Diurnal variation in glutathione and cysteine redox states in human plasma

BACKGROUND: Plasma glutathione/glutathione disulfide (GSH/GSSG) and cysteine/cystine (Cys/CySS) couples are oxidized in humans in association with oxidative stress and cardiovascular disease risk. Animal studies show that both pools undergo diurnal variations associated with dietary intake of sulfur amino acids. OBJECTIVE: The objective of this study was to determine whether the redox state of GSH, Cys, GSH/GSSG, or Cys/CySS undergoes diurnal variation in healthy adults. DESIGN: Plasma samples were collected every hour for 24 h from 63 persons aged 18-86 y who were consuming normal food (protein, 0.8 g kg(-1) d(-1); sulfur amino acids, 20 mg kg(-1) d(-1)) at standardized mealtimes. Measurements of Cys, CySS, GSH, and GSSG were used with the Nernst equation to calculate the redox states. RESULTS: Plasma Cys and GSH concentrations varied with the time of day. The highest values for plasma Cys occurred approximately 3 h after meals. Glutathione was maximal 6 h after peak plasma Cys. The calculated redox states of the GSH/GSSG and Cys/CySS couples varied in association with the concentrations of the thiol forms. Maximal reduction and oxidation of the Cys/CySS couple occurred at 2130 and 0630, whereas the respective values for the GSH/GSSG couple occurred at 0330 and 1330. The mean diurnal variation for Cys/CySS redox in persons aged >or=60 y was 1.8-fold that in persons aged <40 y. CONCLUSIONS: Cys/CySS and GSH/GSSG redox states in human plasma undergo diurnal variation with an increased magnitude of variation in Cys/CySS redox state in older persons. This variation could alter sensitivity to oxidative stress over a course of hours.     

Thiol/disulfide redox status is oxidized in plasma and small intestinal and colonic mucosa of rats with inadequate sulfur amino acid intake

Low molecular weight thiol/disulfide redox pools are dependent upon extracellular cysteine (Cys) availability. We determined whether dietary sulfur amino acid (SAA) deficiency induces oxidative stress in vivo, as determined by redox state of major thiol/disulfide couples in plasma [Cys/cystine (CySS)] and intestinal mucosa [glutathione (GSH)/glutathione disulfide (GSSG)]. Rats were fed isocaloric, isonitrogenous semipurified diets: either SAA-adequate (control), SAA-deficient, or SAA-supplemented, pair-fed to intake of the SAA-deficient group. Reference rats consumed standard rat food ad libitum. After 7 d, plasma and gut mucosal samples were analyzed for Cys, CySS, GSH and GSSG, and the redox potentials of Cys/CySS and GSH/GSSG were determined. Mean daily food intake in the pair-fed rats was similar (approximately one-half of reference-rat intake). Body weight decreased in all pair-fed groups, but rats fed the SAA-deficient diet lost significantly more body weight. Dietary SAA deficiency decreased GSH concentrations in both plasma and gut mucosa, increased plasma GSSG, and oxidized plasma and gut mucosal GSH/GSSG redox and plasma Cys/CySS redox. SAA supplementation resulted in a more reducing plasma Cys/CySS redox potential. Reference rats exhibited similar tissue and plasma GSH/GSSG redox as rats that ate semipurified SAA-adequate rat food, which provided similar net SAA intake. Our in vivo data show that inadequate dietary SAA intake oxidizes the thiol/disulfide redox status in rat-gut mucosa and plasma. Such oxidation of redox pools is associated with oxidative stress and the onset or progression of several pathological conditions. Thus, dietary SAA deficiency could contribute to the progression of disease by causing an oxidation of these components.     

Intestinal Redox Status of Major Intracellular Thiols in a Rat Model of Chronic Alcohol Consumption

Background: Alcohol consumption is associated with oxidative stress in multiple tissues in vivo, yet the effect of chronic alcohol intake on intestinal redox state has received little attention. In this study, we investigated the redox status of 2 major intracellular redox regulating couples: glutathione (GSH)/glutathione disulfide (GSSG) and cysteine (Cys)/cystine (CySS) in a rat model of chronic alcohol ingestion. Methods: Sprague‐Dawley rats were fed the liquid Lieber‐DeCarli diet consisting of 36% ethanol of total calories for 6 weeks. Control rats were pair‐fed with an isocaloric, ethanol‐free liquid diet. Defined mucosal samples from the jejunum, ileum, and colon were obtained and analyzed by high‐performance liquid chromatography (HPLC) for GSH and Cys pool redox status. Mucosal free malondialdehyde (MDA) was measured as an indicator of lipid peroxidation. Results: In the ethanol‐fed rats, Cys and mixed disulfide (GSH‐Cys) were significantly decreased in all 3 segments of intestinal mucosa. Free MDA was increased in jejunal but not in ileal or colonic mucosa. Chronic ethanol ingestion significantly increased mucosal GSH concentration in association with a more reducing GSH/GSSG redox potential in the jejunum, but these indices were unchanged in the ileum. In the colon, chronic ethanol ingestion increased oxidant stress as suggested by decreased GSH and oxidized GSH/GSSG redox potential. Conclusions: Chronic alcohol intake differentially alters the mucosal redox status in proximal to distal intestinal segments in rats. Such changes may reflect different adaptability of these intestinal segments to the oxidative stress challenge induced by chronic ethanol ingestion.     

