Associations of gestational and childhood exposure to lead, cadmium, and fluoride with cognitive abilities, behavior, and social communication at 4 years of age: NICE birth cohort study.

BACKGROUND: Early-life lead exposure affects cognitive development and emerging evidence suggests similar effects of cadmium and fluoride. OBJECTIVE: To assess the impact of gestational and childhood exposure to lead, cadmium, and fluoride on cognitive abilities and behavioral and social communication problems. METHODS: We studied 470 pregnant women (gestational week 29) and their 4-year-old children from the NICE cohort in northern Sweden. Concentrations of erythrocyte lead and cadmium and urinary cadmium were measured using inductively coupled plasma mass spectrometry and urinary fluoride with an ion-selective electrode. Urinary concentrations were specific-gravity adjusted. Associations of log2-transformed exposure concentrations with cognitive abilities (full-scale IQ and verbal comprehension by Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition), behavioral problems (Child Behavior Checklist), and social communication (Social Responsiveness Scale-Second Edition) were evaluated with multivariable-adjusted linear regression analysis. RESULTS: Both gestational and cord erythrocyte lead concentrations were non-significantly inversely associated with child cognitive abilities (full-scale IQ: B [95%CI]: -1.2 [-2.9, 0.5] and -1.6 [-3.7, 0.4], respectively; per doubling of exposure). Similarly, both gestational and child urinary cadmium were inversely associated with cognitive abilities (full-scale IQ: -1.1 [-2.5, 0.3] and -1.1 [-2.5, 0.4], verbal comprehension: -1.2 [-3.1, 0.6] and -1.4 [-3.4, 0.6], respectively). Urinary fluoride concentrations showed no association with cognitive abilities. However, gestational fluoride was associated with increasing externalizing problems (0.9 [-0.3, 2.0]) and ADHD raw scores (0.3 [0.0, 0.6]). Childhood erythrocyte lead and urinary cadmium were non-significantly associated with increased behavioral problems (lead with total problems: 1.2 [-0.4, 2.9] and internalizing problems: 1.5 [-0.4, 3.4]; cadmium with externalizing problems: 1.1 [-0.2, 2.4]). CONCLUSION: Despite non-significant associations, both lead and cadmium exposure showed consistent inverse associations with cognitive abilities at 4 years, whereas associations with behavioral problems were less conclusive, especially for cadmium. Results on fluoride indicated association with externalizing problems, including ADHD, but prevalence of behavioral problems was low, increasing uncertainty.

Toxic metals and essential trace elements in placenta and their relation to placental function.

INTRODUCTION: Placental function is essential for fetal development, but it may be susceptible to malnutrition and environmental stressors. OBJECTIVE: To assess the impact of toxic and essential trace elements in placenta on placental function. METHODS: Toxic metals (cadmium, lead, mercury, cobalt) and essential elements (copper, manganese, zinc, selenium) were measured in placenta of 406 pregnant women in northern Sweden using ICP-MS. Placental weight and birth weight were obtained from hospital records and fetoplacental weight ratio was used to estimate placental efficiency. Placental relative telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) were determined by quantitative PCR (n = 285). Single exposure-outcome associations were evaluated using linear or spline regression, and joint associations and interactions with Bayesian kernel machine regression (BKMR), all adjusted for sex, maternal smoking, and age or BMI. RESULTS: Median cadmium, mercury, lead, cobalt, copper, manganese, zinc, and selenium concentrations in placenta were 3.2, 1.8, 4.3, 2.3, 1058, 66, 10626, and 166 µg/kg, respectively. In the adjusted regression, selenium (>147 µg/kg) was inversely associated with placental weight (B: -158; 95 % CI: -246, -71, per doubling), as was lead at low selenium (B: -23.6; 95 % CI: -43.2, -4.0, per doubling). Manganese was positively associated with placental weight (B: 41; 95 % CI: 5.9, 77, per doubling) and inversely associated with placental efficiency (B: -0.01; 95 % CI: -0.019, -0.004, per doubling). Cobalt was inversely associated with mtDNAcn (B: -11; 95 % CI: -20, -0.018, per doubling), whereas all essential elements were positively associated with mtDNAcn, individually and joint. CONCLUSION: Among the toxic metals, lead appeared to negatively impact placental weight and cobalt decreased placental mtDNAcn. Joint essential element concentrations increased placental mtDNAcn. Manganese also appeared to increase placental weight, but not birth weight. The inverse association of selenium with placental weight may reflect increased transport of selenium to the fetus in late gestation.

Urinary phosphate is associated with cardiovascular disease incidence.

