Prenatal exposure to metal mixtures and childhood temporal processing in the PROGRESS Birth Cohort Study: Modification by childhood obesity.

Children are frequently exposed to various biological trace metals, some essential for their development, while others can be potent neurotoxicants. Furthermore, the inflammatory and metabolic conditions associated with obesity may interact with and amplify the impact of metal exposure on neurodevelopment. However, few studies have assessed the potential modification effect of body mass index (BMI). As a result, we investigated the role of child BMI phenotype on the relationship between prenatal exposure to metal mixtures and temporal processing. Leveraging the PROGRESS birth cohort in Mexico City, children (N = 563) aged 6-9 years completed a Temporal Response Differentiation (TRD) task where they had to hold a lever down for 10-14 s. Blood and urinary metal (As, Pb, Cd, and Mn) measurements were collected from mothers in the 2nd and 3rd trimesters. Child BMI z-scores were dichotomized to normal (between -2 and +0.99) and high (≥1.00). Covariate-adjusted weighted quantile sum (WQS) regression models were used to estimate and examine the combined effect of metal biomarkers (i.e., blood and urine) on TRD measures. Effect modification by the child's BMI was evaluated using 2-way interaction terms. Children with a high BMI and greater exposure to the metal mixture during prenatal development exhibited significant temporal processing deficits compared to children with a normal BMI. Notably, children with increased exposure to the metal mixture and higher BMI had a decrease in the percent of tasks completed (ß = -10.13; 95 % CI: -19.84, -0.42), number of average holds (ß = -2.15; 95 % CI: -3.88, -0.41), longer latency (ß = 0.78; 95 % CI: 0.13, 1.44), and greater variability in the standard deviation of the total hold time (ß = 2.08; 95 % CI: 0.34, 3.82) compared to normal BMI children. These findings implicate that high BMI may amplify the effect of metals on children's temporal processing. Understanding the relationship between metal exposures, temporal processing, and childhood obesity can provide valuable insights for developing targeted environmental interventions.

Associations between oxidative stress biomarkers during pregnancy and infant cognition at 7.5 months.

Oxidative stress has been identified as an important biological pathway leading to neurodevelopmental delay. However, studies assessing the effects of oxidative stress on cognitive outcomes during infancy, a critical period of neurodevelopment, are limited. Our analysis included a subset of those enrolled in the Illinois Kids Development Study (N = 144). Four oxidative stress biomarkers (8-isoprostane-PGF2α , 2,3-dinor-5,6-dihydro-8-iso-PGF2α , 2,3-dinor-8-iso-PGF2α , and prostaglandin-F2α ) were measured in second and third trimesters urine and were averaged. Infant cognition was measured using a visual recognition memory task consisting of five blocks, each with one familiarization trial (two identical stimuli) and two test trials (one familiar and one novel stimulus). Outcomes measured included average run duration (a measure of information processing speed), novelty preference (a measure of recognition memory), time to reach familiarization, and shift rate (measures of attention). Linear regression was used to estimate associations between individual oxidative stress biomarkers and each outcome. Increasing 8-isoprostane-PGF2α , 2,3-dinor-8-iso-PGF2α , and prostaglandin-F2α were associated with a decrease in novelty preference (ß = -0.02, 95% confidence interval [CI] = -0.03, 0.00; ß = -0.02, 95% CI = -0.04, 0.00; ß = -0.01, 95% CI = -0.02, 0.00, respectively), as well as a modest increase in shift rate. These findings suggest that oxidative stress may be associated with poorer recognition memory in early infancy.

Associations between a metal mixture and infant negative affectivity: Effect modification by prenatal cortisol and infant sex.