Chlorogenic Acid Differentially Alters Hepatic and Small Intestinal Thiol Redox Status Without Protecting Against Azoxymethane-Induced Colon Carcinogenesis in Mice

Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States. Epidemiological data have suggested that coffee consumption is inversely related to CRC risk, which may be attributed to chlorogenic acid (CGA), an ester of caffeic acid (CA) and quinic acid. This study was conducted to determine whether chronic dietary CGA supplementation would attenuate tumorigenesis and oxidative stress in a mouse model of azoxymethane (AOM)-induced colon cancer. Mice (4-wk old; n = 15/group) were fed CGA (0%, 0.01%, or 0.1%) for 20 wk and received 6 weekly intraperitoneal AOM injections (10 mg/kg). CGA and CA dose-dependently accumulated in the small intestinal mucosa. AOM induced (P < 0.05) colonic aberrant crypt foci (14.2 ± 1.9/field) and tumors (14.6 ± 1.1/colon), which were correlated (r = .677; P < 0.05), and CGA at either dose did not reduce tumorigenesis. Hepatic GSH/GSSG and Cys/CySS ratios were unaffected by AOM, but CGA at 0.1% increased these ratios by decreasing GSSG and CySS. CGA did not affect the ratios of small intestinal GSH/GSSG or Cys/CySS, which were decreased in response to AOM treatment. Collectively, these data indicated that CGA did not protect against AOM-induced tumorigenesis but affected hepatic thiol redox status in this colon cancer model.     

Serum Perfluorooctanoic Acid and Perfluorooctane Sulfonate Concentrations in Relation to Birth Outcomes in the Mid-Ohio Valley, 2005–2010

Background: Previous research suggests perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) may be associated with adverse pregnancy outcomes.Objective: We conducted a population-based study of PFOA and PFOS and birth outcomes from 2005 through 2010 in a Mid-Ohio Valley community exposed to high levels of PFOA through drinking-water contamination.Methods: Women provided serum for PFOA and PFOS measurement in 2005–2006 and reported reproductive histories in subsequent follow-up interviews. Reported singleton live births among 1,330 women after 1 January 2005 were linked to birth records (n = 1,630) to identify the outcomes of preterm birth (< 37 weeks gestation), pregnancy-induced hypertension, low birth weight (< 2,500 g), and birth weight (grams) among full-term infants.Results: We observed little or no evidence of association between maternal serum PFOA or PFOS and preterm birth (n = 158) or low birth weight (n = 88). Serum PFOA and PFOS were both positively associated with pregnancy-induced hypertension (n = 106), with adjusted odds ratios (ORs) per log unit increase in PFOA and PFOS of 1.27 (95% CI: 1.05, 1.55) and 1.47 (95% CI: 1.06, 2.04), respectively, but associations did not increase monotonically when categorized by quintiles. Results of subanalyses restricted to pregnancies conceived after blood collection were consistent with the main analyses. There was suggestion of a modest negative association between PFOS and birth weight in full-term infants (–29 g per log unit increase; 95% CI: –66, 7), which became stronger when restricted to births conceived after the blood sample collection (–49 g per log unit increase; 95% CI: –90, –8).Conclusion: Results provide some evidence of positive associations between measured serum perfluorinated compounds and pregnancy-induced hypertension and a negative association between PFOS and birth weight among full-term infants.Citation: Darrow LA, Stein CR, Steenland K. 2013. Serum perfluorooctanoic acid and perfluorooctane sulfonate concentrations in relation to birth outcomes in the Mid-Ohio Valley, 2005–2010. Environ Health Perspect 121:1207–1213; http://dx.doi.org/10.1289/ehp.1206372     

Dietary sulfur amino acid effects on fasting plasma cysteine/cystine redox potential in humans

Objective

Oxidation of plasma cysteine/cystine (Cys/CySS) redox potential (E_hCySS) has been associated with risk factors for cardiovascular disease in humans. Cys and CySS are derived from dietary sulfur amino acids (SAA), but the specific effects of SAA depletion and repletion on Cys/CySS redox indices are unknown. The present study examined the effect of dietary SAA intake level on free Cys, free CySS, and E_hCySS in human plasma under fasting conditions.

