Associations between neonicotinoids and liver function measures in US adults: National Health and Nutrition Examination Survey 2015-2016.

Background: Toxicological studies indicate that neonicotinoids may be associated with disruptions in liver function due to an increase in oxidative stress. There are scant epidemiological studies investigating the chronic hepatotoxic effects of neonicotinoids. Objective: To examine the association between detectable concentrations of parent neonicotinoids and neonicotinoid metabolites with liver function markers among US adults, and whether sex modifies this association. Methods: National Health and Nutrition Examination Survey 2015-2016 data were used to estimate associations between detectable neonicotinoids and serum alkaline phosphatase (ALP), alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transaminase (GGT), albumin, total bilirubin, total protein, and Hepatic Steatosis Index (HSI) using multiple linear regression. Results: Detectable levels of N-desmethyl-acetamiprid were associated with a decrease in GGT (ß = -3.54 unit/l; 95% confidence interval [CI] = -6.48, -0.61) and detectable levels of 5-hydroxy-imidacloprid were associated with a decrease in HSI (ß = -1.11; 95% CI = -2.14, -0.07). Sex modified the association between any parent neonicotinoid and ALP (Pint = 0.064) and the association between clothianidin and ALP (Pint = 0.019), with a pattern of positive associations in males and inverse associations in females, though stratified associations did not reach statistical significance. Sex also modified the association between 5-hydroxy-imidacloprid and total protein (Pint = 0.062), with a significant positive association in females (ß = 0.14 g/dl; 95% CI = 0.03, 0.25) and a null association in males. Conclusion: Detectable concentrations of neonicotinoid metabolites were inversely associated with GGT and HSI in US adults. Evidence suggests neonicotinoids may influence liver function differently depending on sex. Future research is recommended to replicate the findings as the study was limited in its cross-sectional nature and inability to examine continuous neonicotinoid concentrations with liver function.

Gestational PBDE concentrations, persistent externalizing, and emerging internalizing behaviors in adolescents: The HOME study.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental chemicals used as flame retardants in commercial and consumer products. Gestational PBDE concentrations are associated with adverse behaviors in children; however, the persistence of these associations into adolescence remains understudied. OBJECTIVE: We estimated the association of gestational PBDE serum concentrations with early adolescent self- and caregiver-reported behaviors at age 12 years and determined the consistency with previously observed associations in childhood with caregiver-reported behaviors in a prospective pregnancy and birth cohort. METHODS: We measured maternal serum concentrations of five individual PBDE congeners and created a summary exposure variable (∑5BDE: 28, -47, -99, -100 and -153) during pregnancy. At age 12 years, we assessed behaviors for 237 adolescents using self- and caregiver-reports with the Behavioral Assessment System for Children-3 (BASC3). We used multivariable linear regression models to estimate covariate-adjusted associations of lipid standardized, log10-transformed gestational PBDE concentrations with BASC3 scores. We obtained estimates and 95% confidence intervals through a bootstrapping approach. We evaluated potential effect measure modification (EMM) of adolescent sex by examining sex-stratified regression models and estimating the EMM p-values. RESULTS: Gestational PBDE concentrations were positively associated with adolescent-reported BASC3 composite indices for inattention & hyperactivity (BDE-28, -47, -99, -100, ∑5BDE), internalizing problems (BDE-28, -47, -99), functional impairment (BDE-28, ∑5BDE), and emotional symptoms (BDE-28). Gestational PBDE concentrations were positively associated with caregiver-reported BASC3 composite indices for externalizing problems (BDE-28, -47, -99, -100, -153, ∑5BDE) and behavioral symptoms (BDE-99). For caregiver reported behaviors, we observed stronger associations with gestational BDE concentrations among males, especially for executive functioning (BDE-28, -47, -99, -100, ∑5BDE). DISCUSSION: Gestational PBDE serum concentrations were associated with self-reported internalizing and externalizing behavior problems in early adolescence. Caregiver-reported externalizing behaviors recognized during childhood remain associated with gestational PBDE concentrations and persist into early adolescence. Internalizing behaviors were less recognized by caregivers.

Maternal and newborn metabolomic changes associated with urinary polycyclic aromatic hydrocarbon metabolite concentrations at delivery: an untargeted approach.

