Oxidative stress as a potential mechanism linking gestational phthalates exposure to cognitive development in infancy.

BACKGROUND: Gestational exposure to phthalates, endocrine disrupting chemicals widely used in consumer products, has been associated with poor recognition memory in infancy. Oxidative stress may represent one pathway linking this association. Hence, we examined whether exposure to phthalates was associated with elevated oxidative stress during pregnancy, and whether oxidative stress mediates the relationship between phthalate exposure and recognition memory. METHODS: Our analysis included a subset of mother-child pairs enrolled in the Illinois Kids Development Study (IKIDS, N = 225, recruitment years 2013-2018). Concentrations of 12 phthalate metabolites were quantified in 2nd trimester urine samples. Four oxidative stress biomarkers (8-isoprostane-PGF2α, 2,3-dinor-5,6-dihydro-8-isoPGF2α, 2,3-dinor-8-isoPGF2α, and prostaglandin-F2α) were measured in 2nd and 3rd trimester urine. Recognition memory was evaluated at 7.5 months, with looking times to familiar and novel stimuli recorded via infrared eye-tracking. Novelty preference (proportion of time looking at a novel stimulus when paired with a familiar one) was considered a measure of recognition memory. Linear mixed effect models were used to estimate associations between monoethyl phthalate (MEP), sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP), sum of di(isononyl) phthalate metabolites (ΣDINP), and sum of anti-androgenic phthalate metabolites (ΣAA) and oxidative stress biomarkers. Mediation analysis was performed to assess whether oxidative stress biomarkers mediated the effect of gestational phthalate exposure on novelty preference. RESULTS: The average maternal age at delivery was 31 years and approximately 50 % of participants had a graduate degree. A natural log unit increase in ΣAA, ΣDINP, and ΣDEHP was associated with a statistically significant increase in 8-isoPGF2α, 2,3-dinor-5,6-dihydro-8-isoPGF2α, and 2,3-dinor-8-isoPGF2α. The association was greatest in magnitude for ΣAA and 2,3-dinor-5,6-dihydro-8-isoPGF2α (ß = 0.45, 95 % confidence interval = 0.14, 0.76). The relationship between ΣAA, ΣDINP, ΣDEHP, and novelty preference was partially mediated by 2,3-dinor-8-isoPGF2α. CONCLUSIONS: Gestational exposure to some phthalates is positively associated with oxidative stress biomarkers, highlighting one mechanistic pathway through which these chemicals may impair early cognitive development.

Associations of prenatal maternal urinary concentrations of triclosan and benzophenone-3 with cognition in 7.5-month-old infants.

BACKGROUND: Endocrine-disrupting chemicals (EDCs) have been linked to adverse health outcomes and prenatal exposure is known to impact infant and child development. However, few studies have assessed early developmental consequences of prenatal exposure to two common phenolic compounds, benzophenone-3 (BP-3) and triclosan (TCS). OBJECTIVE: We evaluated the relationship of prenatal exposure to BP-3 and TCS with infant cognition at 7.5 months via performance on a visual recognition memory (VRM) task. METHODS: Drawing from the Illinois Kids Development Study (IKIDS) cohort, prenatal exposure to BP-3 and TCS was assessed in pools of five urine samples collected from each woman across pregnancy. Cognition was measured in 310 infants using a VRM task assessing information processing speed, attention, and recognition memory through infrared eye-tracking. Generalized linear regression estimated exposure-outcome associations, followed by stratification to investigate modification of associations by infant sex and stimulus set. RESULTS: Sampled mothers were more likely to be white, college educated, and middle or high income relative to the US population. Mean chemical exposures were significantly higher than those of adult women in the NHANES cohort. In models adjusted for income, gestational age at birth, and testing age, prenatal BP-3 exposure was associated with an increase in run duration (average time spent looking at the stimuli before looking away) (ß = 0.0011, CI -0.0001:0.0022), indicating slower information processing speed, while TCS was associated with significantly longer time to familiarization (time to accrue a total of 20 s of looking time to the stimuli) (ß = 0.0686, CI 0.0203:0.1168, p < 0.01), indicating poorer attention. Stratum-specific analyses isolated both effects to male infants who viewed the second of two stimulus sets. CONCLUSION: Higher prenatal exposure to triclosan was associated with poorer attention in infancy, while benzophenone-3 may be associated with slower information processing speed, particularly among males.

