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Background: Gestational lead (Pb) exposure can adversely affect offspring health through multiple mechanisms, including epigenomic alterations via DNA methylation (5mC) and hydroxymethylation (5hmC), an intermediate in oxidative demethylation. Most current methods do not distinguish between 5mC and 5hmC, limiting insights into their individual roles. Objective: Our study sought to identify the association of trimester-specific (T1, T2, T3) prenatal Pb exposure with 5mC and 5hmC levels at multiple cytosine-phosphate-guanine sites within gene regions previously associated with prenatal Pb (HCN2, NINJ2, RAB5A, TPPP) in whole blood leukocytes of children ages 11-18 years of age. Methods: Participants from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) birth cohorts were selected (n = 144) for pyrosequencing analysis following oxidative or standard sodium bisulfite treatment. This workflow directly quantifies total methylation (5mC+5hmC) and 5mC only; 5hmC is estimated by subtraction. Results: Participants were 51% male, and mean maternal blood lead levels (BLL) were 6.43 [+ or -]5.16 [micro]g/dL in Trimester 1 (T1), 5.66[+ or -]5.21 [micro]g/dL in Trimester 2 (T2), and 5.86[+ or -]4.34 lg/dL in Trimester 3 (T3). In addition, 5hmC levels were calculated for HCN2 (mean[+ or -]standard deviation(SD), 2.08 [+ or -]4.18%), NINJ2 (G/C: 2.01 [+ or -]5.95; GG: 0.90[+ or -]3.97), RAB5A (0.66[+ or -]0.80%), and TPPP (1.11 [+ or -]6.67%). Furthermore, 5mC levels were measured in HCN2 (81.3[+ or -]9.63%), NINJ2 (heterozygotes: 38.6[+ or -]7.39%; GG homozygotes: 67.3[+ or -]9.83%), RAB5A (1.41 [+ or -]1.21%), and TPPP (92.5 [+ or -] 8.03%). Several significant associations between BLLs and 5mC/5hmC were identified: T1 BLLs with 5mC in HCN2 (b = -0.37, p = 0.03) and 5hmC in NINJ2 (b = 0.49, p = 0.003); T2 BLLs with 5mC in HCN2 (b = 0.37, p = 0.03) and 5hmC in NINJ2 (b = 0.27, p = 0.008); and T3 BLLs with 5mC in HCN2 (b = 0.50, p = 0.01) and NINJ2 (b = -0.35, p = 0.004) and 5hmC in NINJ2 (b = 0.45, p < 0.001). NINJ2 5mC was negatively correlated with gene expression (Pearson r = -0.5, p-value = 0.005), whereas 5hmC was positively correlated (r = 0.4, p-value = 0.04). Discussion: These findings suggest there is variable 5hmC in human whole blood and that prenatal Pb exposure is associated with gene-specific 5mC and 5hmC levels at adolescence, providing evidence to consider 5hmC as a regulatory mechanism that is responsive to environmental exposures. https://doi.org/10.1289/EHP8507, Introduction The Developmental Origins of Health and Disease (DOHaD) hypothesis (Barker 2007) postulates that in utero exposures, including exposure to environmental contaminants such as lead (Pb), can permanently modify an [...]

BACKGROUND: The impact of prenatal lead exposure on neurodevelopment remains unclear in terms of consistency, the trimester of greatest vulnerability, and the best method for estimating fetal lead exposure. OBJECTIVE: [...]

BACKGROUND: Phthalate exposure is ubiquitous and may affect biological pathways related to regulators of blood pressure. Given the profound changes in vasculature during pregnancy, pregnant women may be particularly susceptible to the potential effects of phthalates on blood pressure. OBJECTIVES: We examined associations of phthalate exposure during pregnancy with maternal blood pressure trajectories from mid-pregnancy through 72 months postpartum. METHODS: Women with singleton pregnancies delivering a live birth in Mexico City were enrolled during the second trimester (푛 = 892). Spot urine samples from the second and third trimesters were analyzed for 15 phthalate metabolites. Blood pressure and covariate data were collected over nine visits through 72 months postpartum. We used linear, logistic, and linear mixed models; latent class growth models (LCGMs); and Bayesian kernel machine regression to estimate the relationship of urinary phthalate biomarkers with maternal blood pressure. RESULTS: As a joint mixture, phthalate biomarker concentrations during pregnancy were associated with higher blood pressure rise during mid-to-late gestation. With respect to individual biomarkers, second trimester concentrations of monobenzyl phthalate (MBzP) and di(2-ethylhexyl) phthalate biomarkers (ΣDEHP) were associated with higher third trimester blood pressure. Two trajectory classes were identified by LCGM, characterized by increasing blood pressure through 72 months postpartum ("increase-increase") or decreased blood pressure through 18 months postpartum with a gradual increase thereafter ("decrease-increase"). Increasing exposure to phthalate mixtures during pregnancy was associated with higher odds of being in the increase-increase class. Similar associations were observed for mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and dibutyl phthalate (ΣDBP) biomarkers. When specific time periods were examined, we observed specific temporal relationships were observed for RDEHP, MECPTP, MBzP, and ΣDBP. DISCUSSION: In our cohort of pregnant women from Mexico City, exposure to phthalates and phthalate biomarkers was associated with higher blood pressure during late pregnancy, as well as with long-term changes in blood pressure trajectories. [ABSTRACT FROM AUTHOR]