In-utero exposures interact in complex ways that influence neurodevelopment. Animal research demonstrates that fetal sex moderates the impact of joint exposure to metals and prenatal stress measures, including cortisol, on offspring socioemotional outcomes. Further research is needed in humans. We evaluated the joint association of prenatal exposures to a metal mixture and cortisol with infant negative affectivity, considering sex differences. Analyses included 226 (29% White, Non-Hispanic) mother-infant pairs with data on exposures and negative affectivity assessed using the Infant Behavior Questionnaire-Revised in 6-month-olds. Results showed that girls whose mothers had higher cortisol had significantly higher scores of Fear and Sadness with greater exposure to the mixture. Examining higher-order interactions may better elucidate the effects of prenatal exposure to metals and cortisol on socioemotional functioning.

Associations between area-level arsenic exposure and adverse birth outcomes: An Echo-wide cohort analysis.

BACKGROUND: Drinking water is a common source of exposure to inorganic arsenic. In the US, the Safe Drinking Water Act (SDWA) was enacted to protect consumers from exposure to contaminants, including arsenic, in public water systems (PWS). The reproductive effects of preconception and prenatal arsenic exposure in regions with low to moderate arsenic concentrations are not well understood. OBJECTIVES: This study examined associations between preconception and prenatal exposure to arsenic violations in water, measured via residence in a county with an arsenic violation in a regulated PWS during pregnancy, and five birth outcomes: birth weight, gestational age at birth, preterm birth, small for gestational age (SGA), and large for gestational age (LGA). METHODS: Data for arsenic violations in PWS, defined as concentrations exceeding 10 parts per billion, were obtained from the Safe Drinking Water Information System. Participants of the Environmental influences on Child Health Outcomes Cohort Study were matched to arsenic violations by time and location based on residential history data. Multivariable, mixed effects regression models were used to assess the relationship between preconception and prenatal exposure to arsenic violations in drinking water and birth outcomes. RESULTS: Compared to unexposed infants, continuous exposure to arsenic from three months prior to conception through birth was associated with 88.8 g higher mean birth weight (95% CI: 8.2, 169.5), after adjusting for individual-level confounders. No statistically significant associations were observed between any preconception or prenatal violations exposure and gestational age at birth, preterm birth, SGA, or LGA. CONCLUSIONS: Our study did not identify associations between preconception and prenatal arsenic exposure, defined by drinking water exceedances, and adverse birth outcomes. Exposure to arsenic violations in drinking water was associated with higher birth weight. Future studies would benefit from more precise geodata of water system service areas, direct household drinking water measurements, and exposure biomarkers.

The PFAS-Tox Database: A systematic evidence map of health studies on 29 per- and polyfluoroalkyl substances.

BACKGROUND: PFAS (per-and polyfluoroalkyl substances) are a large class of synthetic chemicals widely used in consumer products and industrial processes. The scientific literature on PFAS has increased dramatically in the last decade. Many stakeholders, including regulators, scientists, non-governmental organizations, and concerned individuals could benefit from an efficient way to access the health and toxicological literature related to PFAS. OBJECTIVE: To create a systematic evidence map of the available peer-reviewed health or toxicological research for 29 PFAS. METHODS: A protocol for conducting this systematic evidence map was initially published on Zenodo (Pelch et al. 2019c), then peer reviewed and published in Environment International (Pelch et al. 2019d). PubMed database was searched through January 25, 2021. Studies were screened for inclusion and exclusion according to the Populations, Exposures, Comparators, and Outcomes (PECO) statement. Inclusion criteria were intentionally broad and included any human, animal, and/or in vitro study that investigated exposure to one of the 29 PFAS of interest and a human health or toxicological effect. Selected study details were extracted from included studies as described in the protocol. Study appraisal was not conducted. The included studies and extracted meta-data are freely available in the online, interactive systematic evidence map at https://pfastoxdatabase.org. RESULTS: Over 15,000 studies were retrieved from the PubMed literature searches. After manual screening, 1,067 studies were identified and included as investigating the health or toxicological effect of one or more PFAS of interest. There were 505 human, 385 animal, and 220 in vitro studies. Summary tables of the extracted data and overall observations are included in this report. CONCLUSIONS: The PFAS-Tox Database is a useful tool for searching, filtering, and identifying peer reviewed research on the health and toxicological effects of the included PFAS. In this summary of the evidence map we provide examples of data gaps and clusters revealed by the database, with the goal of helping direct future research efforts, facilitate systematic reviews (e.g. on immune effects, mixtures of PFAS, or effects of short chain PFAS), inform regulatory risk assessments, and improve opportunities for cross-disciplinary coordination. We also discuss how this tool supports scientists, regulatory agencies, and other individuals by increasing awareness and access to current evidence regarding the health effects associated with PFAS exposure.