INTRODUCTION: Prenatal exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with adverse human health outcomes. To explore the plausible associations between maternal PAH exposure and maternal/newborn metabolomic outcomes, we conducted a cross-sectional study among 75 pregnant people from Cincinnati, Ohio. METHOD: We quantified 8 monohydroxylated PAH metabolites in maternal urine samples collected at delivery. We then used an untargeted high-resolution mass spectrometry approach to examine alterations in the maternal (n = 72) and newborn (n = 63) serum metabolome associated with PAH metabolites. Associations between individual maternal urinary PAH metabolites and maternal/newborn metabolome were assessed using linear regression adjusted for maternal and newborn factors while accounting for multiple testing with the Benjamini-Hochberg method. We then conducted functional analysis to identify potential biological pathways. RESULTS: Our results from the metabolome-wide associations (MWAS) indicated that an average of 1% newborn metabolome features and 2% maternal metabolome features were associated with maternal urinary PAH metabolites. Individual PAH metabolite concentrations in maternal urine were associated with maternal/newborn metabolome related to metabolism of vitamins, amino acids, fatty acids, lipids, carbohydrates, nucleotides, energy, xenobiotics, glycan, and organic compounds. CONCLUSION: In this cross-sectional study, we identified associations between urinary PAH concentrations during late pregnancy and metabolic features associated with several metabolic pathways among pregnant women and newborns. Further studies are needed to explore the mediating role of the metabolome in the relationship between PAHs and adverse pregnancy outcomes.

Patterns of urinary organophosphate ester metabolite trajectories in children: the HOME Study.

BACKGROUND: Organophosphate esters (OPEs) have replaced flame retardant polybrominated diphenyl ethers as flame retardants in consumer products, but few longitudinal studies have characterized childhood OPE exposure. OBJECTIVE: We aimed to examine the exposure pattern of urinary OPE metabolites in children. METHODS: We quantified three urinary OPE metabolites five times in children (1, 2, 3, 5, 8 years) from 312 mother-child pairs in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio, USA. We examined the associations of average maternal OPE metabolite concentrations with OPE metabolite concentrations in childhood, characterized childhood OPE trajectories with latent class growth analysis (LCGA), and examined factors related to trajectory membership. RESULTS: Bis(2-chloroethyl) phosphate (BCEP) had the lowest median concentrations over time (0.66-0.97 mg/L) while the median concentrations of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) increased with age (1.44-3.80 mg/L). The median concentrations of diphenyl phosphate (DPHP) fluctuated between 1.96 and 2.69 mg/L. Intraclass correlation coefficients for urinary metabolites measured at five time points indicated high variability within individuals (0.13-0.24). Average maternal urinary BCEP and BDCIPP were associated with concentrations in early childhood. Maternal education, the birth year of the child, and having a carpet in the main activity room were associated with BCEP and BDCIPP trajectory while none of the factors were associated with DPHP trajectory. SIGNIFICANCE: The trajectory analysis showed different patterns of urinary OPE metabolite concentrations, suggesting the need to collect multiple samples to adequately reflect OPE exposure. IMPACT STATEMENT: In this well-established cohort, we evaluated the patterns of urinary OPE metabolites in children ages 1-8 years. The number of repeated measures over childhood has not been achieved in prior studies. Our results suggested the high variability of urinary OPE metabolites within individuals. Maternal metabolite concentrations during pregnancy were related to child concentrations at ages 1-3 years. BCEP, BDCIPP, and DPHP demonstrated different trajectories in children, which suggests that multiple samples may be required to capture OPE exposure patterns in childhood.

Early-life exposure to a mixture of organophosphate esters and child behavior.

Organophosphate esters (OPEs), widely used as flame retardants and plasticizers for commercial and residential purposes, are suspected of being neurotoxic. We aimed to assess exposure to an OPE mixture in early life and its relationship to parent-reported child behavior. We measured urinary concentrations of three OPE metabolites, bis-2-chloroethyl phosphate (BCEP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), and diphenyl phosphate (DPHP), at pregnancy (16 and 26 weeks of gestation and delivery) and postnatal time points (ages 1, 2, 3, and 5 years) in the Health Outcomes and Measures of the Environment Study, a longitudinal pregnancy and birth cohort in Cincinnati, Ohio, USA (enrolled 2003-2006, n = 219). We used latent variable analysis in structural equations models and quantile g-computation to investigate associations of a mixture of the three OPE metabolites with parent-reported child behaviors at 3 and 8 years, measured using the Behavioral Assessment System for Children, Second Edition. Higher log-transformed urinary OPE latent variable values at 16 weeks were associated with fewer externalizing problem behaviors (ß = -5.74; 95% CI = -11.24, -0.24) and fewer overall behavioral problems at age 3 years (ß = -5.26; 95% CI = -10.33, -0.19), whereas having higher OPEs at delivery was associated with poorer overall behavioral problems at age 3 years (ß = 2.87; 95% CI = 0.13, 5.61). OPE latent variable values at 16 weeks, 26 weeks, and delivery were not associated with child behavior at 8 years. However, higher OPE latent variable values at 3 years were associated with fewer externalizing behaviors at 8 years (ß = -2.62; 95% CI = -5.13, -0.12). The quantile g-computation estimates had directions largely consistent with the latent variable analysis results. Pregnancy and postnatal urinary OPE metabolite mixtures were associated with child internalizing, externalizing, and overall negative behaviors at 3 and 8 years, but we did not identify a consistent pattern in terms of the direction of the effects or a particularly sensitive time point.