Methods

Healthy individuals aged 18-36 y (n = 13) were equilibrated to foods providing the RDA for SAA and then fed chemically defined diets without SAA (0 mg·kg^-1·d^-1; n = 13) followed by SAA at levels approximating the mean (56 mg·kg^-1·d^-1; n = 8) or 99th percentile (117 mg·kg^-1·d^-1; n = 5) intake levels of Americans. Fasting plasma samples were collected daily during 4-d study periods and analyzed for free Cys, free CySS, and the E_hCySS.

Results

The SAA-free diet significantly (P < 0.05) decreased plasma-free Cys concentrations and oxidized E_hCySS values after 4 d of SAA depletion. With SAA repletion at 56 mg·kg^-1·d^-1, plasma-free Cys increased significantly and values for E_hCySS became more reduced. Administration of a diet providing a higher dose of SAA (117 mg·kg^-1·d^-1) resulted in a significantly higher level of free Cys and a more reduced E_hCySS.

Conclusions

These results show that free Cys and Cys/CySS redox potential (E_hCySS) in fasting plasma are affected by dietary SAA intake level in humans. Significant changes occur slowly over 4 d with insufficient SAA intake, but rapidly (after 1 d) with repletion.     

Lead Exposure and Tremor among Older Men: The VA Normative Aging Study

Background: Tremor is one of the most common neurological signs, yet its etiology is poorly understood. Case–control studies suggest an association between blood lead and essential tremor, and that this association is modified by polymorphisms in the δ-aminolevulinic acid dehydrogenase (ALAD) gene.Objective: We aimed to examine the relationship between lead and tremor, including modification by ALAD, in a prospective cohort study, using both blood lead and bone lead—a biomarker of cumulative lead exposure.Methods: We measured tibia (n = 670) and patella (n = 672) bone lead and blood lead (n = 807) among older men (age range, 50–98 years) in the VA Normative Aging Study cohort. A tremor score was created based on an approach using hand-drawing samples. ALAD genotype was dichotomized as ALAD-2 carriers or not. We used linear regression adjusted for age, education, smoking, and alcohol intake to estimate the associations between lead biomarkers and tremor score.Results: In unadjusted analyses, there was a marginal association between quintiles of all lead biomarkers and tremor scores (p-values < 0.13), which did not persist in adjusted models. Age was the strongest predictor of tremor. Among those younger than the median age (68.9 years), tremor increased significantly with blood lead (p = 0.03), but this pattern was not apparent for bone lead. We did not see modification by ALAD or an association between bone lead and change in tremor score over time.Conclusion: Our results do not strongly support an association between lead exposure and tremor, and suggest no association with cumulative lead biomarkers, although there is some suggestion that blood lead may be associated with tremor among the younger men in our cohort.Citation: Ji JS, Power MC, Sparrow D, Spiro A III, Hu H, Louis ED, Weisskopf MG. 2015. Lead exposure and tremor among older men: the VA Normative Aging Study. Environ Health Perspect 123:445–450; http://dx.doi.org/10.1289/ehp.1408535     

Pesticide Exposure and Depression among Male Private Pesticide Applicators in the Agricultural Health Study

Background: Pesticide exposure may be positively associated with depression. Few previous studies have considered the episodic nature of depression or examined individual pesticides.Objective: We evaluated associations between pesticide exposure and depression among male private pesticide applicators in the Agricultural Health Study.Methods: We analyzed data for 10 pesticide classes and 50 specific pesticides used by 21,208 applicators enrolled in 1993–1997 who completed a follow-up telephone interview in 2005–2010. We divided applicators who reported a physician diagnosis of depression (n = 1,702; 8%) into those who reported a previous diagnosis of depression at enrollment but not follow-up (n = 474; 28%), at both enrollment and follow-up (n = 540; 32%), and at follow-up but not enrollment (n = 688; 40%) and used polytomous logistic regression to estimate odds ratios (ORs) and 95% CIs. We used inverse probability weighting to adjust for potential confounders and to account for the exclusion of 3,315 applicators with missing covariate data and 24,619 who did not complete the follow-up interview.Results: After weighting for potential confounders, missing covariate data, and dropout, ever-use of two pesticide classes, fumigants and organochlorine insecticides, and seven individual pesticides—the fumigants aluminum phosphide and ethylene dibromide; the phenoxy herbicide (2,4,5-trichlorophenoxy)acetic acid (2,4,5-T); the organochlorine insecticide dieldrin; and the organophosphate insecticides diazinon, malathion, and parathion—were all positively associated with depression in each case group, with ORs between 1.1 and 1.9.Conclusions: Our study supports a positive association between pesticide exposure and depression, including associations with several specific pesticides.Citation: Beard JD, Umbach DM, Hoppin JA, Richards M, Alavanja MCR, Blair A, Sandler DP, Kamel F. 2014. Pesticide exposure and depression among male private pesticide applicators in the Agricultural Health Study. Environ Health Perspect 122:984–991; http://dx.doi.org/10.1289/ehp.1307450     