INTRODUCTION: Elevated phosphate (P) in urine may reflect a high intake of inorganic P salts from food additives. Elevated P in plasma is linked to vascular dysfunction and calcification. OBJECTIVE: To explore associations between P in urine as well as in plasma and questionnaire-estimated P intake, and incidence of cardiovascular disease (CVD). METHODS: We used the Swedish Mammography Cohort-Clinical, a population-based cohort study. At baseline (2004-2009), P was measured in urine and plasma in 1625 women. Dietary P was estimated via a food-frequency questionnaire. Incident CVD was ascertained via register-linkage. Associations were assessed using Cox proportional hazards regression. RESULTS: After a median follow-up of 9.4 years, 164 composite CVD cases occurred (63 myocardial infarctions [MIs] and 101 strokes). Median P (percentiles 5-95) in urine and plasma were 2.4 (1.40-3.79) mmol/mmol creatinine and 1.13 (0.92-1.36) mmol/L, respectively, whereas dietary P intake was 1510 (1148-1918) mg/day. No correlations were observed between urinary and plasma P (r = -0.07) or dietary P (r = 0.10). Urinary P was associated with composite CVD and MI. The hazard ratio of CVD comparing extreme tertiles was 1.57 (95% confidence interval 1.05, 2.35; P trend 0.037)-independently of sodium excretion, the estimated glomerular filtration rate, both P and calcium in plasma, and diuretic use. Association with CVD for plasma P was 1.41 (0.96, 2.07; P trend 0.077). CONCLUSION: Higher level of urinary P, likely reflecting a high consumption of highly processed foods, was linked to CVD. Further investigation is needed to evaluate the potential cardiovascular toxicity associated with excessive intake of P beyond nutritional requirements.

Prediagnostic Blood Metal Levels and the Risk of Parkinson's Disease: A Large European Prospective Cohort.

BACKGROUND: Metals have been postulated as environmental concerns in the etiology of Parkinson's disease (PD), but metal levels are typically measured after diagnosis, which might be subject to reverse causality. OBJECTIVE: The aim of this study was to investigate the association between prediagnostic blood metal levels and PD risk. METHODS: A case-control study was nested in a prospective European cohort, using erythrocyte samples collected before PD diagnosis. RESULTS: Most assessed metals were not associated with PD risk. Cadmium has a suggestive negative association with PD (odds ratio [95% confidence interval] for the highest quartile, 0.70 [0.42-1.17]), which diminished among never smokers. Among current smokers only, lead was associated with decreased PD risk (0.06 [0.01-0.35]), whereas arsenic showed associations toward an increased PD risk (1.85 [0.45-7.93]). CONCLUSIONS: We observe no strong evidence to support a role of metals in the development of PD. In particular, smoking may confound the association with tobacco-derived metals. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Biomarkers of seafood intake during pregnancy - Pollutants versus fatty acids and micronutrients.

Intake of fish and seafood during pregnancy may have certain beneficial effects on fetal development, but measurement of intake using questionnaires is unreliable. Here, we assessed several candidate biomarkers of seafood intake, including long-chain omega 3 fatty acids (n-3 LCPUFA), selenium, iodine, methylmercury, and different arsenic compounds, in 549 pregnant women (gestational week 29) in the prospective birth cohort NICE (Nutritional impact on Immunological maturation during Childhood in relation to the Environment). Proportions of the fatty acids eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) in erythrocytes were measured using gas chromatography with flame ionization detector. Selenium was measured in blood plasma and erythrocytes, mercury and arsenic in erythrocytes, and iodine and several arsenic compounds in urine, using inductively coupled plasma mass spectrometry, arsenic compounds after first being separated by ion exchange high-performance liquid chromatography (HPLC). Each biomarker was related to intake of total seafood and to intake of fatty and lean fish, and shellfish in third trimester, estimated from a semi-quantitative food frequency questionnaire filled out in gestational week 34. The pregnant women reported a median total seafood intake of 184 g/week (5th-95th percentiles: 34-465 g/week). This intake correlated most strongly with erythrocyte mercury concentrations (rho = 0.49, p < 0.001), consisting essentially of methylmercury, followed by total arsenic in erythrocytes (rho = 0.34, p < 0.001), and arsenobetaine in urine (rho = 0.33, p < 0.001), the main form of urinary arsenic. These biomarkers correlated well with intake of both fatty fish, lean fish, and shellfish. Erythrocyte DHA and plasma selenium correlated, although weakly, mainly with fatty fish (rho = 0.25 and 0.22, respectively, both p < 0.001). In conclusion, elevated concentrations of erythrocyte mercury and urinary arsenobetaine can be useful indicators of seafood intake, more so than the n-3 LCPUFAs. However, the relative importance of the biomarkers may differ depending on the type and amount of seafood consumed.

