Early Childhood Development Index) was 25.3%. Children exposed to SFU were 1.47 times more likely to have developmental delays (95% CI: 1.25, 1.73; p<0.001) compared with children with no SFU exposure. SFU was significantly associated with developmental delay in socioemotional (aPR: 1.17; 95% CI: 1.01, 1.36; p=0.035) and learning-cognitive (aPR: 1.90; 95% CI: 1.39, 2.60; p<0.001) domains. Similarly, children moderately exposed and highly exposed to HAP had higher prevalence of developmental delays than unexposed children. We did not observe effect modification by sex or urbanicity. CONCLUSION: Public health policies should promote the use of clean cooking fuels and cookstoves to reduce the high burden of HAP exposure in low-resource countries for helping younger children to meet their developmental milestones.

Associations between persistent organic pollutants and type 1 diabetes in youth.

BACKGROUND: Diabetes affects millions of people worldwide with a continued increase in incidence occurring within the pediatric population. The potential contribution of persistent organic pollutants (POPs) to diabetes in youth remains poorly known, especially regarding type 1 diabetes (T1D), generally the most prevalent form of diabetes in youth. OBJECTIVES: We investigated the associations between POPs and T1D in youth and studied the impacts of POPs on pancreatic ß-cell function and viability in vitro. METHODS: We used data and plasma samples from the SEARCH for Diabetes in Youth Case Control Study (SEARCH-CC). Participants were categorized as Controls, T1D with normal insulin sensitivity (T1D/IS), and T1D with insulin resistance (T1D/IR). We assessed plasma concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides and estimated the odds of T1D through multivariable logistic regression. In addition, we performed in vitro experiments with the INS-1E pancreatic ß-cells. Cells were treated with PCB-153 or p,p'-DDE at environmentally relevant doses. We measured insulin production and secretion and assessed the mRNA expression of key regulators involved in insulin synthesis (Ins1, Ins2, Pdx1, Mafa, Pcsk1/3, and Pcsk2), glucose sensing (Slc2a2 and Gck), and insulin secretion (Abcc8, Kcnj11, Cacna1d, Cacna1b, Stx1a, Snap25, and Sytl4). Finally, we assessed the effects of PCB-153 and p,p'-DDE on ß-cell viability. RESULTS: Among 442 youths, 112 were controls, 182 were classified with T1D/IS and 148 with T1D/IR. The odds ratios (OR) of T1D/IS versus controls were statistically significant for p,p'-DDE (OR 2.0, 95% confidence interval (CI) 1.0, 3.8 and 2.4, 95% CI 1.2, 5.0 for 2nd and 3rd tertiles, respectively), trans-nonachlor (OR 2.5, 95% CI 1.3, 5.0 and OR 2.3, 95% CI 1.1, 5.1 for 2nd and 3rd tertiles, respectively), and PCB-153 (OR 2.3, 95% CI 1.1, 4.6 for 3rd tertile). However, these associations were not observed in participants with T1D/IR. At an experimental level, treatment with p,p'-DDE or PCB-153, at concentrations ranging from 1 × 10-15 M to 5 × 10-6 M, impaired the ability of pancreatic ß-cells to produce and secrete insulin in response to glucose. These failures were paralleled by impaired Ins1 and Ins2 mRNA expression. In addition, among different targeted genes, PCB-153 significantly reduced Slc2a2 and Gck mRNA expression whereas p,p'-DDE mainly affected Abcc8 and Kcnj11. While treatment with PCB-153 or p,p'-DDE for 2 days did not affect ß-cell viability, longer treatment progressively killed the ß-cells. CONCLUSION: These results support a potential role of POPs in T1D etiology and demonstrate a high sensitivity of pancreatic ß-cells to POPs.

Blood metals and vitamin D status in a pregnancy cohort: A bidirectional biomarker analysis.

Low 25-hydroxyvitamin D (25OHD), a biomarker of vitamin D status, is associated with reduced immune function and adverse pregnancy outcomes, such as preterm birth. Observational studies indicate that long-term, high level exposure to metals such as cadmium (Cd) and lead (Pb) can impact a person's vitamin D status. However, the directionality of the association is uncertain, particularly for low-level exposures. We used three distinct longitudinal data analysis methods to investigate cross-sectional, longitudinal and bidirectional relationships of Cd and Pb biomarkers with 25-hydroxyvitamin D (25OHD) in a Canadian pregnancy cohort. Maternal whole blood Cd and Pb and plasma 25OHD concentrations were measured in the 1st (n = 1905) and 3rd (n = 1649) trimester and at delivery (25OHD only, n = 1542). Our multivariable linear regression analysis showed weak inverse associations between Cd and 25OHD concentrations cross-sectionally and longitudinally while the latent growth curve models showed weak associations with Pb on the 25OHD intercept. In the bidirectional analysis, using cross lagged panel models, we found no association between 1st trimester metals and 3rd trimester 25OHD. Instead, 1st trimester 25OHD was associated with 9% (-15%, -3%) lower 3rd trimester Cd and 3% (-7, 0.1%) lower Pb. These findings suggest the 25OHD may modify metal concentrations in pregnancy and demonstrates the value of controlling for contemporaneous effects and the persistence of a biomarker over time, in order to rule out reverse causation.