Modification of the Association between PM10 and Lung Function Decline by Cadherin 13 Polymorphisms in the SAPALDIA Cohort: A Genome-Wide Interaction Analysis

Background: Both air pollution and genetic variation have been shown to affect lung function. Their interaction has not been studied on a genome-wide scale to date.Objectives: We aimed to identify, in an agnostic fashion, genes that modify the association between long-term air pollution exposure and annual lung function decline in an adult population-based sample.Methods: A two-stage genome-wide interaction study was performed. The discovery (n = 763) and replication (n = 3,896) samples were derived from the multi-center SAPALDIA cohort (Swiss Cohort Study on Air Pollution and Lung Disease in Adults). Annual rate of decline in the forced mid-expiratory flow (FEF_25–75%) was the main end point. Multivariate linear regression analyses were used to identify potential multiplicative interactions between genotypes and 11-year cumulative PM₁₀ exposure.Results: We identified a cluster of variants intronic to the CDH13 gene as the only locus with genome-wide significant interactions. The strongest interaction was observed for rs2325934 (p = 8.8 × 10^–10). Replication of the interaction between this CDH13 variant and cumulative PM₁₀ exposure on annual decline in FEF_25–75% was successful (p = 0.008). The interaction was not sensitive to adjustment for smoking or body weight.Conclusions: CDH13 is functionally linked to the adipokine adiponectin, an inflammatory regulator. Future studies need to confirm the interaction and assess how the result relates to previously observed interactions between air pollution and obesity on respiratory function.Citation: Imboden M, Kumar A, Curjuric I, Adam M, Thun GA, Haun M, Tsai MY, Pons M, Bettschart R, Turk A, Rochat T, Künzli N, Schindler C, Kronenberg F, Probst-Hensch NM. 2015. Modification of the association between PM₁₀ and lung function decline by cadherin 13 polymorphisms in the SAPALDIA cohort: a genome-wide interaction analysis. Environ Health Perspect 123:72–79; http://dx.doi.org/10.1289/ehp.1307398     

Prenatal Exposure to Maternal Cigarette Smoking and DNA Methylation: Epigenome-Wide Association in a Discovery Sample of Adolescents and Replication in an Independent Cohort at Birth through 17 Years of Age

Background: Prenatal exposure to maternal cigarette smoking (prenatal smoke exposure) had been associated with altered DNA methylation (DNAm) at birth.Objective: We examined whether such alterations are present from birth through adolescence.Methods: We used the Infinium HumanMethylation450K BeadChip to search across 473,395 CpGs for differential DNAm associated with prenatal smoke exposure during adolescence in a discovery cohort (n = 132) and at birth, during childhood, and during adolescence in a replication cohort (n = 447).Results: In the discovery cohort, we found five CpGs in MYO1G (top-ranking CpG: cg12803068, p = 3.3 × 10^–11) and CNTNAP2 (cg25949550, p = 4.0 × 10^–9) to be differentially methylated between exposed and nonexposed individuals during adolescence. The CpGs in MYO1G and CNTNAP2 were associated, respectively, with higher and lower DNAm in exposed versus nonexposed adolescents. The same CpGs were differentially methylated at birth, during childhood, and during adolescence in the replication cohort. In both cohorts and at all developmental time points, the differential DNAm was in the same direction and of a similar magnitude, and was not altered appreciably by adjustment for current smoking by the participants or their parents. In addition, four of the five EWAS (epigenome-wide association study)–significant CpGs in the adolescent discovery cohort were also among the top sites of differential methylation in a previous birth cohort, and differential methylation of CpGs in CYP1A1, AHRR, and GFI1 observed in that study was also evident in our discovery cohort.Conclusions: Our findings suggest that modifications of DNAm associated with prenatal maternal smoking may persist in exposed offspring for many years—at least until adolescence.Citation: Lee KW, Richmond R, Hu P, French L, Shin J, Bourdon C, Reischl E, Waldenberger M, Zeilinger S, Gaunt T, McArdle W, Ring S, Woodward G, Bouchard L, Gaudet D, Davey Smith G, Relton C, Paus T, Pausova Z. 2015. Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environ Health Perspect 123:193–199; http://dx.doi.org/10.1289/ehp.1408614     