Polycyclic aromatic hydrocarbon (PAH) exposure during pregnancy and child anthropometry from birth to 10 years of age: Sex-specific evidence from a cohort study in rural Bangladesh.

Polycyclic aromatic hydrocarbons (PAHs) have endocrine disrupting properties and they cross the placental barrier, but studies on gestational exposure and child anthropometry are inconclusive. We aimed to elucidate the impact of early gestational PAH exposure on anthropometry from birth to 10 years of age in 1295 mother-child pairs from a nested sub-cohort of the MINIMat trial in Bangladesh. Several PAH metabolites [1-hydroxyphenanthrene (1-OH-Phe), Σ2-,3-hydroxyphenanthrene (Σ2-,3-OH-Phe), 4-hydroxyphenanthrene (4-OH-Phe), 1-hydroxypyrene (1-OH-Pyr), Σ2-,3-hydroxyfluorene (Σ2-,3-OH-Flu)] were quantified in spot urine collected around gestational week 8 using LC-MS/MS. Child weight and height were measured at 19 occasions from birth to 10 years. Multivariable-adjusted regression models were used to assess associations of maternal PAH metabolites (log2-transformed) with child anthropometry. The median concentration of 1-OH-Phe, Σ2-,3-OH-Phe, 4-OH-Phe, 1-OH-Pyr and Σ2-,3-OH-Flu was 1.5, 1.9, 0.14, 2.5, and 2.0 ng/mL, respectively. All maternal urinary PAH metabolites were positively associated with newborn weight and length and all associations were more pronounced in boys than in girls (p interaction for all <0.14). In boys, the strongest associations were observed with Σ2-,3-OH-Phe and Σ2-,3-OH-Flu for which each doubling increased mean birth weight by 41 g (95% CI: 13; 69 and 12; 70) and length by 0.23 cm (0.075; 0.39) and 0.21 cm (0.045; 0.37), respectively. Maternal urinary PAH metabolites were not associated with child anthropometry at 10 years. In longitudinal analysis, however, maternal urinary PAH metabolites were positively associated with boys' weight-for-age (WAZ) and height-for-age Z-scores (HAZ) from birth to 10 years, but only the association of 4-OH-Phe with HAZ was significant (B: 0.080 Z-scores; 95% CI 0.013, 0.15). No associations were observed with girls' WAZ or HAZ. In conclusion, gestational PAH exposure was positively associated with fetal and early childhood growth, especially in boys. Further studies are needed to confirm causality and to explore long-term health effects.

Blood Metal Levels and Amyotrophic Lateral Sclerosis Risk: A Prospective Cohort.

OBJECTIVE: Metals have been suggested as a risk factor for amyotrophic lateral sclerosis (ALS), but only retrospective studies are available to date. We compared metal levels in prospectively collected blood samples from ALS patients and controls, to explore whether metals are associated with ALS mortality. METHODS: A nested ALS case-control study was conducted within the prospective EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. Cases were identified through death certificates. We analyzed metal levels in erythrocyte samples obtained at recruitment, as a biomarker for metal exposure from any source. Arsenic, cadmium, copper, lead, manganese, mercury, selenium, and zinc concentrations were measured by inductively coupled plasma-mass spectrometry. To estimate ALS risk, we applied conditional logistic regression models. RESULTS: The study population comprised 107 cases (65% female) and 319 controls matched for age, sex, and study center. Median time between blood collection and ALS death was 8 years (range = 1-15). Comparing the highest with the lowest tertile, cadmium (odds ratio [OR] = 2.04, 95% confidence interval [CI] = 1.08-3.87) and lead (OR = 1.89, 95% CI = 0.97-3.67) concentrations suggest associations with increased ALS risk. Zinc was associated with a decreased risk (OR = 0.50, 95% CI = 0.27-0.94). Associations for cadmium and lead remained when limiting analyses to noncurrent smokers. INTERPRETATION: This is the first study to compare metal levels before disease onset, minimizing reverse causation. The observed associations suggest that cadmium, lead, and zinc may play a role in ALS etiology. Cadmium and lead possibly act as intermediates on the pathway from smoking to ALS. ANN NEUROL 20209999:n/a-n/a.

Assessment of Joint Impact of Iodine, Selenium, and Zinc Status on Women's Third-Trimester Plasma Thyroid Hormone Concentrations.

