Subject demographics, distribution of model covariates, and outcome variables (N = 328).

<p>Values are mean ± SD or n (percent). Unless indicated, N = 328.</p>a<p>Includes living with same partner for >7 years.</p><p>Subject demographics, distribution of model covariates, and outcome variables (N = 328).</p

Adjusted mean WISC-IV total score and subtest scored by lowest to highest quartile of maternal prenatal phthalate metabolite concentration (where q0 = lowest quartile, q4 = highest quartile, q2 and q3 intermediate quartiles).

<p>Means adjusted for urine specific gravity, maternal IQ, ethnicity, alcohol use during pregnancy, education, marital status, quality of the home environment (HOME score) and sex of child. *<i>p</i><0.05, **<i>p</i>≤0.01.</p

Distribution of Phthalate metabolites (ng/ml) in maternal spot urine during the third trimester of pregnancy (n = 328).

<p>ND = not detected.</p><p>Distribution of Phthalate metabolites (ng/ml) in maternal spot urine during the third trimester of pregnancy (n = 328).</p

Estimated adjusted regression coefficients relating maternal prenatal urinary phthalate concentrations to the WISC-IV full scale IQ and subscales at child age 7 years.

<p>*<i>p</i><0.05, **<i>p</i>≤0.01. ^@Wald Test.</p><p>Adjusted model for specific gravity, maternal IQ, ethnicity, alcohol use during pregnancy, education, marital status, total home score, and sex of child.</p><p>Estimated adjusted regression coefficients relating maternal prenatal urinary phthalate concentrations to the WISC-IV full scale IQ and subscales at child age 7 years.</p

Newborn global DNA methylation and maternal urinary As exposure.

<p>Mean (SE) newborn global methylation levels as measured by the methyl-incorporation assay by quartiles of maternal uAs exposure adjusted for the sex-specific effect of uCrn. * Q1 and Q2 vs. Q4; p = 0.06 and 0.04, respectively.</p

Spearman correlation coefficients for newborn global DNA methylation vs. urinary creatinine and indicators of one-carbon metabolism in plasma, combined and stratified by newborn sex.

*<p>p<0.05;</p>**<p>p<0.01.</p>a<p>p<0.05;</p>b<p>p<0.01 from Wald test for sex differences in correlations.</p

Spearman correlation coefficients for global DNA methylation between maternal vs. newborn pairs, combined and stratified by newborn sex.

*<p>p<0.05;</p>**<p>p<0.01.</p

Estimated parameter for associations between biomarkers of As exposure and newborn global DNA methylation assays combined and stratified by sex.

1<p>Sex- specific effect of uCrn was controlled in the models for DPM/DNA, Alu and Line-1.</p>2<p>Interaction by newborn sex.</p

Demographics and clinical data of the study population.

a<p>Values are mean (SD).</p>b<p>N = 100,</p>c<p>N = 99,</p>d<p>N = 95,</p>e<p>N = 57,</p>f<p>N = 56,</p>g<p>N = 54,</p>h<p>N = 42,</p>i<p>N = 41,</p>j<p>N = 40,</p>k<p>N = 37.</p>*<p>P<0.05; Wilcoxon rank sum test for differences between newborn sex.</p>**<p>P<0.01; Wilcoxon rank sum test for differences between newborn sex.</p

Arsenic metabolism and creatine synthesis.

<p>(A) Guanadinoacetate methyltransferase (GAMT) and phosphatidyl ethanolamine methyltransferase (PEMT), which catalyze the synthesis of creatine (Cr) and phosphatidylcholine, are the major consumers of S-adenosylmethionine (SAM). Arsenic methyltransferase (AS3MT) uses quantitatively much less SAM. (B) In the first, and rate-limiting, step of Cr biosynthesis, guanadinoacetate (GAA) is formed in the kidney by arginine:glycine amidinotransferase (AGAT). Dietary creatine (e.g. primarily from meat) leads to pre-translational inhibition of AGAT, thereby inhibiting endogenous creatine biosynthesis. GAA is transported to the liver, where it is methylated by GAMT to generate Cr, with SAM as the methyl donor. SAM also serves as the methyl donor for the methylation of trivalent inorganic arsenic (InAs^III) to monomethylarsonic acid (MMA^V), and for the methylation of monomethylaronous acid (MMA^III) to dimethylarsinic acid (DMA^V). The by-product of these methylation reactions is S-adenosylhomocysteine (SAH). Creatine, whether derived from endogenous biosynthesis or dietary sources, is transported to tissues with high energy requirements such as skeletal muscle, heart, and brain, where it is phosphorylated to phosphoryl-creatine (PCr). PCr is used for the regeneration of ATP during intensive exercise. Creatine and PCr are converted non-enzymatically at a constant rate to creatinine (Crn), which is then excreted in the urine. Image credit: Brandilyn A. Peters.</p