Gestational exposure to organophosphate esters and infant anthropometric measures in the first 4 weeks after birth.

BACKGROUND: Few studies have examined whether gestational exposure to organophosphate esters (OPEs), widely used chemicals with potential endocrine-disrupting potency and developmental toxicity, is associated with impaired infant growth. METHODS: We analyzed data from 329 mother-infant pairs in the Health Outcomes and Measures of the Environment (HOME) Study (2003-2006, Cincinnati, Ohio, USA). We quantified concentrations of four OPE metabolites in maternal urine collected at 16 and 26 weeks of gestation, and at delivery. We calculated z-scores using 2006 World Health Organization (WHO) child growth standards for the 4-week anthropometric measures (weight, length, and head circumference), the ponderal index, and weekly growth rates. We used multiple informant models to examine window-specific associations between individual OPE metabolites and anthropometric outcomes. We further modeled OPEs as a mixture for window-specific associations with 4-week anthropometric outcomes using mean field variational Bayesian inference procedure for lagged kernel machine regression (MFVB-LKMR). We stratified the models by infant sex. RESULTS: Diphenyl phosphate (DPHP) in mothers at 16 weeks, and bis(2-chloroethyl) phosphate (BCEP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) at delivery were positively associated with z-scores of weight, length, and head circumference in all infants at 4 weeks of age. After stratifying by infant sex, positive associations were only observed in males for DPHP at 16 weeks and BCEP at delivery and in females for BDCIPP at delivery. Negative associations not present in all infants were observed in males for di-n-butyl phosphate (DNBP) at 26 weeks of gestation with weight z-score and DPHP at delivery with head circumference z-score. Results were generally similar using MFVB-LKMR models with more conservative 95 % credible intervals. We did not identify consistent associations of gestational OPE metabolite concentrations with the ponderal index and weekly growth rates. CONCLUSION: In this cohort, exposure to OPEs during gestation was associated with altered infant anthropometry at 4 weeks after birth.

Associations of gestational exposure to organophosphate esters with gestational age and neonatal anthropometric measures: The HOME study.

Organophosphate esters (OPEs) are developmental toxicants in experimental studies of animals, but limited evidence is available in humans. We included 340 mother-infant pairs in the Health Outcomes and Measures of the Environment (HOME) Study (Cincinnati, Ohio, USA) for the analysis. We evaluated gestational exposure to OPEs with gestation age at birth and newborn anthropometric measures. We quantified four OPE urinary metabolites at 16 weeks and 26 weeks of gestation. We extracted gestational age at birth, newborn weight, length, and head circumference from the chart review. We calculated z-scores for these anthropometric measures and the ponderal index. We used multiple informant models to examine the associations between repeated OPE measurements and the outcomes. We used modified Poisson regression to estimate the association of gestational exposure to OPEs with preterm birth. We also explored effect modification by infant sex and the potential mediation effect by the highest maternal blood pressure and glucose levels. We found that bis(2-chloroethyl) phosphate (BCEP) at 16 weeks and diphenyl phosphate at 26 weeks of pregnancy were positively associated with gestational age and inversely associated with preterm birth. In female newborns, BCEP at 16 weeks was inversely related to birth weight and length z-scores. In male newborns, we observed negative associations of 26-week di-n-butyl phosphate with the ponderal index at birth. No mediation by the highest maternal blood pressure or glucose levels during pregnancy was identified. In this cohort, gestational exposure to some OPEs was associated with gestational age, preterm birth, and neonatal anthropometric measures. Certain associations tended to be window- and infant sex-specific.

Postprandial changes of oxidative stress biomarkers in healthy individuals.

Food consumption induces oxidative stress in humans, but the changes in oxidative stress levels after a regular meal are still unclear. We conducted an experimental study on 20 healthy volunteers (10 males, 10 females), who matched in age (±2 years). They were given a regular diet (total energy of 704 kcal, which contains 75 g of carbohydrates, 35 g of protein, and 29 g of lipids) at 11:30 a.m. after a fast of over 12 h. We collected 6-repeated measures of venous blood samples at 2-h intervals via heparin anticoagulant tubes immediately after the meal (indicated as "0" h) and up to 10 h post-consumption. Biomarkers included plasma fluorescent products, plasma malondialdehyde, plasma total antioxidant capacity, and plasma superoxide dismutase. FlOPs were measured at three excitation/emission wavelengths (FlOP_320, FlOP_360, and FlOP_400). The average age and BMI for the twenty participants were 22.70 ± 1.98 years and 20.67 ± 2.34 kg/m2, respectively. Within 10 h after the meal, the overall trend of FlOPs were generally similar. There was no evidence of dose response for any of the three FlOPs (all P > 0.05). However, levels of MDA decreased with the time of fasting (P linear and P quadratic < 0.05), with the biggest decrease occurring between 0 and 2 h post-meal. The overall trend of T-AOC and SOD levels also decreased with fasting time (P linear and P quadratic < 0.05), though an increase was observed between 0 and 2 h following consumption. Levels of MDA, T-AOC, and SOD but not FlOPs, decreased with fasting time.