Associations of prenatal phthalate exposure with neurobehavioral outcomes in 4.5- and 7.5-month-old infants.

Phthalates are ubiquitous endocrine-disrupting chemicals, and research indicates that prenatal exposure to some phthalates may affect neurodevelopment. In a prospective birth cohort study, five first-morning urine samples collected across pregnancy were pooled and the following phthalate biomarkers assessed: sum of di-(2-ethylhexyl) phthalate metabolites (ΣDEHP), sum of diisononyl phthalate metabolites (ΣDINP), sum of dibutyl phthalate metabolites (ΣDBP), sum of anti-androgenic metabolites (ΣAA), monoethyl phthalate (MEP), and sum of all phthalate metabolites (ΣAll). The Ages & Stages Questionnaires® (ASQ), a standardized parent-reported, age-adapted screening tool, measured communication, personal-social, problem solving, and motor domains in infants at 4.5 and 7.5 months (n = 123). Adjusting for maternal age, annual household income, gestational age at birth, infant age at assessment, and sex, repeated-measures generalized linear regression models were used to examine associations between prenatal phthalate urine biomarker concentrations and domain scores (assuming a Poisson distribution). Beta estimates were exponentiated back to the domain scale for ease of interpretation. Mothers were mostly white and college-educated, and most reported an annual household income of ≥$60,000. Associations of phthalate concentrations with ASQ outcomes are presented as follows: (1) anti-androgenic phthalate metabolites (ΣDEHP, ΣDINP, ΣDBP, and ΣAA), (2) MEP, which is not anti-androgenic, and (3) ΣAll. Overall, anti-androgenic phthalates were associated with higher (i.e., better) scores. However, there were exceptions, including the finding that a one-unit increase in ΣDBP was associated with a 12% increase in problem solving scores in 4.5-month-old females (ß = 1.12; 95% CI: 0.99, 1.28; p = 0.067) but a 85% decrease for 7.5-month-old females (ß = 0.54; 95% CI: 0.3, 0.99; p = 0.047). In contrast, MEP was associated with poorer scores on several outcomes. Sex- and timepoint-specific estimates demonstrated a one-unit increase in MEP was associated with: a 52% decrease in personal-social scores in 7.5-month-old males (ß = 0.66; 95% CI: 0.46, 0.95; p = 0.02), a 39% decrease in fine motor scores in 7.5-month-old males (ß = 0.72; 95% CI: 0.52, 0.98; p = 0.035), and a 6% decrease in fine motor scores in 4.5-month-old females (ß = 0.94; 95% CI: 0.88, 0.99; p = 0.03). A one-unit increase in ΣAll was associated with a 4% increase in personal-social scores in 4.5-month-old males (ß = 1.04; 95% CI: 0.99, 1.1; p = 0.08) but a 17% decrease in 7.5-month-old males (ß = 0.85; 95% CI: 0.73, 0.99; p = 0.03). These data suggest age- and sex-specific associations of prenatal phthalates with infant neurobehavior. The current findings should be confirmed by longitudinal studies with larger sample sizes.

Prenatal trace elements mixture is associated with learning deficits on a behavioral acquisition task among young children.

