Cross-Sectional Associations between Prenatal Per- and Poly-Fluoroalkyl Substances and Bioactive Lipids in Three Environmental Influences on Child Health Outcomes (ECHO) Cohorts.

Prenatal per- and poly-fluoroalkyl substances (PFAS) exposure may influence gestational outcomes through bioactive lipids─metabolic and inflammation pathway indicators. We estimated associations between prenatal PFAS exposure and bioactive lipids, measuring 12 serum PFAS and 50 plasma bioactive lipids in 414 pregnant women (median 17.4 weeks' gestation) from three Environmental influences on Child Health Outcomes Program cohorts. Pairwise association estimates across cohorts were obtained through linear mixed models and meta-analysis, adjusting the former for false discovery rates. Associations between the PFAS mixture and bioactive lipids were estimated using quantile g-computation. Pairwise analyses revealed bioactive lipid levels associated with PFDeA, PFNA, PFOA, and PFUdA (p < 0.05) across three enzymatic pathways (cyclooxygenase, cytochrome p450, lipoxygenase) in at least one combined cohort analysis, and PFOA and PFUdA (q < 0.2) in one linear mixed model. The strongest signature revealed doubling in PFOA corresponding with PGD2 (cyclooxygenase pathway; +24.3%, 95% CI: 7.3-43.9%) in the combined cohort. Mixture analysis revealed nine positive associations across all pathways with the PFAS mixture, the strongest signature indicating a quartile increase in the PFAS mixture associated with PGD2 (+34%, 95% CI: 8-66%), primarily driven by PFOS. Bioactive lipids emerged as prenatal PFAS exposure biomarkers, deepening insights into PFAS' influence on pregnancy outcomes.

Associations of per- and polyfluoroalkyl substances with maternal early second trimester sex-steroid hormones.

BACKGROUND/AIMS: Pregnant women are exposed to persistent environmental contaminants, including per- and polyfluoroalkyl substances (PFAS) that disrupt thyroid function. However, it is unclear if PFAS alter maternal sex-steroid hormone levels, which support pregnancy health and fetal development. METHODS: In Illinois women with relatively high socioeconomic status (n = 460), we quantified perfluorononanoic (PFNA), perfluorooctane sulfonic (PFOS), perfluorooctanoic (PFOA), methyl-perfluorooctane sulfonamide acetic acid, perfluorohexanesulphonic (PFHxS), perfluorodecanoic (PFDeA), and perfluoroundecanoic (PFUdA) acid concentrations in fasting serum samples at median 17 weeks gestation, along with plasma progesterone, testosterone, and estradiol. We evaluated covariate-adjusted associations of ln-transformed hormones with each ln-transformed PFAS individually using linear regression and with the PFAS mixture using quantile-based g-computation (QGComp). RESULTS: Interquartile range (IQR) increases in PFOS were associated with higher progesterone (%Δ 3.0; 95%CI: -0.6, 6.6) and estradiol (%Δ: 8.1; 95%CI: 2.2, 14.4) levels. Additionally, PFHxS was positively associated with testosterone (%Δ: 10.2; 95%CI: 4.0, 16.7), whereas both PFDeA and PFUdA were inversely associated with testosterone (%Δ: -5.7; 95%CI: -10.3, -0.8, and %Δ: -4.1; 95%CI: -7.6, -0.4, respectively). The IQR-standardized PFAS mixture was not associated with progesterone (%Δ: 1.6; 95%CI: -5.8, 9.2), due equal partial positive (%Δ: 9.2; driven by PFOA) and negative (%Δ: -7.4; driven by PFOS) mixture associations. Similarly, the mixture was not associated with testosterone (%Δ: 5.3; 95%CI: -9.0, 20.1), due to similar partial positive (%Δ: 23.6; driven by PFHxS) and negative (%Δ: -17.4; driven by PFDeA) mixture associations. However, we observed a slightly stronger partial positive (%Δ: 25.6; driven by PFOS and PFUdA) than negative (%Δ: -16.3; driven by PFOA) association resulting in an overall non-significant positive trend between the mixture and estradiol (%Δ: 8.5; 95%CI: -3.7, 20.9). CONCLUSION: PFAS mixture modeled using QGComp was not associated with maternal sex-steroid hormones due to potential opposing effects of certain PFAS. Additional prospective studies could corroborate these findings.