Childhood urinary organophosphate esters and cognitive abilities in a longitudinal cohort study.

The use of organophosphate esters (OPEs) as flame retardants, which has increased over the past two decades, raises concerns that OPEs may be harmful to humans, especially children. Animal studies and some human studies have reported that OPEs may adversely impact brain development, but few human studies evaluated OPE exposure during early childhood and neurodevelopmental outcomes. We aimed to fill this knowledge gap with the present study on urinary OPE metabolite concentrations at ages 1-5 years and cognitive abilities at 8 years. We used data of 223 children from the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio. The point estimates for bis-2-chloroethyl-phosphate (BCEP) and bis(1,3-dichloro-2-propyl)-phosphate (BDCIPP) in association with IQ tended to be small and positive, while the point estimates for diphenyl-phosphate (DPHP) were small and negative, with 95% CIs including the null. However, we did find that socioeconomic status (SES) variables modified associations between OPEs and child IQ, with adverse OPE-IQ associations being stronger in socioeconomically disadvantaged children than in others. We identified an additional 1- to 2-point decrease in Full Scale IQ for every log-unit increase in BDCIPP, BCEP, and DPHP among those with lower maternal education, non-white race, lower income, or living in more deprived neighborhoods. We observed similar results for the Perceptual Reasoning, Verbal Comprehension, and Working Memory Index Scores. We suspect that there is residual confounding related to socioeconomic disadvantage, which was not captured with the available SES variables typically used in epidemiologic studies.

Early life organophosphate ester exposures and bone health at age 12 years: The Health Outcomes and Measures of the Environment (HOME) Study.

BACKGROUND: No human studies have evaluated early life organophosphate ester (OPE) exposures with bone health outcomes, despite evidence of osteotoxicity. OBJECTIVES: We assessed associations of urinary OPE metabolites measured across early life with areal bone mineral density (aBMD) and bone mineral content (BMC) at age 12 years. METHODS: Among 223 mother-child dyads enrolled in the Health Outcomes and Measures of the Environment (HOME) Study, we quantified concentrations of bis-2-chloroethyl phosphate (BCEP), bis-(1,3-dichloro-2-propyl) (BDCIPP), di-n-butyl phosphate (DnBP), and diphenyl phosphate (DPHP) in urine collected from mothers during pregnancy and children at ages 1, 2, 3, 5, and 8 years. At age 12 years, we performed dual energy x-ray absorptiometry and calculated aBMD and BMC z-scores at six skeletal sites. We estimated overall and sex-stratified BMD/BMC z-score differences per interquartile range (IQR) increase in OPE concentrations at multiple exposure timepoints: gestation (average) and 1-3 (average), 5, and 8 years. RESULTS: In adjusted models, overall associations of BCEP and BDCIPP with total hip and 1/3rd distal radius aBMD and BMC varied significantly by exposure timepoint, as did BDCIPP with whole body aBMD. For example, differences (95 % CI) in total hip aBMD z-score per IQR increase in BDCIPP were 0.33 (0.01, 0.64), -0.10 (-0.34, 0.14), -0.18 (-0.40, 0.05), and 0.14 (-0.09, 0.38) for concentrations during gestation and at 1-3, 5, and 8 years, respectively. Overall DnBP and DPHP associations were generally null at all timepoints. We observed sex-specific associations for some timepoints and skeletal sites. For example, an IQR increase in 8-year DPHP was associated with a 0.21 (0.05, 0.38) greater total hip aBMD z-score among females but -0.19 (-0.43, 0.05) lower z-score among males. DISCUSSION: Early life OPE exposures may be associated with sex- and exposure period-dependent alterations in early adolescent bone mineral accrual and strength.

Maternal urinary organophosphate ester metabolite concentrations and glucose tolerance during pregnancy: The HOME Study.