BACKGROUND: Iodine is essential for synthesizing thyroid hormones, but other micronutrients are also required for optimal thyroid function. However, there is a lack of data on combined micronutrient status in relation to thyroid hormones in pregnancy. OBJECTIVES: We aimed to assess the joint associations of iodine, selenium, and zinc status with plasma concentrations of thyroid hormones and thyroid-stimulating hormone (TSH) in pregnancy. METHODS: We included 531 pregnant women (aged 22-40 y) participating in a Swedish birth cohort who provided blood and spot urine samples in gestational weeks 27-33 (mean: 29). Associations of urinary iodine concentration (UIC), plasma selenium concentration, and plasma zinc concentration (measured by inductively coupled plasma mass spectrometry) with plasma hormone concentrations [total and free thyroxine (tT4, fT4), total and free triiodothyronine (tT3, fT3), and TSH] were explored with Bayesian kernel machine regression (BKMR; n = 516; outliers excluded) and multivariable-adjusted linear regression (n = 531; splined for nonlinear associations). RESULTS: Median (IQR) micronutrient concentrations were 112 µg/L (80-156 µg/L) for UIC, 67 µg/L (58-76 µg/L) for plasma selenium, and 973 µg/L (842-1127 µg/L) for plasma zinc; the former 2 median values were below recommended concentrations (150 µg/L and 70 µg/L, respectively). Mean ± SD TSH concentration was 1.7 ± 0.87 mIU/L, with 98% < 4 mIU/L. BKMR showed a positive trend of joint micronutrient concentrations in relation to TSH. Plasma zinc was most influential for all hormones but tT3, for which plasma selenium was most influential. In adjusted linear regression models, zinc was positively associated with tT4, tT3, and TSH, and <1200 µg/L also with fT4 and fT3. Selenium was inversely associated with fT3, and <85 µg/L with tT3. CONCLUSIONS: Pregnant women's plasma TSH concentrations in the early third trimester increased with increasing joint status of iodine, selenium, and zinc. Zinc and selenium were more influential than iodine for the hormone concentrations. Multiple micronutrients need consideration in future studies of thyroid hormone status.

Association of maternal urinary fluoride concentrations during pregnancy with size at birth and the potential mediation effect by maternal thyroid hormones: The Swedish NICE birth cohort.

BACKGROUND: Observational studies have indicated that elevated maternal fluoride exposure during pregnancy may impair child neurodevelopment but a potential impact on birth outcomes is understudied. OBJECTIVES: To evaluate the impact of gestational fluoride exposure on birth outcomes (birth size and gestational age at birth) and to assess the potential mediating role of maternal thyroid hormones. METHODS: We studied 583 mother-child dyads in the NICE cohort in northern Sweden. Maternal fluoride exposure was assessed by measuring urinary concentrations at late pregnancy (median: 29th gestational week) using an ion selective electrode. Plasma levels of free and total thyroxine (fT4, tT4) and triiodothyronine (fT3, tT3), and thyroid stimulating hormone (TSH) were measured with electrochemiluminescence immunoassays. The infant's weight, length, head circumference, and gestational age at birth were extracted from hospital records. RESULTS: Median urinary fluoride concentration was 0.71 mg/L (5th-95th percentile 0.31-1.9 mg/L; specific gravity adjusted). In multivariable-adjusted regression models, every 1 mg/L increase of maternal urinary fluoride was associated with a mean increase in birth weight by 84 g (95%CI: 30, 138), length by 0.41 cm (95%CI: 0.18, 0.65), head circumference by 0.3 cm (95%CI: 0.1, 0.4), and with increased odds of being born large for gestational age (OR = 1.39, 95%CI: 1.03, 1.89). Every 1 mg/L increase of maternal urinary fluoride was also associated with a mean increase of the plasma fT3:fT4 ratio (B = 0.007, 95%CI: 0.000, 0.014), but not with the hormones or TSH. In mediation analyses, the maternal fT3:fT4 ratio did not explain the urinary fluoride-birth size relationships. DISCUSSION: Gestational urinary fluoride concentrations were associated with increased size at birth and even with increased odds of being born large for gestational age. The fluoride-related associations with increased size at birth were not explained by changes in maternal thyroid hormone levels.

Prenatal metal mixtures and child blood pressure in the Rhea mother-child cohort in Greece.