Associations of per- and polyfluoroalkyl substances with maternal metabolic and inflammatory biomarkers in early-to-mid-pregnancy.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) can disrupt metabolism. Early-to-mid pregnancy is characterized by amplified metabolic processes and inflammation to support maternal adaptations and fetal growth. Thus, we cross-sectionally evaluated whether PFAS are individually and jointly associated with these processes in early-to-mid pregnancy. METHODS: Pregnant Illinois women (n = 452) provided fasted blood samples at median 17 weeks gestation. We quantified serum perfluorononanoic (PFNA), perfluorooctane sulfonic (PFOS), perfluorooctanoic (PFOA), methyl-perfluorooctane sulfonamide acetic acid (Me-PFOSA-AcOH), perfluorohexanesulfonic (PFHxS), perfluorodecanoic (PFDeA), and perfluoroundecanoic (PFUdA) acid. Key outcomes were plasma glucose, insulin, C-peptide, insulin-like growth factor 1 (IGF-1), adiponectin, leptin, triglycerides, free fatty acids, total cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein, tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6. We calculated homeostatic model assessment for insulin resistance (HOMA-IR), low-density lipoprotein (LDL) cholesterol, and very low-density lipoprotein (VLDL). We evaluated associations of PFAS with each metabolic/inflammatory biomarker individually using covariate-adjusted linear regression and jointly using quantile-based g-computation. RESULTS: In linear regression, all PFAS (except Me-PFOSA-AcOH) were negatively associated with insulin, HOMA-IR, and leptin, whereas all PFAS were positively associated with HDL cholesterol. We also observed negative associations of some PFAS with TNF-α and MCP-1; positive associations with adiponectin and total cholesterol also emerged. Additionally, PFOS was positively, whereas Me-PFOSA-AcOH was negatively, associated with triglycerides and VLDL. Each 25% increase in the PFAS mixture was associated with -31.3% lower insulin (95%CI: -45.8, -12.9), -31.9% lower HOMA-IR (95%CI: -46.4, -13.4), and -9.4% lower leptin (95%CI: -17.3, -0.8), but 7.4% higher HDL cholesterol (95%CI: 4.6, 10.3). For most outcomes, the major contributors to the PFAS mixture often differed compared to single-PFAS analyses. IMPLICATIONS: Individual and joint PFAS exposures were associated with markers of maternal metabolism and inflammation in pregnancy. Further investigation is needed to elucidate possible mechanisms and consequences of these findings.

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.

Prenatal phthalate exposure and adverse birth outcomes in the USA: a prospective analysis of births and estimates of attributable burden and costs.