BACKGROUND: Endocrine-disrupting chemicals may alter glucose homeostasis, especially during pregnancy. Biomonitoring studies suggest ubiquitous human exposure to organophosphate esters (OPEs), chemicals with endocrine-disrupting capabilities. Few studies have examined the association between maternal exposure to OPEs and blood glucose during pregnancy. METHODS: With data from 301 pregnant women in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio, USA, we examined whether OPE concentrations were associated with changes in blood glucose. We quantified four OPE metabolites in maternal spot urine samples collected at 16- and 26-weeks pregnancy. We extracted results from the glucose challenge test (GCT) and oral glucose tolerance test (OGTT) via medical chart review. Women with GCT ≥ 140 mg/dL or any abnormal values in OGTT (≥ 95 mg/dL fasting glucose, ≥ 180 mg/dL 1-h glucose, ≥ 155 mg/dL 2-h glucose, ≥ 140 mg/dL 3-h glucose) were defined as having elevated glucose levels. We used linear regression and Bayesian Kernel Machine Regression (BKMR) to estimate the associations of individual OPE metabolites and OPE mixtures with blood glucose levels during pregnancy. We used modified Poisson regression to estimate the associations of OPE metabolite concentrations with elevated glucose levels. We further examined effect measure modification by maternal characteristics (age, pre-pregnancy body mass index [BMI], and race/ethnicity). RESULTS: Diphenyl phosphate (DPHP) had the highest geometric mean concentration of the urinary OPE metabolites (1.83 µg/L at 16 weeks, 1.24 µg/L at 26 weeks). Thirty women (10.0%) had elevated glucose levels. Individual OPE metabolites or their mixtures were not significantly associated with continuous GCT results. We did not observe effect measure modification by maternal age, pre-pregnancy BMI categories, or race/ethnicity. Compared with women in the 1st tertile of average DPHP of 16- and 26 weeks of pregnancy, women in the 3rd tertile tended to have a reduced risk of elevated glucose levels (RR = 0.41, 95% CI = 0.16-1.06, p for trend = 0.06). CONCLUSION: In this cohort, maternal urinary OPE metabolite concentrations were weakly associated with blood glucose levels during pregnancy.

Circulating Carnitine Levels and Breast Cancer: A Matched Retrospective Case-Control Study.

Introduction: Epidemiological studies investigating the association between carnitine and breast cancer are scarce. Materials and Methods: This 1:1 age-matched retrospective case-control study identified 991 female breast cancer cases and 991 female controls without breast cancer using pathological testing. We used targeted metabolomics technology to measure 16 types of whole blood carnitine compounds, such as free carnitine (C0) and octadecanoylcarnitine (C18). Results: The average age for cases and controls was approximately 50 ± 8.7 years. After adjusting for covariates, each standard deviation (SD) increase in malonylcarnitine (C3DC; OR 0.91; 95% CI 0.83-1.00), decenoylcarnitine (C10:1; OR 0.87; 95% CI 0.79-0.96), and decadienoylcarnitine (C10:2; OR 0.90; 95% CI 0.82-0.99) level was associated with decreased odds of breast cancer. However, higher butyrylcarnitine (C4) levels were associated with increased odds of breast cancer (OR 1.12; 95% CI 1.02-1.23). No statistically significant relationship was noted between other carnitine compounds and breast cancer. The false discovery rates for C3DC, C4, C10:1 and C10:2 were 0.172, 0.120, 0.064 and 0.139, respectively. Conclusions: Higher levels of C3DC, C10:1, and C10:2 were protective factors for breast cancer, whereas increased C4 levels were a risk factor for the disease.

Exploratory analysis of the associations between neonicotinoids and measures of adiposity among US adults: NHANES 2015-2016.

BACKGROUND: Toxicology studies suggest that neonicotinoids may be associated with adiposity development via thyroid hormone disruption and increased oxidative stress. Prior epidemiological studies report mixed results for the association between neonicotinoids and adiposity measures. OBJECTIVE: To examine the association between detectable concentrations of parent neonicotinoids (imidacloprid, acetamiprid, clothianidin) and neonicotinoid metabolites (5-hydroxy-imidacloprid, N-desmethyl-acetamiprid) with adiposity measures among US adults, and whether sex modifies the associations for neonicotinoid metabolites with adiposity. METHODS: National Health and Nutrition Examination Survey (NHANES) 2015-2016 data was utilized to estimate covariate-adjusted associations between detectable neonicotinoids and fat mass index (FMI), lean mass index (LMI), waist circumference, body fat percentage, and body mass index (BMI) using multiple linear regression. We estimated incidence rate ratios (IRRs) for overweight or obese status with detectable neonicotinoid concentrations using Poisson's modified regression. Sampling strategies were accounted for in the regression models. RESULTS: Detectable levels of acetamiprid were associated with a decrease in FMI (ß = -3.17 kg/m2, 95% CI [-4.79, -1.54]), LMI (ß = -3.17 kg/m2, 95% CI [-5.17, -1.17]), body fat percentage (ß = -4.41, 95% CI [-8.20, -0.62]), waist circumference (ß = -9.80 cm, 95% CI [-19.08, -0.51]), and BMI (ß = -3.88kg/m2, 95% CI [-7.25, -0.51]) among adults. In contrast, detectable levels of 5-hydroxy-imidacloprid were associated with greater rates of being overweight/obese (IRR = 1.11, 95% CI [1.04, 1.18)) and increased LMI (ß = 0.67 kg/m2, 95% CI [0.04, 1.29]). Sex modified the association between N-desmethyl-acetamiprid and LMI (pint = 0.075) with a positive association among males (ß = 1.14 kg/m2, 95% CI [0.38, 1.90]), and an insignificant inverse association in females. Sex also modified the association for N-desmethyl-acetamiprid with FMI (pint = 0.095) and body fat percentage (pint = 0.072), with suggestive evidence showing positive associations for males and inverse associations for females. CONCLUSION: Detectable concentrations of acetamiprid were inversely associated with adiposity, while there were mixed findings for 5-hydroxy-imidacloprid. Findings suggest sex differences, though results are not clear with regard to the directionality of the association by sex.