Children are exposed to many trace elements throughout their development. Given their ubiquity and potential to have effects on children's neurodevelopment, these exposures are a public health concern. This study sought to identify trace element mixture-associated deficits in learning behavior using operant testing in a prospective cohort. We included 322 participants aged 6-7 years recruited in Mexico City with complete data on prenatal trace elements measurements (third trimester blood lead and manganese levels, and & urine cadmium and arsenic levels), demographic covariates, and the Incremental Repeated Acquisition (IRA), an associative learning task. Weighted quantile sum (WQS) regression models were used to estimate the joint association of the mixture of all four trace elements and IRA performance. Performance was adversely impacted by the mixture, with different elements relating to different aspects of task performance suggesting that prenatal exposure to trace element mixtures yields a broad dysregulation of learning behavior.

Sexually dimorphic associations between prenatal blood lead exposure and performance on a behavioral testing battery in children.

BACKGROUND: Associations between lead (Pb) and neurodevelopment have been studied widely in the context of global measures of cognitive function, such as IQ. Operant test batteries consist of behavioral tasks that can be used to target discrete cognitive and behavioral mechanisms, which contribute to global cognitive faculties. OBJECTIVES: The goals of this study were to identify Pb-associated deficits in cognitive development and determine the underlying mechanisms involved, utilizing an operant test battery. We evaluated effect modification by child sex. METHODS: This study utilized data from a prospective cohort in Mexico City. We included 549 participants aged 6-to-7 years with complete data on prenatal blood Pb measurements, Operant Test Battery (OTB) tasks, and demographic covariates. General linear models were used to examine the association of Pb levels at each prenatal timepoint and OTB performance. Effect modification by child sex was evaluated using 2-way interaction terms. RESULTS: In three of the operant tasks, we observed that higher late-pregnancy blood Pb concentrations were associated with greater response latencies. In the temporal processing task, we observed that higher late-pregnancy Pb exposure was associated with worse overall task performance. Further, in two operant tasks, the effects of Pb were dependent on the sex of the child, such that the effects of Pb were more pronounced in females in the condition position responding task, but stronger in males in the temporal processing task. CONCLUSIONS: Our results suggest that prenatal Pb concentrations yield broad dysregulation of executive functions, which can be attributed to dysregulation of temporal processing. In addition, we observed sex differences in two operant tasks suggesting that some Pb effects on neurocognitive function may be sexually dimorphic.

Metal mixtures and neurodevelopment: recent findings and emerging principles.

Children are constantly exposed to a wide range of environmental factors including essential and non-essential metals. In recent years, the mixtures paradigm has emerged to foster the examination of combined effects that emerge from exposures to multiple elements. In this review, we summarized recent literature studying the relationship between prenatal and childhood metal mixtures with neurodevelopmental outcomes. Our review highlights two basic principles to emerge from this approach. First, recent findings emphasize that the effect of a given exposure is contextual and may be dependent on past or concurrent metal exposures. Second, the timing of exposures is equally critical to the mixture composition in determining neurodevelopmental effects. Our discussion emphasizes how these principles may apply to future exposure-related neurodevelopmental studies.

Associations of Prenatal Exposure to Phthalates with Measures of Cognition in 4.5-Month-Old Infants.

The association of prenatal phthalate exposure with physical reasoning was assessed in 159 (78 female; 81 male) 4.5-month-old infants from a prospective cohort. Phthalate metabolites were quantified in urine from 16-18 gestational weeks and a pool of five urines from across pregnancy. Infants' looking times to physically impossible and possible events were recorded via infrared eye-tracking. Infants that recognize that one of the events is impossible will look at that event longer. Associations of phthalate biomarkers with looking time differences (impossible-possible) were adjusted for maternal age, infant sex, and order of event presentation, and effect modification by infant sex was assessed. Each interquartile range (IQR) increase of monoethyl phthalate in the pooled sample was associated with females' increased looking time (ß = 1.0; 95%CI = 0.3, 1.7 s) to the impossible event. However, for males, an IQR increase in monoethyl phthalate at 16-18 weeks (ß = -2.5; 95%CI = -4.4,-0.6 s), the sum of di(isononyl) phthalate metabolites in the pooled sample (ß = -1.0; 95%CI = -1.8, -0.1 s), and the sum of all phthalate metabolites in both samples (ß = -2.3; 95%CI = -4.4, -0.2 s) were associated with increased looking to the possible event, suggesting that higher prenatal phthalate exposure is associated with poorer physical reasoning in male infants.