Temporal Trends in Phthalate Exposures: Findings from the National Health and Nutrition Examination Survey, 2001–2010

Background: Phthalates are ubiquitous environmental contaminants. Because of potential adverse effects on human health, butylbenzyl phthalate [BBzP; metabolite, monobenzyl phthalate (MBzP)], di-n-butyl phthalate [DnBP; metabolite, mono-n-butyl phthalate (MnBP)], and di(2-ethylhexyl) phthalate (DEHP) are being replaced by substitutes including other phthalates; however, little is known about consequent trends in population-level exposures.Objective: We examined temporal trends in urinary concentrations of phthalate metabolites in the general U.S. population and whether trends vary by sociodemographic characteristics.Methods: We combined data on 11 phthalate metabolites for 11,071 participants from five cycles of the National Health and Nutrition Examination Survey (2001–2010). Percent changes and least square geometric means (LSGMs) were calculated from multivariate regression models.Results: LSGM concentrations of monoethyl phthalate, MnBP, MBzP, and ΣDEHP metabolites decreased between 2001–2002 and 2009–2010 [percent change (95% CI): –42% (–49, –34); –17% (–23, –9); –32% (–39, –23) and –37% (–46, –26), respectively]. In contrast, LSGM concentrations of monoisobutyl phthalate, mono(3-carboxypropyl) phthalate (MCPP), monocarboxyoctyl phthalate, and monocarboxynonyl phthalate (MCNP) increased over the study period [percent change (95% CI): 206% (178, 236); 25% (8, 45); 149% (102, 207); and 15% (1, 30), respectively]. Trends varied by subpopulations for certain phthalates. For example, LSGM concentrations of ΣDEHP metabolites, MCPP, and MCNP were higher in children than adults, but the gap between groups narrowed over time (p_interaction < 0.01).Conclusions: Exposure of the U.S. population to phthalates has changed in the last decade. Data gaps make it difficult to explain trends, but legislative activity and advocacy campaigns by nongovernmental organizations may play a role in changing trends.Citation: Zota AZ, Calafat AM, Woodruff TJ. 2014. Temporal trends in phthalate exposures: findings from the National Health and Nutrition Examination Survey, 2001–2010. Environ Health Perspect 122:235–241; http://dx.doi.org/10.1289/ehp.1306681     

Oxidation of the glutathione/glutathione disulfide redox state is induced by cysteine deficiency in human colon carcinoma HT29 cells

Glutathione (GSH) has a central role in the maintenance of the thiol-disulfide redox state in mammalian cells. GSH synthesis can be physiologically limited by the availability of cysteine (Cys), and Cys and its precursors are variable in the human diet. The purpose of this study was to determine the effect of severe Cys deficiency and readdition of Cys on the redox state of the GSH/glutathione disulfide (GSSG) pool in human colon carcinoma HT29 cells. Cells were cultured in Cys- (and cystine-)limiting medium for 48 h followed by culture in medium containing either Cys or cystine for 24 h. GSH and GSSG were measured by HPLC. Cys limitation decreased cellular GSH and GSSG concentrations with an associated >80 mV oxidation of the GSH/GSSG redox state. Upon addition of either Cys or its disulfide cystine (CySS), redox of GSH/GSSG recovered in 4 h, whereas GSH concentration continued to increase over 12 h. Maximal GSH concentrations attained were 200% of control cell values. These results show that severe Cys deficiency can have marked effects on cellular redox state but that redox recovers rapidly upon resupply. The magnitude of oxidation during Cys limitation in this cell model is sufficient to result in a >100-fold change in the reduced/oxidized ratio of redox-sensitive dithiol/disulfide motifs in proteins. If redox changes occur in vivo in association with variations in dietary Cys and its precursors, these changes could have important physiologic effects through altered redox signaling and control of cell proliferation and apoptosis.     