Associations of neonicotinoids with insulin and glucose homeostasis parameters in US adults: NHANES 2015-2016.

Neonicotinoids are replacement insecticides increasingly used for organophosphates, methylcarbamates, and pyrethroids. Experimental evidence suggests neonicotinoids may affect glucose metabolism and insulin secretion through pancreatic ß cell dysfunction, oxidative stress, and inflammation. However, no epidemiologic study has investigated neonicotinoids as potential diabetogens. We examined associations between neonicotinoids with insulin and glucose homeostasis parameters among 1381 non-diabetic adults in the National Health and Nutrition Examination Survey (2015-2016). Urinary concentrations of acetamiprid, clothianidin, imidacloprid, N-desmethyl-acetamiprid, and 5-hydroxy-imidacloprid were quantified. Fasting plasma glucose, insulin, and hemoglobin A1c (HbA1c) were assessed. Insulin resistance was defined as a homeostatic model assessment of insulin resistance ≥2.5. We used weighted linear and logistic regression to estimate associations between detectable neonicotinoids with insulin and glucose homeostasis parameters compared to non-detectable neonicotinoid concentrations. Weighted detection frequencies for imidacloprid, 5-hydroxy-imidacloprid, and N-desmethyl-acetamiprid were 4.4 %, 21.5 %, and 32.8 %, respectively. Detectable imidacloprid (ß = -4.7 µIU/mL, 95 % confidence interval [CI] -8.5, -0.8) and 5-hydroxy-imidacloprid (ß = -2.4 µIU/mL, 95 % CI -4.6, -0.2) were associated with lower fasting plasma insulin levels. Individuals with detectable 5-hydroxy-imidacloprid had lower odds of insulin resistance (odds ratio [OR] = 0.3, 95 % CI 0.2, 0.7). We observed evidence of sexually dimorphic associations between N-desmethyl-acetamiprid with glucose (pint = 0.079) and 5-hydroxy-imidacloprid with HbA1c (pint = 0.038), with patterns suggesting positive associations in males and negative associations in females. Associations between 5-hydroxy-imidacloprid and insulin were modified by body mass index (BMI) (pint = 0.013). We additionally observed age modified associations between 5-hydyroxy-imidacloprid and glucose (pint = 0.048). Results suggest neonicotinoids may be associated with insulin and glucose homeostasis indices and call for prospective studies to examine the metabolic impact of these replacement insecticides in humans.

Maternal urinary OPE metabolite concentrations and blood pressure during pregnancy: The HOME study.

BACKGROUND: Few studies have examined the association between maternal exposure to organophosphate esters (OPEs) and systolic/diastolic blood pressure (SBP/DBP) during pregnancy. METHODS: We analyzed data from 346 women with a singleton live birth in the HOME Study, a prospective birth cohort in Cincinnati, Ohio, USA. We quantified four OPE metabolites in maternal spot urine samples collected at 16 and 26 weeks pregnancy, standardized by specific gravity. We calculated intraclass correlation coefficients (ICCs). We extracted the first two recorded BP measurements (<20 weeks), the two highest recorded BP measurements (≥20 weeks), and diagnoses of hypertensive disorders of pregnancy (HDP) via chart review. Women with two BP measurements ≥140/90 mmHg or HDP noted in the chart at ≥20 weeks pregnancy were defined as HDP cases. We used linear mixed models and modified Poisson regression with covariate adjustment to estimate associations between OPE concentrations as continuous variables or in tertiles with maternal BP and HDP. RESULTS: ICCs of OPEs were 0.17-0.45. Diphenyl phosphate (DPHP) had the highest geometric mean concentration among OPE metabolites. Increasing the average bis(2-chloroethyl) phosphate (BCEP) concentrations were positively associated with two highest recorded DBP ≥20 weeks pregnancy. Compared with women in the 1st DPHP tertile, women in the 3rd tertile at 16 weeks pregnancy had 1.72 mmHg (95% CI: -0.01, 3.46) higher DBP <20 weeks pregnancy, and women in the 3rd tertile of the average DPHP concentrations had 2.25 mmHg (95% CI: 0.25, 4.25) higher DBP ≥20 weeks pregnancy. 33 women (9.5%) were identified with HDP. Di-n-butyl phosphate (DNBP) concentrations at 16 weeks were positively associated with HDP, with borderline significance (RR = 2.98, 95% CI 0.97-9.15). Other OPE metabolites were not significantly associated with HDP. CONCLUSION: Maternal urinary BCEP and DPHP concentrations were associated with increased BP during pregnancy. Maternal urinary DNBP concentrations were associated with HDP, with borderline significance.