BACKGROUND: Phthalates are synthetic chemicals widely used in consumer products and have been identified to contribute to preterm birth. Existing studies have methodological limitations and potential effects of di-2-ethylhexyl phthalate (DEHP) replacements are poorly characterised. Attributable fractions and costs have not been quantified, limiting the ability to weigh trade-offs involved in ongoing use. We aimed to leverage a large, diverse US cohort to study associations of phthalate metabolites with birthweight and gestational age, and estimate attributable adverse birth outcomes and associated costs. METHODS: In this prospective analysis we used extant data in the US National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Program from 1998 to 2022 to study associations of 20 phthalate metabolites with gestational age at birth, birthweight, birth length, and birthweight for gestational age z-scores. We also estimated attributable adverse birth outcomes and associated costs. Mother-child dyads were included in the study if there were one or more urinary phthalate measurements during the index pregnancy; data on child's gestational age and birthweight; and singleton delivery. FINDINGS: We identified 5006 mother-child dyads from 13 cohorts in the ECHO Program. Phthalic acid, diisodecyl phthalate (DiDP), di-n-octyl phthalate (DnOP), and diisononyl phthalate (DiNP) were most strongly associated with gestational age, birth length, and birthweight, especially compared with DEHP or other metabolite groupings. Although DEHP was associated with preterm birth (odds ratio 1·45 [95% CI 1·05-2·01]), the risks per log10 increase were higher for phthalic acid (2·71 [1·91-3·83]), DiNP (2·25 [1·67-3·00]), DiDP (1·69 [1·25-2·28]), and DnOP (2·90 [1·96-4·23]). We estimated 56 595 (sensitivity analyses 24 003-120 116) phthalate-attributable preterm birth cases in 2018 with associated costs of US$3·84 billion (sensitivity analysis 1·63- 8·14 billion). INTERPRETATION: In a large, diverse sample of US births, exposure to DEHP, DiDP, DiNP, and DnOP were associated with decreased gestational age and increased risk of preterm birth, suggesting substantial opportunities for prevention. This finding suggests the adverse consequences of substitution of DEHP with chemically similar phthalates and need to regulate chemicals with similar properties as a class. FUNDING: National Institutes of Health.

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.

Prenatal Phenol and Paraben Exposures and Adverse Birth Outcomes: A Prospective Analysis of U.S. Births.

BACKGROUND: Synthetic chemicals are increasingly being recognized for potential independent contributions to preterm birth (PTB) and low birth weight (LBW). Bisphenols, parabens, and triclosan are consumer product chemicals that act via similar mechanisms including estrogen, androgen, and thyroid disruption and oxidative stress. Multiple cohort studies have endeavored to examine effects on birth outcomes, and systematic reviews have been limited due to measurement of 1-2 spot samples during pregnancy and limited diversity of populations. OBJECTIVE: To study the effects of prenatal phenols and parabens on birth size and gestational age (GA) in 3,619 mother-infant pairs from 11 cohorts in the NIH Environmental influences on Child Health Outcomes program. RESULTS: While many associations were modest and statistically imprecise, a 1-unit increase in log10 pregnancy averaged concentration of benzophenone-3 and methylparaben were associated with decreases in birthweight, birthweight adjusted for gestational age and SGA. Increases in the odds of being SGA were 29% (95% CI: 5%, 58%) and 32% (95% CI: 3%, 70%), respectively. Bisphenol S in third trimester was also associated with SGA (OR 1.52, 95% CI 1.08, 2.13). Associations of benzophenone-3 and methylparaben with PTB and LBW were null. In addition, a 1-unit increase in log10 pregnancy averaged concentration of 2,4-dichlorophenol was associated with 43% lower (95% CI: -67%, -2%) odds of low birthweight; the direction of effect was the same for the highly correlated 2,5-dichlorophenol, but with a smaller magnitude (-29%, 95% CI: -53%, 8%). DISCUSSION: In a large and diverse sample generally representative of the United States, benzophenone-3 and methylparaben were associated with lower birthweight as well as birthweight adjusted for gestational age and higher odds of SGA, while 2,4-dichlorophenol. These associations with smaller size at birth are concerning in light of the known consequences of intrauterine growth restriction for multiple important health outcomes emerging later in life.

Associations of urinary non-persistent endocrine disrupting chemical biomarkers with early-to-mid pregnancy plasma sex-steroid and thyroid hormones.