Associations of prenatal maternal stress with measures of cognition in 7.5-month-old infants.

Studies have shown that prenatal stress can negatively impact neurodevelopment, but little is known about its effect on early cognitive development. We assessed the impact of prenatal stress on cognition in 152 7.5-month-old infants using Cohen's Perceived Stress Scale (PSS), maternal telomere length (MTL), and a Stressful Life Events (SLE) Scale. A visual recognition memory task consisting of nine blocks, each with one familiarization trial (two identical stimuli) followed by two test trials (one familiar stimulus, one novel), was administered. Outcomes assessed included: average time looking at stimuli (measure: processing speed), time to reach looking time criterion (measure: attention), and the proportion of time looking at the novel stimulus (measure: recognition memory). We examined the association of each stress measure with each outcome adjusted for infant age and sex, which of the two stimuli in each set was novel, household income, and maternal age, education, and IQ. Higher prenatal stress was associated with shorter looking durations [PSS (ß = -1.6, 95% CI: -2.5, -0.58); SLE (ß = 0.58, 95% CI: -0.08, 1.24); MTL (ß = 1.81, 95% CI: 0.18, 3.44)] and longer time to reach criterion [PSS (ß = 9.1, 95% CI: 1.6, 16.6); SLE (ß = 12.2, 95% CI: 1.9, 24.1); MTL (ß = -23.1, 95% CI: -45.3, -0.9)], suggesting that higher prenatal stress is associated with decreased visual attention in infancy.

Characterization of performance on an automated visual recognition memory task in 7.5-month-old infants.

Infant looking behaviors measured during visual assessment paradigms may be more reliable predictors of long-term cognitive outcomes than standard measures such as the Bayley Scales of Infant Development typically used in environmental epidemiology. Infrared eye tracking technology offers an innovative approach to automate collection and processing of looking behavior data, making it possible to efficiently assess large numbers of infants. The goals of this study were to characterize infant looking behavior measures including side preference, fixation duration, and novelty preference using eye tracking and an automated version of an established visual recognition memory paradigm that includes both human faces and geometric figures as stimuli. An ancillary goal was to assess the feasibility of obtaining a precise measure of looking to the eye region of faces from the eye-tracking data. In this study, 309 7.5-month-old infants from a prospective birth cohort were assessed using a visual recognition memory (VRM) paradigm. Infrared eye tracking was used to record looking time as infants were shown nine blocks of trials with a pair of identical faces or shapes followed by two trials in which the familiar stimulus was paired with a novel one. Infants were assessed in one of four conditions: in conditions A and B, stimulus set 1 were the familiar stimuli and set 2 were novel; in conditions C and D, set 2 were familiar and set 1 novel. The novel stimuli were presented on the right first in conditions A and C and on the left first in conditions B and D. We observed a significant right side preference, which has not been reported before (57% of looking time spent looking at right side stimulus, p-value < 0.0001). Infants showed a preference for the novel stimuli similar to that published in prior studies (57-60% of looking time spent looking at the novel stimulus, p-value < 0.0001), as well as average fixation durations similar to previous studies. Infants also showed a strong preference for the eyes versus the rest of the face (p-value < 0.0001). Novelty preference was significantly higher when set 2 stimuli were novel (p-value < 0.0001), suggesting a preference among infants for set 2 stimuli compared to set 1 stimuli. The pattern of novelty preference across trials was significantly different between infants who saw the novel stimuli on the left first and those who saw them on the right first (p-value < 0.0001) but the overall mean novelty preference was not significantly different between these groups. There were also significant differences in average fixation duration and eyes preference measures across stimuli (p-values < 0.05). These findings show that VRM assessment can be automated for use in large-scale epidemiological studies using infrared eye tracking with looking behavior measure results similar to those obtained with standard non-automated methods, and that side and stimulus preferences are important modifiers of looking behavior that are critical to consider in this type of assessment.