Plasma Fluorescent Oxidation Products and Bone Mineral Density Among Male Veterans: A Cross-Sectional Study.

In vitro and vivo studies indicate that oxidative stress contributes to bone loss. Fluorescent oxidation products (FlOPs) are novel biomarkers of oxidative stress; they reflect global oxidative damage of lipids, proteins, carbohydrates, and DNA. However, whether FlOPs are associated with bone mineral density (BMD) is still unclear. In the present study, we examined the association between FlOPs and BMD among male veterans. This cross-sectional study was conducted among participants recruited from the Department of Medical Examination, The Second Hospital of Jilin University in Jilin, China. We identified male veterans who were at least 50 y old between June and October of 2019. Plasma FlOPs were measured with a fluorescent microplate reader (excitation/emission wavelength: 320/420 nm). BMD were measured by dual-energy X-ray absorptiometry (DXA). The association between FlOPs and BMD was tested by multivariable linear regression models. A total of 164 male veterans were enrolled in the study, the average age was 56.6 y. After adjusting for covariates, veterans who had FlOP levels in the highest tertile had a statistically significant lower femoral neck (ß = -0.044; p = 0.007) and total hip BMD (ß = -0.045; p = 0.020) as compared to those with FlOP levels in the lowest tertile. Similar results were found when FlOPs were treated as a continuous variable (per 1-SD increase, ß = -0.014 and p = 0.033 for femoral neck BMD; ß = -0.016 and p = 0.047 for total hip BMD). Higher FlOP levels were associated with lower BMD among male veterans.

Gestational exposure to polybrominated diphenyl ethers and social skills and problem behaviors in adolescents: The HOME study.

BACKGROUND: Polybrominated diphenyl ethers (PBDEs) are persistent environmental pollutants used as flame retardants. Gestational PBDE exposure has been associated with a variety of behavior problems in children, but little is known about its impact into adolescence, particularly on social skills, which are important for achieving social competence, establishing identity, and forming lasting relationships. OBJECTIVE: We investigated associations between gestational exposure to PBDEs and social skills and problem behaviors in early adolescence in a longitudinal pregnancy and birth cohort in Cincinnati, Ohio (recruited 2003-2006). METHODS: We measured maternal serum concentrations of five PBDE congeners during gestation. At age 12, we measured social skills and problem behaviors scores for 243 adolescents using self- and caregiver-report on the Social Skills Improvement System (SSiS). We used multivariable linear regression models to estimate associations between maternal PBDE concentrations and SSiS scores, controlling for potential covariates. We report associations for the five congeners and a summary exposure variable (∑5BDE: the sum of BDE- 28, 47, 99, 100, and 153, n = 197). RESULTS: We found sex-specific associations of ∑5BDE concentrations with adolescent-reported Problem Behaviors (∑5BDE × sex pint = 0.02) and caregiver-reported Social Skills (∑5BDE × sex pint = 0.02). In sex-stratified models, log10 transformed data revealed increased maternal ∑5BDE concentration among males was associated with decreased caregiver-reported Social Skills composite score (ß = -10.2, 95% CI: -19.5, -1.0), increased adolescent-reported Problem Behaviors composite score (ß = 12.1, 95% CI: 5.4, 18.8), and increased caregiver-reported Problem Behaviors composite score (ß = 6.2, 95% CI: 0.7, 11.7). Further analysis on SSiS subscales revealed similar patterns in significant associations among males. There were no statistically significant associations in stratified models among females despite higher ∑5BDE exposure (Female GM=40.15 ng/g lipid, GSE=1.10; Male GM=35.30 ng/g lipid, GSE=1.09). DISCUSSION: We found gestational PBDE exposure in males was associated with poorer behavioral outcomes, extending previous findings among this cohort into early adolescence.

Association between global biomarker of oxidative stress and quantitative ultrasound parameters in middle-aged and elderly adults: A cross-sectional study.