BACKGROUND: Child blood pressure (BP) is predictive of future cardiovascular risk. Prenatal exposure to metals has been associated with higher BP in childhood, but most studies have evaluated elements individually and measured BP at a single time point. We investigated impacts of prenatal metal mixture exposures on longitudinal changes in BP during childhood and elevated BP at 11 years of age. METHODS: The current study included 176 mother-child pairs from the Rhea Study in Heraklion, Greece and focused on eight elements (antimony, arsenic, cadmium, cobalt, lead, magnesium, molybdenum, selenium) measured in maternal urine samples collected during pregnancy (median gestational age at collection: 12 weeks). BP was measured at approximately 4, 6, and 11 years of age. Covariate-adjusted Bayesian Varying Coefficient Kernel Machine Regression and Bayesian Kernel Machine Regression (BKMR) were used to evaluate metal mixture impacts on baseline and longitudinal changes in BP (from ages 4 to 11) and the development of elevated BP at age 11, respectively. BKMR results were compared using static versus percentile-based cutoffs to define elevated BP. RESULTS: Molybdenum and lead were the mixture components most consistently associated with BP. J-shaped relationships were observed between molybdenum and both systolic and diastolic BP at age 4. Similar associations were identified for both molybdenum and lead in relation to elevated BP at age 11. For molybdenum concentrations above the inflection points (~ 40-80 µg/L), positive associations with BP at age 4 were stronger at high levels of lead. Lead was positively associated with BP measures at age 4, but only at high levels of molybdenum. Potential interactions between molybdenum and lead were also identified for BP at age 11, but were sensitive to the cutoffs used to define elevated BP. CONCLUSIONS: Prenatal exposure to high levels of molybdenum and lead, particularly in combination, may contribute to higher BP at age 4. These early effects appear to persist throughout childhood, contributing to elevated BP in adolescence. Future studies are needed to identify the major sources of molybdenum and lead in this population.

Associations of Prenatal Exposure to Cadmium With Child Growth, Obesity, and Cardiometabolic Traits.

Prenatal cadmium exposure has been associated with impaired fetal growth; much less is known about the impact during later childhood on growth and cardiometabolic traits. To elucidate the associations of prenatal cadmium exposure with child growth, adiposity, and cardiometabolic traits in 515 mother-child pairs in the Rhea Mother-Child Study cohort (Heraklion, Greece, 2007-2012), we measured urinary cadmium concentrations during early pregnancy and assessed their associations with repeated weight and height measurements (taken from birth through childhood), waist circumference, skinfold thickness, blood pressure, and serum lipid, leptin, and C-reactive protein levels at age 4 years. Adjusted linear, Poisson, and mixed-effects regression models were used, with interaction terms for child sex and maternal smoking added. Elevated prenatal cadmium levels (third tertile of urinary cadmium concentration (0.571-2.658 µg/L) vs. first (0.058-0.314 µg/L) and second (0.315-0.570 µg/L) tertiles combined) were significantly associated with a slower weight trajectory (per standard deviation score) in all children (ß = -0.17, 95% confidence interval (CI): -0.32, -0.02) and a slower height trajectory in girls (ß = -0.30, 95% CI: -0.52,-0.09; P for interaction = 0.025) and in children born to mothers who smoked during pregnancy (ß = -0.48, 95% CI: -0.83, -1.13; P for interaction = 0.027). We concluded that prenatal cadmium exposure was associated with delayed growth in early childhood. Further research is needed to understand cadmium-related sex differences and the role of coexposure to maternal smoking during early pregnancy.

Prenatal arsenic exposure is associated with increased plasma IGFBP3 concentrations in 9-year-old children partly via changes in DNA methylation.

Exposure to inorganic arsenic (As), a carcinogen and epigenetic toxicant, has been associated with lower circulating levels of insulin-like growth factor 1 (IGF1) and impaired growth in children of pre-school age. The aim of this study was to assess the potential impact of exposure to As on IGF1 and insulin-like growth factor-binding protein 3 (IGFBP3) as well as DNA methylation changes in 9-year-old children. To this end, we studied 9-year-old children from a longitudinal mother-child cohort in rural Bangladesh (n = 551). Prenatal and concurrent exposure to As was assessed via concentrations in maternal urine at gestational week 8 and in child urine at 9 years, measured by HPLC-HG-ICPMS. Plasma IGF1 and IGFBP3 concentrations were quantified with immunoassays. DNA methylation was measured in blood mononuclear cells at 9 years in a sub-sample (n = 113) using the Infinium HumanMethylation450K BeadChip. In multivariable-adjusted linear regression models, prenatal As (natural log-transformed), but not children's concurrent urinary As, was positively associated with IGFBP3 concentrations (ß = 76, 95% CI 19, 133). As concentrations were not associated with IGF1. DNA methylation analysis revealed CpGs associated with both prenatal As and IGFBP3. Mediation analysis suggested that methylation of 12 CpG sites for all children was mediator of effect for the association between prenatal As and IGFBP3. We also found differentially methylated regions, generally hypermethylated, that were associated with both prenatal As and IGFBP3. In all, our study revealed that prenatal exposure to As was positively associated with IGFBP3 concentrations in children at 9 years, independent of IGF1, and this association may, at least in part, be epigenetically mediated.