The Effect of Elevated Protein Intake on DNA Damage in Older People: Comparative Secondary Analysis of Two Randomized Controlled Trials

A high protein intake at old age is important for muscle protein synthesis, however, this could also trigger protein oxidation with the potential risk for DNA damage. The aim of this study was to investigate whether an increased protein intake at recommended level or well above would affect DNA damage or change levels of reduced (GSH) and oxidised glutathione (GSSG) in community-dwelling elderly subjects. These analyses were performed in two randomized intervention studies, in Austria and in New Zealand. In both randomized control trials, the mean protein intake was increased with whole foods, in the New Zealand study (n = 29 males, 74.2 ± 3.6 years) to 1.7 g/kg body weight/d (10 weeks intervention; p < 0.001)) in the Austrian study (n = 119 males and females, 72.9 ± 4.8 years) to 1.54 g/kg body weight/d (6 weeks intervention; p < 0.001)). In both studies, single and double strand breaks and as formamidopyrimidine—DNA glycosylase-sensitive sites were investigated in peripheral blood mononuclear cells or whole blood. Further, resistance to H₂O₂ induced DNA damage, GSH, GSSG and CRP were measured. Increased dietary protein intake did not impact on DNA damage markers and GSH/GSSG levels. A seasonal-based time effect (p < 0.05), which led to a decrease in DNA damage and GSH was observed in the Austrian study. Therefore, increasing the protein intake to more than 20% of the total energy intake in community-dwelling seniors in Austria and New Zealand did not increase measures of DNA damage, change glutathione status or elevate plasma CRP.     

Manganese Exposure and Neurocognitive Outcomes in Rural School-Age Children: The Communities Actively Researching Exposure Study (Ohio,USA)

Background

Manganese (Mn) plays a vital role in brain growth and development, yet excessive exposure can result in neurotoxicity. Marietta, Ohio, is home to the nation’s longest-operating ferromanganese refinery, and community concern about exposure led to the development of the research study.

Objectives

Our overall goal was to address the community’s primary research question: “Does Mn affect cognitive development of children?” We evaluated the relationships between Mn exposure as measured by blood and hair Mn, along with other neurotoxicants including blood lead (Pb) and serum cotinine, and child cognition.

Methods

Children 7–9 years of age were enrolled (n = 404) in the Communities Actively Researching Exposure Study (CARES) from Marietta and Cambridge, Ohio, and their surrounding communities from October 2008 through March 2013. Blood and hair were analyzed for Mn and Pb, and serum was analyzed for cotinine. We used penalized splines to assess potential nonlinear associations between biological measures and IQ subscale scores, followed by multivariable regression models with categorical variables based on quartiles of the distribution for biological measures with nonlinear associations and continuous variables for biological measures with linear associations.

Results

Geometric mean blood (n = 327) and hair Mn (n = 370) concentrations were 9.67 ± 1.27 μg/L and 416.51 ± 2.44 ng/g, respectively. After adjusting for potential confounders, both low and high blood and hair Mn concentrations were associated with lower Full Scale IQ and subscale scores, with significant negative associations between the highest quartile and middle two quartiles of blood Mn (β –3.51; 95% CI: –6.64, –0.38) and hair Mn (β –3.66; 95% CI: –6.9, –0.43%) and Full Scale IQ.

Conclusions

Both low and high Mn concentrations in blood and hair were negatively associated with child IQ scores. Serum cotinine was negatively associated with child cognitive function.

Citation

Haynes EN, Sucharew H, Kuhnell P, Alden J, Barnas M, Wright RO, Parsons PJ, Aldous KM, Praamsma ML, Beidler C, Dietrich KN. 2015. Manganese exposure and neurocognitive outcomes in rural school-age children: the Communities Actively Researching Exposure Study (Ohio, USA). Environ Health Perspect 123:1066–1071; http://dx.doi.org/10.1289/ehp.1408993     

Estimated Exposure to Arsenic in Breastfed and Formula-Fed Infants in a United States Cohort