Introduction: With the population aging, osteoporosis has become a major public health concern. Elevated oxidative stress is a vital detrimental factor for bone health. Compared to common oxidative stress-related biomarkers, Fluorescent Oxidation Products (FlOPs) reflect the global levels of oxidation from proteins, lipids, and DNA. Nevertheless, whether plasma FlOP levels are related to bone health measured by Quantitative ultrasound (QUS) is unclear. Thus, the present study examined the association between FlOPs and QUS parameters in middle-aged and elderly adults. Methods: This community-based cross-sectional study was conducted in Changchun, northeast China. Plasma FlOPs were determined by a fluorescent microplate reader at a wavelength of 320/420 nm (excitation/emission). QUS parameters [speed of sound (SOS) and broadband ultrasound attenuation (BUA)] of the calcaneus were assessed by an ultrasound bone densitometer. We used multivariable linear regression to examine the association between FlOPs and QUS parameters. Results: A total of 491 subjects were included in this study. Their average age was 65.2 years (standard deviation [SD]: 9.7 years). FlOPs were inversely associated with SOS (ß for an increase of logarithmic interquartile range = -10.64; P = 0.018). Higher FlOP levels were marginally associated with lower SOS in females (ß for an increase of logarithmic interquartile range = -9.68, P = 0.066), but not in males (ß for an increase of logarithmic interquartile range = -11.84, P = 0.131). No significant relationship between FlOPs and BUA was observed. Conclusions: Plasma FlOP levels were inversely associated with SOS, but not with BUA in middle-aged and elderly adults.

Dietary carotenoid intake and osteoporosis: the National Health and Nutrition Examination Survey, 2005-2018.

Higher intake of ß-carotene and ß-cryptoxanthin were associated with lower risk of osteoporosis. A very high intake of lutein + zeaxanthin was also associated with lower risk of osteoporosis. These results support the beneficial role of carotenoids on bone health. PURPOSE: To examine the associations of α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, and lutein + zeaxanthin intake with the risk of osteoporosis based on the cross-sectional data from the National Health and Nutrition Examination Survey (NHANES), 2005-2018. METHODS: This study identified individuals ≥ 50 years old with valid and complete data on carotenoid intake and bone mineral density (BMD). Intake of α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, and lutein + zeaxanthin was averaged from two 24-h recall interviews. BMD was measured by dual-energy X-ray absorptiometry (DXA) and converted to T-scores; osteoporosis was defined as a T-score ≤ - 2.5. We used logistic regression models to test the associations between carotenoids and osteoporosis, adjusting for factors such as age, sex, race, and education. RESULTS: Participants were on average 61.9 years of age, with 57.5% identifying as females. Higher quintiles of ß-carotene (odds ratio [OR] for quintile 5 vs. 1:0.33; 95% CI: 0.19-0.59; P for trend = 0.010) and ß-cryptoxanthin intake (OR for quintile 5 vs. 1:0.61; 95% CI: 0.39-0.97; P for trend = 0.037) were associated with reduced risk of osteoporosis. Similar and marginally significant results for lutein + zeaxanthin intake was found (OR for quintile 5 vs. 1:0.53; 95% CI: 0.30-0.94; P for trend = 0.076). There was no association of α-carotene and lycopene intake with osteoporosis. These associations did not differ by sex (all P_interaction > 0.05). CONCLUSIONS: Higher ß-carotene and ß-cryptoxanthin intake was associated with decreased osteoporosis risk. A very high intake of lutein + zeaxanthin was also associated with lower risk of osteoporosis.

Prenatal exposure to a mixture of organophosphate esters and intelligence among 8-year-old children of the HOME Study.

Many environmental chemicals are being identified as suspected neurotoxicants based on the findings of both experimental and epidemiological studies. Organophosphate esters (OPEs), which are among the chemicals that have replaced neurotoxic polybrominated diphenyl ethers (PBDEs) after 2004, have also become an important public health topic as evidence regarding their potential for early-life neurotoxicity is growing. In 233 mother child pairs from Cincinnati, OH, we measured concentrations of the OPE metabolites bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis-2-chloroethyl phosphate (BCEP), diphenyl phosphate (DPHP), and di-n-butyl phosphate (DNBP) in the urine of pregnant women at 16 and 26 weeks gestation and at delivery. At age 8 years, we assessed children's cognition using the Wechsler Intelligence Scale for Children-IV. In models adjusted for maternal race, income, body mass index, and IQ, maternal urinary BCEP was associated with a modest increase in child full-scale IQ (ß: 0.81 per a ln-unit BCEP increase; 95 % CI: 0.00, 1.61) while other OPEs were not associated with changes in full-scale IQ or any IQ subscales. Maternal serum PBDE concentrations did not confound the relationships between urinary OPE metabolites and child IQ. Using Bayesian kernel machine regression, we did not find that concentrations of a mixture of OPE metabolites during gestation was associated with any child cognition measures. The results of this study are not consistent with other published work, and a larger sample size would be beneficial to explore potential associations more fully. Therefore, additional studies are necessary to continue studying prenatal OPE exposure and child neurodevelopment and behavior.