Dietary exposure to polychlorinated biphenyls and risk of breast, endometrial and ovarian cancer in a prospective cohort.

BACKGROUND: Observational studies on polychlorinated biphenyl (PCB) exposure and hormone-related cancer risk are either inconsistent or lacking. We aimed to assess associations of dietary PCB exposure with breast, endometrial and ovarian cancer risk in middle-aged and elderly women. METHODS: We included 36 777 cancer-free women at baseline in 1997 from the prospective population-based Swedish Mammography Cohort. Validated estimates of dietary PCB exposure were obtained via a food frequency questionnaire. Incident cancer cases were ascertained through register linkage. RESULTS: During 14 years of follow-up, we ascertained 1593, 437 and 195 incident cases of breast, endometrial and ovarian cancer. We found no overall association between dietary PCB exposure and any of these cancer forms. The multivariable-adjusted relative risks comparing women in the highest and lowest tertile of PCB exposure were 0.96 (95% confidence interval (CI): 0.75, 1.24), 1.21 (95% CI: 0.73, 2.01) and 0.90 (95% CI: 0.45, 1.79) for breast, endometrial and ovarian cancer. In analyses stratified by factors influencing oestrogen exposure, possibly masking associations with PCBs, indications of higher risks were observed for endometrial cancer. CONCLUSIONS: This study suggests that dietary exposure to PCBs play no critical role in the development of breast, endometrial or ovarian cancer during middle-age and old ages.

Arsenic alters global histone modifications in lymphocytes in vitro and in vivo.

Arsenic, an established carcinogen and toxicant, occurs in drinking water and food and affects millions of people worldwide. Arsenic appears to interfere with gene expression through epigenetic processes, such as DNA methylation and post-translational histone modifications. We investigated the effects of arsenic on histone residues in vivo as well as in vitro. Analysis of H3K9Ac and H3K9me3 in CD4+ and CD8+ sorted blood cells from individuals exposed to arsenic through drinking water in the Argentinean Andes showed a significant decrease in global H3K9me3 in CD4+ cells, but not CD8+ cells, with increasing arsenic exposure. In vitro studies of inorganic arsenic-treated T lymphocytes (Jurkat and CCRF-CEM, 0.1, 1, and 100 µg/L) showed arsenic-related modifications of H3K9Ac and changes in the levels of the histone deacetylating enzyme HDAC2 at very low arsenic concentrations. Further, in vitro exposure of kidney HEK293 cells to arsenic (1 and 5 µM) altered the protein levels of PCNA and DNMT1, parts of a gene expression repressor complex, as well as MAML1. MAML1 co-localized and interacted with components of this complex in HEK293 cells, and in silico studies indicated that MAML1 expression correlate with HDAC2 and DNMT1 expression in kidney cells. In conclusion, our data suggest that arsenic exposure may lead to changes in the global levels of H3K9me3 and H3K9Ac in lymphocytes. Also, we show that arsenic exposure affects the expression of PCNA and DNMT1-proteins that are part of a gene expression silencing complex.

Impact of prenatal exposure to cadmium on cognitive development at preschool age and the importance of selenium and iodine.

The evidence regarding a potential link of low-to-moderate iodine deficiency, selenium status, and cadmium exposure during pregnancy with neurodevelopment is either contradicting or limited. We aimed to assess the prenatal impact of cadmium, selenium, and iodine on children's neurodevelopment at 4 years of age. The study included 575 mother-child pairs from the prospective "Rhea" cohort on Crete, Greece. Exposure to cadmium, selenium and iodine was assessed by concentrations in the mother's urine during pregnancy (median 13 weeks), measured by ICPMS. The McCarthy Scales of Children's Abilities was used to assess children's general cognitive score and seven different sub-scales. In multivariable-adjusted regression analysis, elevated urinary cadmium concentrations (≥0.8 µg/L) were inversely associated with children's general cognitive score [mean change: -6.1 points (95 % CI -12; -0.33) per doubling of urinary cadmium; corresponding to ~0.4 SD]. Stratifying by smoking status (p for interaction 0.014), the association was restricted to smokers. Urinary selenium was positively associated with children's general cognitive score [mean change: 2.2 points (95 % CI -0.38; 4.8) per doubling of urinary selenium; ~0.1 SD], although the association was not statistically significant. Urinary iodine (median 172 µg/L) was not associated with children's general cognitive score. In conclusion, elevated cadmium exposure in pregnancy of smoking women was inversely associated with the children's cognitive function at pre-school age. The results indicate that cadmium may adversely affect neurodevelopment at doses commonly found in smokers, or that there is an interaction with other toxicants in tobacco smoke. Additionally, possible residual confounding cannot be ruled out.