Background: Previous studies indicate that concentrations of arsenic in breast milk are relatively low even in areas with high drinking-water arsenic. However, it is uncertain whether breastfeeding leads to reduced infant exposure to arsenic in regions with lower arsenic concentrations.Objective: We estimated the relative contributions of breast milk and formula to arsenic exposure during early infancy in a U.S. population.Methods: We measured arsenic in home tap water (n = 874), urine from 6-week-old infants (n = 72), and breast milk from mothers (n = 9) enrolled in the New Hampshire Birth Cohort Study (NHBCS) using inductively coupled plasma mass spectrometry. Using data from a 3-day food diary, we compared urinary arsenic across infant feeding types and developed predictive exposure models to estimate daily arsenic intake from breast milk and formula.Results: Urinary arsenic concentrations were generally low (median, 0.17 μg/L; maximum, 2.9 μg/L) but 7.5 times higher for infants fed exclusively with formula than for infants fed exclusively with breast milk (β = 2.02; 95% CI: 1.21, 2.83; p < 0.0001, adjusted for specific gravity). Similarly, the median estimated daily arsenic intake by NHBCS infants was 5.5 times higher for formula-fed infants (0.22 μg/kg/day) than for breastfed infants (0.04 μg/kg/day). Given median arsenic concentrations measured in NHBCS tap water and previously published for formula powder, formula powder was estimated to account for ~ 70% of median exposure among formula-fed NHBCS infants.Conclusions: Our findings suggest that breastfed infants have lower arsenic exposure than formula-fed infants, and that both formula powder and drinking water can be sources of exposure for U.S. infants.Citation: Carignan CC, Cottingham KL, Jackson BP, Farzan SF, Gandolfi AJ, Punshon T, Folt CL, Karagas MR. 2015. Estimated exposure to arsenic in breastfed and formula-fed infants in a United States cohort. Environ Health Perspect 123:500–506; http://dx.doi.org/10.1289/ehp.1408789     

Characteristics of Walkable Built Environments and BMI z-Scores in Children: Evidence from a Large Electronic Health Record Database

Background: Childhood obesity remains a prominent public health problem. Walkable built environments may prevent excess weight gain.Objectives: We examined the association of walkable built environment characteristics with body mass index (BMI) z-score among a large sample of children and adolescents.Methods: We used geocoded residential address data from electronic health records of 49,770 children and adolescents 4 to < 19 years of age seen at the 14 pediatric practices of Harvard Vanguard Medical Associates from August 2011 through August 2012. We used eight geographic information system (GIS) variables to characterize walkable built environments. Outcomes were BMI z-score at the most recent visit and BMI z-score change from the earliest available (2008–2011) to the most recent (2011–2012) visit. Multivariable models were adjusted for child age, sex, race/ethnicity, and neighborhood median household income.Results: In multivariable cross-sectional models, living in closer proximity to recreational open space was associated with lower BMI z-score. For example, children who lived in closest proximity (quartile 1) to the nearest recreational open space had a lower BMI z-score (β = –0.06; 95% CI: –0.08, –0.03) compared with those living farthest away (quartile 4; reference). Living in neighborhoods with fewer recreational open spaces and less residential density, traffic density, sidewalk completeness, and intersection density were associated with higher cross-sectional BMI z-score and with an increase in BMI z-score over time.Conclusions: Overall, built environment characteristics that may increase walkability were associated with lower BMI z-scores in a large sample of children. Modifying existing built environments to make them more walkable may reduce childhood obesity.Citation: Duncan DT, Sharifi M, Melly SJ, Marshall R, Sequist TD, Rifas-Shiman SL, Taveras EM. 2014. Characteristics of walkable built environments and BMI z-scores in children: evidence from a large electronic health record database. Environ Health Perspect 122:1359–1365; http://dx.doi.org/10.1289/ehp.1307704     

Traffic-Related Air Pollution and Congenital Anomalies in Barcelona

Background: A recent meta-analysis suggested evidence for an effect of exposure to ambient air pollutants on risk of certain congenital heart defects. However, few studies have investigated the effects of traffic-related air pollutants with sufficient spatial accuracy.Objectives: We estimated associations between congenital anomalies and exposure to traffic-related air pollution in Barcelona, Spain.Method: Cases with nonchromosomal anomalies (n = 2,247) and controls (n = 2,991) were selected from the Barcelona congenital anomaly register during 1994–2006. Land use regression models from the European Study of Cohorts for Air Pollution Effects (ESCAPE), were applied to residential addresses at birth to estimate spatial exposure to nitrogen oxides and dioxide (NO_x, NO₂)_, particulate matter with diameter ≤ 10 μm (PM₁₀), 10–2.5 μm (PM_coarse), ≤ 2.5 μm (PM_2.5), and PM_2.5 absorbance. Spatial estimates were adjusted for temporal trends using data from routine monitoring stations for weeks 3–8 of each pregnancy. Logistic regression models were used to calculate odds ratios (ORs) for 18 congenital anomaly groups associated with an interquartile-range (IQR) increase in exposure estimates.Results: In spatial and spatiotemporal exposure models, we estimated statistically significant associations between an IQR increase in NO₂ (12.2 μg/m³) and coarctation of the aorta (OR_{spatiotemporal} = 1.15; 95% CI: 1.01, 1.31) and digestive system defects (OR_{spatiotemporal} = 1.11; 95% CI: 1.00, 1.23), and between an IQR increase in PM_coarse (3.6 μg/m³) and abdominal wall defects (OR_{spatiotemporal} = 1.93; 95% CI: 1.37, 2.73). Other statistically significant increased and decreased ORs were estimated based on the spatial model only or the spatiotemporal model only, but not both.Conclusions: Our results overall do not indicate an association between traffic-related air pollution and most groups of congenital anomalies. Findings for coarctation of the aorta are consistent with those of the previous meta-analysis.Citation: Schembari A, Nieuwenhuijsen MJ, Salvador J, de Nazelle A, Cirach M, Dadvand P, Beelen R, Hoek G, Basagaña X, Vrijheid M. 2014. Traffic-related air pollution and congenital anomalies in Barcelona. Environ Health Perspect 122:317–323; http://dx.doi.org/10.1289/ehp.1306802     