Abstract Background Blood lead has been associated with an elevated risk of miscarriage. The plasmatic fraction of lead represents the toxicologically active fraction of lead. Women with a tendency to have a higher plasma/whole blood Pb ratio could tend towards an elevated risk of miscarriage due to a higher plasma Pb for a given whole blood Pb and would consequently have a history of spontaneous abortion. Methods We studied 207 pregnant Mexico City residents during the 1st trimester of pregnancy, originally recruited for two cohorts between 1997 and 2004. Criteria for inclusion in this study were having had at least one previous pregnancy, and having valid plasma and blood Pb measurements. Pb was measured in whole blood and plasma by inductively coupled plasma mass spectrometry using ultra-clean techniques. History of miscarriage in previous pregnancies was obtained by interview. The incidence rate of spontaneous abortion was defined as the proportion of previous pregnancies that resulted in miscarriage. Data were analyzed by means of Poisson regression models featuring the incidence rate of spontaneous abortion as the outcome and continuous or categorized plasma/blood Pb ratios as predictor variables. All models were adjusted for age and schooling. Additionally, logistic regression models featuring inclusion in the study sample as the outcome were fitted to assess potential selection bias. Results The mean number of miscarriages was 0.42 (range 0 to 4); mean Pb concentrations were 62.4 and 0.14 μg/L in whole blood and plasma respectively. Mean plasma/blood Pb ratio was 0.22%. We estimated that a 0.1% increment in the plasma/blood Pb ratio lead was associated to a 12% greater incidence of spontaneous abortion (p = 0.02). Women in the upper tertile of the plasma/blood Pb ratio had twice the incidence rate of those in the lower tertile (p = 0.02). Conditional on recruitment cohort, inclusion in the study sample was unrelated to observable characteristics such as number of abortions, number of pregnancies, blood Pb levels, age schooling, weight and height. Conclusion Women with a large plasma/whole blood Pb ratio may be at higher risk of miscarriage, which could be due to a greater availability of placental barrier-crossing Pb.

BACKGROUND: Some evidence suggests that fluoride may be neurotoxic to children. Few of the epidemiologic studies have been longitudinal, had individual measures of fluoride exposure, addressed the impact of prenatal exposures or involved more than 100 participants. OBJECTIVE: Our aim was to estimate the association of prenatal exposure to fluoride with offspring neurocognitive development. METHODS: We studied participants from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) project. An ion-selective electrode technique was used to measure fluoride in archived urine samples taken from mothers during pregnancy and from their children when 6-12 y old, adjusted for urinary creatinine and specific gravity, respectively. Child intelligence was measured by the General Cognitive Index (GCI) of the McCarthy Scales of Children's Abilities at age 4 and full scale intelligence quotient (IQ) from the Wechsler Abbreviated Scale of Intelligence (WASI) at age 6-12. RESULTS: We had complete data on 299 mother-child pairs, of whom 287 and 211 had data for the GCI and IQ analyses, respectively. Mean (SD) values for urinary fluoride in all of the mothers (n = 299) and children with available urine samples (n = 211) were 0.90 (0.35) mg/L and 0.82 (0.38) mg/L, respectively. In multivariate models we found that an increase in maternal urine fluoride of 0.5 mg/L (approximately the IQR) predicted 3.15 (95% CI: -5.42, -0.87) and 2.50 (95% CI -4.12, -0.59) lower offspring GCI and IQ scores, respectively. CONCLUSIONS: In this study, higher prenatal fluoride exposure, in the general range of exposures reported for other general population samples of pregnant women and nonpregnant adults, was associated with lower scores on tests of cognitive function in the offspring at age 4 and 6-12 y. https:// doi.org/10.1289/EHP655, Introduction Community water, salt, milk, and dental products have been fluoridated in varying degrees for more than 60 y to prevent dental caries, while fluoride supplementation has been recommended to [...]

We thank Ronchetti for his comments on our recent article (Hu et al. 2006). We are aware of what he noted was the wide scatter of points surrounding the correlation [...]