Association of Phenols, Parabens, and Their Mixture with Maternal Blood Pressure Measurements in the PROTECT Cohort.

BACKGROUND: Phenols and parabens are two classes of high production volume chemicals that are used widely in consumer and personal care products and have been associated with reproductive harm and pregnancy complications, such as preeclampsia and gestational diabetes. However, studies examining their influence on maternal blood pressure and gestational hypertension are limited. OBJECTIVES: We investigated associations between individual phenols, parabens, and their mixture on maternal blood pressure measurements, including systolic and diastolic blood pressure (SBP and DBP) and hypertension during pregnancy (defined as stage 1 or 2 hypertension), among N=1,433 Puerto Rico PROTECT study participants. METHODS: We examined these relationships cross-sectionally at two time points during pregnancy (16-20 and 24-28 wks gestation) and longitudinally using linear mixed models (LMMs). Finally, we used quantile g-computation to examine the mixture effect on continuous (SBP, DBP) and binary (hypertension during pregnancy) blood pressure outcomes. RESULTS: We observed a trend of higher odds of hypertension during pregnancy with exposure to multiple analytes and the overall mixture [including bisphenol A (BPA), bisphenol S (BPS), triclocarbon (TCC), triclosan (TCS), benzophenone-3 (BP-3), 2,4-dichlorophenol (2,4-DCP), 2,5-dichlorophenol (2,5-DCP), methyl paraben (M-PB), propyl paraben (P-PB), butyl paraben (B-PB), and ethyl paraben (E-PB)], especially at 24-28 wk gestation, with an adjusted mixture odds ratio(OR)=1.57 (95% CI: 1.03, 2.38). Lower SBP and higher DBP were also associated with individual analytes, with results from LMMs most consistent for methyl paraben (M-PB) or propyl paraben (P-PB) and increased DBP across pregnancy [adjusted M-PB ß=0.78 (95% CI: 0.17, 1.38) and adjusted P-PB ß=0.85 (95% CI: 0.19, 1.51)] and for BPA, which was associated with decreased SBP (adjusted ß=-0.57; 95% CI: -1.09, -0.05). Consistent with other literature, we also found evidence of effect modification by fetal sex, with a strong inverse association observed between the overall exposure mixture and SBP at visit 1 among participants carrying female fetuses only. CONCLUSIONS: Our findings indicate that phenol and paraben exposure may collectively increase the risk of stage 1 or 2 hypertension during pregnancy, which has important implications for fetal and maternal health. https://doi.org/10.1289/EHP14008.

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.

The relationship of prenatal acetaminophen exposure and attention-related behavior in early childhood.

Acetaminophen is currently the only analgesic considered safe for use throughout pregnancy, but recent studies indicate that prenatal exposure to acetaminophen may be related to poorer neurodevelopmental outcomes. Multiple studies have suggested that it may be associated with attention problems, but few have examined this association by trimester of exposure. The Illinois Kids Development Study is a prospective birth cohort located in east-central Illinois. Exposure data were collected between December 2013 and March 2020, and 535 newborns were enrolled during that period. Mothers reported the number of times they took acetaminophen at six time points across pregnancy. When children were 2, 3, and 4 years of age, caregivers completed the Child Behavior Checklist for ages 1.5-5 years (CBCL). Associations of acetaminophen use during pregnancy with scores on the Attention Problems and ADHD Problems syndrome scales, the Internalizing and Externalizing Behavior composite scales, and the Total Problems score were evaluated. Higher acetaminophen exposure during the second trimester of fetal development was associated with higher Attention Problems, ADHD Problems, Externalizing Behavior, and Total Problems scores at ages 2 and 3. Higher second trimester exposure was only associated with higher Externalizing Behavior and Total Problems scores at 4 years. Higher cumulative exposure across pregnancy was associated with higher Attention Problems and ADHD Problems scores at ages 2 and 3. Findings suggest that prenatal acetaminophen exposure, especially during the second trimester, may be related to problems with attention in early childhood.