Early-Life Bisphenol A Exposure and Child Body Mass Index: A Prospective Cohort Study

Background: Early-life exposure to bisphenol A (BPA) may increase childhood obesity risk, but few prospective epidemiological studies have investigated this relationship.Objective: We sought to determine whether early-life exposure to BPA was associated with increased body mass index (BMI) at 2–5 years of age in 297 mother–child pairs from Cincinnati, Ohio (HOME Study).Methods: Urinary BPA concentrations were measured in samples collected from pregnant women during the second and third trimesters and their children at 1 and 2 years of age. BMI z-scores were calculated from weight/height measures conducted annually from 2 through 5 years of age. We used linear mixed models to estimate BMI differences or trajectories with increasing creatinine-normalized BPA concentrations.Results: After confounder adjustment, each 10-fold increase in prenatal (β = –0.1; 95% CI: –0.5, 0.3) or early-childhood (β = –0.2; 95% CI: –0.6, 0.1) BPA concentrations was associated with a modest and nonsignificant reduction in child BMI. These inverse associations were suggestively stronger in girls than in boys [prenatal effect measure modification (EMM) p-value = 0.30, early-childhood EMM p-value = 0.05], but sex-specific associations were imprecise. Children in the highest early-childhood BPA tercile had lower BMI at 2 years (difference = –0.3; 95% CI: –0.6, 0.0) and larger increases in their BMI slope from 2 through 5 years (BMI increase per year = 0.12; 95% CI: 0.07, 0.18) than children in the lowest tercile (BMI increase per year = 0.07; 95% CI: 0.01, 0.13). All associations were attenuated without creatinine normalization.Conclusions: Prenatal and early-childhood BPA exposures were not associated with increased BMI at 2–5 years of age, but higher early-childhood BPA exposures were associated with accelerated growth during this period.Citation: Braun JM, Lanphear BP, Calafat AM, Deria S, Khoury J, Howe CJ, Venners SA. 2014. Early-life bisphenol A exposure and child body mass index: a prospective cohort study. Environ Health Perspect 122:1239–1245; http://dx.doi.org/10.1289/ehp.1408258     

Urinary Polycyclic Aromatic Hydrocarbons and Childhood Obesity: NHANES (2001–2006)

Background: Polycyclic aromatic hydrocarbons (PAHs) are known carcinogens and suspected endocrine disruptors. Prenatal exposure to PAHs has been associated with obesity in early childhood.Objective: We examined the association of urinary PAH metabolites with adiposity outcomes [body mass index (BMI) z-score, waist circumference (WC), and rate of obesity] in children and adolescents.Methods: We performed whole-sample analyses of 3,189 individuals 6–19 years of age who participated in the 2001–2006 National Health and Nutrition Examination Survey. We performed multivariate linear and logistic regression to analyze the association of BMI z-score, WC, and obesity with concentrations of single urinary PAH compounds and the sum of PAHs. Furthermore, the analyses were stratified by developmental stage [i.e., children (6–11 years) and adolescents (12–19 years)].Results: BMI z-score, WC, and obesity were positively associated with the molecular mass sum of the PAHs and the total sum of naphthalene metabolites. Most associations increased monotonically with increasing quartiles of exposure among children 6–11 years of age, whereas dose–response trends were less consistent for adolescents (12–19 years of age). Neither total PAHs nor total naphthalene metabolites were associated with overweight in either age group, and there was little evidence of associations between the outcomes and individual PAHs.Conclusions: Total urinary PAH metabolites and naphthalene metabolites were associated with higher BMI, WC, and obesity in children 6–11 years of age, with positive but less consistent associations among adolescents.Citation: Scinicariello F, Buser MC. 2014. Urinary polycyclic aromatic hydrocarbons and childhood obesity: NHANES (2001–2006). Environ Health Perspect 122:299–303; http://dx.doi.org/10.1289/ehp.1307234