Prenatal lead exposure and childhood blood pressure and kidney function.

BACKGROUND: Exposure to lead, a common environmental pollutant, is known to cause cardiovascular and nephrotoxic effects in adults. Potential effects of early-life lead exposure on these functions are, however, less well characterized. OBJECTIVES: To assess blood pressure and kidney function in preschool-aged children in relation to prenatal lead exposure. METHODS: This prospective study in rural Bangladesh measured children's systolic and diastolic blood pressure in triplicate at the follow-up at 4.5±0.11 years. Their kidney function was assessed by the estimated glomerular filtration rate (eGFR), calculated based on serum cystatin C concentrations, and by kidney volume, measured by sonography. Exposure to lead was assessed by concentrations in the mothers' blood (erythrocyte fraction; Ery-Pb) in gestational weeks (GW) 14 and 30, the effects of which were evaluated separately in multivariable-adjusted linear regression analyses. RESULTS: We found no associations between maternal exposure to lead [n~1500 for GW14 and 700 for GW30] and children's blood pressure or eGFR. However, we found an inverse association between late gestation lead and kidney volume, although the sample size was limited (n=117), but not with early gestation lead (n=573). An increase of 85µg/kg in Ery-Pb (median concentration at GW30) was associated with a 6.0cm3/m2 decrease in kidney volume (=0.4SD; p=0.041). After stratifying on gender, there seemed to be a somewhat stronger association in girls. CONCLUSIONS: Prenatal lead exposure may cause long-lasting effects on the kidney. This warrants follow-up studies in older children, as well as additional studies in other populations.

Anthroposophic lifestyle influences the concentration of metals in placenta and cord blood.

Allergic diseases develop in genetically susceptible individuals in a complex interplay with the environment, usually early in life. We have previously shown that the anthroposophic lifestyle is associated with reduced risk of allergic disease in children, but details on the influencing environmental factors are largely unknown. This study aims to elucidate if anthroposophic lifestyle influences fetal exposure to selected toxic and essential elements. Randomly selected non-smoking mothers with (n=40) and without (n=40) anthroposophic lifestyle from the prospective birth cohort ALADDIN were included. Concentrations of 12 toxic and essential elements were analyzed in full term placentas and in the erythrocyte fractions of maternal peripheral blood and of umbilical cord blood, using inductively coupled plasma mass spectrometry. Cadmium concentrations in maternal blood and placenta were significantly higher in mothers with an anthroposophic lifestyle (p<0.001), while concentrations in cord blood were generally low, irrespective of lifestyle. Cobalt concentrations were higher in both maternal blood, placenta and cord blood in the anthroposophic group. Lead concentrations were higher in maternal blood and cord blood, but not placenta, of mothers with anthroposophic lifestyle. Analysis of covariance, including lifestyle, parity, maternal age, gestational age, vegetarian diet, use of herbal medicine and occupation in the model, showed that mainly the anthroposophic lifestyle was significantly associated with cadmium concentrations. In conclusion, women with an anthroposophic lifestyle had higher concentrations of cadmium, cobalt and lead concentrations. Cadmium concentrations might have been influenced by a diet rich in vegetables and/or low iron status of the mothers.

Kidney function and blood pressure in preschool-aged children exposed to cadmium and arsenic--potential alleviation by selenium.