Examining the relationship of acetaminophen use during pregnancy with early language development in children.

BACKGROUND: Acetaminophen is the only analgesic considered safe for use throughout pregnancy. Recent studies suggest that use during pregnancy may be associated with poorer neurodevelopmental outcomes in children, but few have examined language development. METHODS: The Illinois Kids Development Study is a prospective birth cohort in east-central Illinois. Between December 2013 and March 2020, 532 newborns were enrolled and had exposure data available. Participants reported the number of times they took acetaminophen six times across pregnancy. Language data were collected at 26.5-28.5 months using the MacArthur-Bates Communicative Development Inventories (CDI; n = 298), and 36-38 months using the Speech and Language Assessment Scale (SLAS; n = 254). RESULTS: Taking more acetaminophen during the second or third trimester was associated with marginally smaller vocabularies and shorter utterance length (M3L) at 26.5-28.5 months. More acetaminophen use during the third trimester was also associated with increased odds of M3L scores ≤25th percentile in male children. More use during the second or third trimester was associated with lower SLAS scores at 36-38 months. Third trimester use was specifically related to lower SLAS scores in male children. CONCLUSIONS: Higher prenatal acetaminophen use during pregnancy may be associated with poorer early language development. IMPACT: Taking more acetaminophen during pregnancy, particularly during the second and third trimesters, was associated with poorer scores on measures of language development when children were 26.5-28.5 and 36-38 months of age. Only male children had lower scores in analyses stratified by child sex. To our knowledge, this is the first study that has used a standardized measure of language development to assess the potential impact of prenatal exposure to acetaminophen on language development. This study adds to the growing body of literature suggesting that the potential impact of acetaminophen use during pregnancy on fetal neurodevelopment should be carefully evaluated.

Associations of prenatal exposure to per- and polyfluoroalkyl substances (PFAS) with measures of cognition in 7.5-month-old infants: An exploratory study.

BACKGROUND: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has been linked to a wide array of adverse maternal and child health outcomes. However, studies examining PFAS in relation to offspring cognition have been inconclusive. OBJECTIVE: We examined whether prenatal exposure to a mixture of PFAS was related to cognition in 7.5-month-old infants. METHODS: Our analytic sample included participants enrolled in the Chemicals in Our Bodies (CIOB) and Illinois Kids Development Study (IKIDS) cohorts (N = 163). Seven PFAS were measured in 2nd trimester maternal serum samples and were detected in >65% of participants. Infant cognition was measured with a visual recognition memory task using an infrared eye tracker when infants were 7.5 months old. This task included familiarization trials where each infant was shown two identical faces and test trials where each infant was shown the familiar face paired with a novel face. In familiarization, we assessed average run duration (time looking at familiarization stimuli before looking away) as a measure of information processing speed, in addition to time to familiarization (time to reach 20 s of looking at stimuli) and shift rate (the number of times infants looked between stimuli), both as measures of attention. In test trials, we assessed novelty preference (proportion of time looking to the novel face) to measure recognition memory. Linear regression was used to estimate associations of individual PFAS with cognitive outcomes, while Bayesian kernel machine regression (BKMR) was used to estimate mixture effects. RESULTS: In adjusted single-PFAS linear regression models, an interquartile range increase in PFNA, PFOA, PFOS, PFHxS, PFDeA, and PFUdA was associated with an increase in shift rate, reflecting better visual attention. Using BKMR, increasing quartiles of the PFAS mixture was similarly associated with a modest increase in shift rate. There were no significant associations between PFAS exposure and time to reach familiarization (another measure of attention), average run duration (information processing speed), or novelty preference (visual recognition memory). CONCLUSION: In our study population, prenatal PFAS exposure was modestly associated with an increase in shift rate and was not strongly associated with any adverse cognitive outcomes in 7.5-month-old infants.