Association between blood metals mixtures concentrations and cognitive performance, and effect modification by diet in older US adults.

BACKGROUND: Chronic exposure to heavy metals has been associated with adverse neurological outcomes in older adults. Inflammatory processes are suspected as an underlying pathway by which metals exert their neurotoxicity. In parallel, a diet rich in antioxidant and anti-inflammatory components may protect against chronic inflammation. OBJECTIVES: We examined the associations of blood concentrations of lead, cadmium, and manganese as a mixture with cognitive performance in older US adults and potential modification of these associations by diet as measured by the Healthy Eating Index 2015 (HEI-2015) and the Adapted Dietary Inflammatory Index (ADII). METHODS: We used data on 1,777 adults ≥60 years old from the US National Health and Nutrition Examination Survey (NHANES; 2011-2014). We derived the ADII and the HEI-2015 from two nonconsecutive 24-hour diet recalls. Cognitive performance was measured by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning subtest, the animal fluency test, and the Digit Symbol Substitution Test (DSST). We also constructed a composite z-score reflecting overall cognitive performance. We used quantile g-computation to evaluate the joint associations of a mixture of metals with cognitive performance test scores. We also evaluated effect modification by sex and diet quality indices using Cochran Q tests. RESULTS: The median (interquartile range) of blood metals were 0.38 µg/L (0.35), 14.70 µg/L (11.70), and 8.74 µg/L (4.06) for cadmium, lead, and manganese, respectively. Increasing blood concentrations of all metals by one quartile was associated with a decrease in overall cognitive performance (-0.04; 95% confidence interval [CI] = -0.09, 0.02), CERAD (-0.04; 95% CI = -0.12, 0.03), animal fluency (-0.02; 95% CI, -0.11, 0.06), and DSST (-0.05; 95% CI = -0.11, 0.02) test scores. These associations were more pronounced in adults with high pro-inflammatory or low-diet quality and null or positive though imprecise associations in participants with a high anti-inflammatory. These associations also varied by sex with inverse associations in men and positive associations in women. CONCLUSIONS: Our findings suggest that adherence to an antioxidant and anti-inflammatory diet may prevent blood metals adverse cognitive effects among older adults. If confirmed, strategies based on diet could provide a potential complementary and efficient approach to counteract effects of environmental pollutants.

Cumulative and independent effects of experiences of social adversity on support for violent radicalization during the COVID-19 pandemic: the mediating role of depression.

PURPOSE: Social adversity experiences have increased during the pandemic and are potential risk factors for both depression and support for violent radicalization (VR). However, the cumulative and independent effects of various social adversity experiences on support for VR have yet to be explored. This paper examines the cumulative and independent effects of COVID- and non-COVID-related discrimination, exposure to violence, traditional and cyberbullying victimization on support for VR. In addition, we investigate whether depression mediates the relationship between these forms of social adversity and support for VR. METHODS: A total of 6003 young adults (Mage = 27, SDage = 4.40, range 18-35) living in metropolitan areas in Canada responded to an online survey. We used multivariable regression models, controlling for socio-demographic characteristics, to infer covariate adjusted associations between social adversity measures and support for VR. Additionally, we conducted a formal mediation analysis to estimate the proportion mediated by depression. RESULTS: There was a cumulative relationship between experiences of social adversity and support for VR (ß = 1.52; 95% CI: 1.32, 1.72). COVID-related discrimination and cyberbullying victimization were independently associated with stronger support for VR. Depression partially mediated the effect of cumulative social adversity, COVID-related discrimination and cyberbullying on support for VR. CONCLUSION: Prevention programs during the present pandemic should prioritize decreasing discrimination and providing psychosocial support to depressed young adults who experience social adversity. Practitioners should prioritize developing programs that foster digital literacy skills and critical thinking among young adults to address the concerning impact of cyberbullying on support for VR.