BACKGROUND: Early-life exposure to toxic compounds may cause long-lasting health effects, but few studies have investigated effects of childhood exposure to nephrotoxic metals on kidney and cardiovascular function. OBJECTIVES: To assess effects of exposure to arsenic and cadmium on kidney function and blood pressure in pre-school-aged children, and potential protection by selenium. METHODS: This cross-sectional study was part of the 4.5 years of age (range: 4.4-5.4 years) follow-up of the children from a supplementation trial in pregnancy (MINIMat) in rural Bangladesh, and nested studies on early-life metal exposures. Exposure to arsenic, cadmium and selenium from food and drinking water was assessed by concentrations in children's urine, measured by ICP-MS. Kidney function was assessed by the estimated glomerular filtration rate (eGFR, n=1106), calculated from serum cystatin C, and by kidney volume, measured by ultrasound (n=375). Systolic and diastolic blood pressure was measured (n=1356) after five minutes rest. RESULTS: Multivariable-adjusted regression analyzes showed that exposure to cadmium, but not arsenic, was inversely associated with eGFR, particularly in girls. A 0.5 µg/L increase in urinary cadmium among the girls (above spline knot at 0.12) was associated with a decrease in eGFR of 2.6 ml/min/1.73 m(2), corresponding to 0.2SD (p=0.022). A slightly weaker inverse association with cadmium was also indicated for kidney volume, but no significant associations were found with blood pressure. Stratifying on children's urinary selenium (below or above median of 12.6 µg/L) showed a three times stronger inverse association of U-Cd with eGFR (all children) in the lower selenium stratum (B=-2.8; 95% CI: -5.5, -0.20; p=0.035), compared to those with higher selenium (B=-0.79; 95% CI: -3.0, 1.4; p=0.49). CONCLUSIONS: Childhood cadmium exposure seems to adversely affect kidney function, but not blood pressure, in this population of young children in rural Bangladesh. Better selenium status appears to be protective. However, it is important to follow up these children to assess potential long-term consequences of these findings.

Maternal urinary iodine concentration up to 1.0 mg/L is positively associated with birth weight, length, and head circumference of male offspring.

Adequate iodine status in early life is crucial for neurodevelopment. However, little is known about the effects of maternal iodine status during pregnancy on fetal growth. The present study investigated the potential impact of maternal iodine status during pregnancy on offspring birth size. This large prospective cohort study was nested in a Bangladeshi population-based randomized supplementation trial in pregnant women [MINIMat (Maternal and Infant Nutrition Interventions in Matlab)]. Urine samples obtained at 8 wk of gestation from 1617 women were analyzed for iodine and other elements, such as arsenic and cadmium, using inductively coupled plasma mass spectrometry. Anthropometric measurements at birth included weight, length, and head and chest circumference. Maternal urinary iodine concentrations (UICs) ranged from 0.020 to 10 mg/L, with a median of 0.30 mg/L. Below ∼1.0 mg/L, UIC was significantly positively associated with birth weight and length. Birth weight and length increased by 9.3 g (95% CI: 2.9, 16) and 0.042 cm (95% CI: 0.0066, 0.076), respectively, for each 0.1-mg/L increase in maternal UIC. No associations were observed between UIC and head or chest circumference. When we stratified the analyses by newborn sex, the positive associations between maternal UIC (<1 mg/L) and measurements of size at birth were restricted to boys, with no evidence in girls. Among boys, the mean weight, length, and head circumference increased by 70 g (P = 0.019), 0.41 cm (P = 0.013), and 0.28 cm (P = 0.031) for every 0.5-mg/L increase in maternal UIC. Maternal iodine status was positively associated with weight, length, and head circumference in boys up to ∼1 mg/L, which is well above the recommended maximum concentration of 0.5 mg/L. The associations leveled off at UIC ≥ 1 mg/L. Our findings support previous conclusions that the advantages of correcting potential iodine deficiency outweigh the risks of excess exposure.

Manganese - a scoping review for Nordic Nutrition Recommendations 2023.

Manganese is an essential trace element that is required for multiple enzymes in the human body. The general population is mainly exposed to manganese via food intake, in particular plant foods. In areas with elevated concentrations of manganese in groundwater, drinking water can also be an important source of exposure. The gastrointestinal absorption of manganese is below 10%, and it appears to be influenced by the amount of manganese in the diet and by the nutritional status of the individual, especially the iron status. In blood, most of the manganese is found in the cellular fractions. Manganese is primarily eliminated via the bile followed by excretion via faeces. To date, no specific biomarkers of manganese intake have been identified. The dietary intake of manganese in the Nordic countries has been reported to be within the range that has been reported for other European countries (2-6 mg/day). Since manganese is found in nutritionally adequate amounts in food, deficiency is not of public health concern. On the other hand, there is emerging epidemiological evidence that various suggested manganese biomarkers may be negatively associated with children's neurodevelopment. However, the limited number of prospective studies, the lack of appropriate exposure biomarkers, and validated neurodevelopmental outcomes render data uncertain and inconclusive. In 2013, the European Food Safety Authority considered the evidence to be insufficient to derive an average requirement or a population reference intake, and instead an adequate intake for adults was set at 3.0 mg/day.