Examining the association between prenatal maternal stress and infant non-nutritive suck.

BACKGROUND: This study examined the relationship between prenatal maternal stress (PREMS) and non-nutritive suck (NNS) and tested its robustness across 2 demographically diverse populations. METHODS: The study involved 2 prospective birth cohorts participating in the national Environmental influences on Child Health Outcomes (ECHO) Program: Illinois Kids Development Study (IKIDS) and ECHO Puerto Rico (ECHO-PROTECT). PREMS was measured during late pregnancy via the 10-item Perceived Stress Scale (PSS-10). NNS was sampled from 1- to 8-week-olds using a custom pacifier for ~5 min. RESULTS: Overall, 237 mother-infant dyads completed this study. Despite several significant differences, including race/ethnicity, income, education, and PREMS levels, significant PREMS-NNS associations were found in the 2 cohorts. In adjusted linear regression models, higher PREMS, measured through PSS-10 total scores, related to fewer but longer NNS bursts per minute. CONCLUSIONS: A significant association was observed between PREMS and NNS across two diverse cohorts. This finding is important as it may enable the earlier detection of exposure-related deficits and, as a result, earlier intervention, which potentially can optimize outcomes. More research is needed to understand how NNS affects children's neurofunction and development. IMPACT: In this double-cohort study, we found that higher maternal perceived stress assessed in late pregnancy was significantly associated with fewer but longer sucking bursts in 1- to 8-week-old infants. This is the first study investigating the association between prenatal maternal stress (PREMS) and infant non-nutritive suck (NNS), an early indicator of central nervous system integrity. Non-nutritive suck is a potential marker of increased prenatal stress in diverse populations. Non-nutritive suck can potentially serve as an early indicator of exposure-related neuropsychological deficits allowing for earlier interventions and thus better prognoses.

Associations of prenatal exposure to phthalates with measures of cognition in 7.5-month-old infants.

BACKGROUND: Phthalates are endocrine disrupting chemicals that have been associated with adverse neurobehavior, but little is known about their influence on infant cognition. METHODS: A visual recognition memory task was used to assess cognition in 244 7-8-month-old infants (121 females; 123 males) from a prospective cohort study. Phthalate metabolites were quantified in maternal urines pooled from across pregnancy. The task included familiarization trials (infant shown 2 identical faces) and test trials (infant shown the now familiar face paired with a novel one). Half of the infants saw one set of faces as familiar (set 1) and half saw the other set as familiar (set 2). During familiarization trials, average run duration (time looking at stimuli before looking away, measure of processing speed), and time to familiarization (time to reach 20 s looking at the stimuli, measure of attention) were assessed. During test trials, novelty preference (proportion of time looking at the novel face, measure of recognition memory) was assessed. Multivariable generalized linear models were used to assess associations of monoethyl phthalate (MEP), sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP), sum of di(isononyl) phthalate metabolites (ΣDINP), and sum of anti-androgenic phthalate metabolites (ΣAA) with each outcome. RESULTS: Mothers were mostly white and college educated, and urine phthalate concentrations were similar to those in reproductive age women in the U.S. POPULATION: All phthalate exposure biomarkers, except MEP, were associated with increases in average run duration. However, depending on the phthalate, associations were only in males or infants who saw the set 2 stimuli as familiar. Unexpectedly, ΣAA was associated with a shorter time to reach familiarization. Phthalate biomarkers also were associated with modest decrements in novelty preference, but these associations were nonsignificant. CONCLUSION: Prenatal exposure to phthalates may be related to slower information processing and poorer recognition memory in infants.