BACKGROUND/OBJECTIVES: Pregnant women are exposed to numerous endocrine disrupting chemicals (EDCs) that can affect hormonal pathways regulating pregnancy outcomes and fetal development. Thus, we evaluated overall and fetal sex-specific associations of phthalate/replacement, paraben, and phenol biomarkers with sex-steroid and thyroid hormones. METHODS: Illinois women (n = 302) provided plasma for progesterone, estradiol, testosterone, free T4 (FT4), total T4 (TT4), and thyroid stimulating hormone (TSH) at median 17 weeks gestation. Women also provided up-to-five first-morning urine samples monthly across pregnancy (8-40 weeks), which we pooled to measure 19 phthalate/replacement metabolites (reflecting ten parent compounds), three parabens, and six phenols. We used linear regression to evaluate overall and fetal sex-specific associations of biomarkers with hormones, as well as weighted quantile sum and Bayesian kernel machine regression (BKMR) to assess cumulative associations, non-linearities, and chemical interactions. RESULTS: In women of relatively high socioeconomic status, several EDC biomarkers were associated with select hormones, without cumulative or non-linear associations with progesterone, FT4, or TT4. The biomarker mixture was negatively associated with estradiol (only at higher biomarker concentrations using BKMR), testosterone, and TSH, where each 10% mixture increase was associated with -5.65% (95% CI: -9.79, -1.28) lower testosterone and -0.09 µIU/mL (95% CI: -0.20, 0.00) lower TSH. Associations with progesterone, testosterone, and FT4 did not differ by fetal sex. However, in women carrying females, we identified an inverted u-shaped relationship of the mixture with estradiol. Additionally, in women carrying females, each 10% increase in the mixture was associated with 1.50% (95% CI: -0.15, 3.18) higher TT4, whereas in women carrying males, the mixture was associated with -1.77% (95% CI: -4.08, 0.58) lower TT4 and -0.18 µIU/mL (95% CI: -0.33, -0.03) lower TSH. We also identified select chemical interactions. CONCLUSION: Some biomarkers were associated with early-to-mid pregnancy hormones. There were some sex-specific and non-linear associations. Future studies could consider how these findings relate to pregnancy/birth outcomes.

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.

Cross-sectional associations between prenatal maternal per- and poly-fluoroalkyl substances and bioactive lipids in three Environmental influences on Child Health Outcomes (ECHO) cohorts.

Background: Per- and poly-fluoroalkyl substances (PFAS) exposure can occur through ingestion of contaminated food and water, and inhalation of indoor air contaminated with these chemicals from consumer and industrial products. Prenatal PFAS exposures may confer risk for pregnancy-related outcomes such as hypertensive and metabolic disorders, preterm birth, and impaired fetal development through intermediate metabolic and inflammation pathways. Objective: Estimate associations between maternal pregnancy PFAS exposure (individually and as a mixture) and bioactive lipids. Methods: Our study included pregnant women in the Environmental influences on Child Health Outcomes Program: Chemicals in our Bodies cohort (CiOB, n=73), Illinois Kids Developmental Study (IKIDS, n=287), and the ECHO-PROTECT cohort (n=54). We measured twelve PFAS in serum and 50 plasma bioactive lipids (parent fatty acids and eicosanoids derived from cytochrome p450, lipoxygenase, and cyclooxygenase) during pregnancy (median 17 gestational weeks). Pairwise associations across cohorts were estimated using linear mixed models and meta-analysis. Associations between the PFAS mixture and individual bioactive lipids were estimated using quantile g-computation. Results: PFDeA, PFOA, and PFUdA were associated (p<0.05) with changes in bioactive lipid levels in all three enzymatic pathways (cyclooxygenase [n=6 signatures]; cytochrome p450 [n=5 signatures]; lipoxygenase [n=7 signatures]) in at least one combined cohort analysis. The strongest signature indicated that a doubling in PFOA corresponded with a 24.3% increase (95% CI [7.3%, 43.9%]) in PGD2 (cyclooxygenase pathway) in the combined cohort. In the mixtures analysis, we observed nine positive signals across all pathways associated with the PFAS mixture. The strongest signature indicated that a quartile increase in the PFAS mixture was associated with a 34% increase in PGD2 (95% CI [8%, 66%]), with PFOS contributing most to the increase. Conclusions: Bioactive lipids were revealed as biomarkers of PFAS exposure and could provide mechanistic insights into PFAS' influence on pregnancy outcomes, informing more precise risk estimation and prevention strategies.

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.

Interrogating Components of 2 Diet Quality Indices in Pregnancy using a Supervised Statistical Mixtures Approach.

BACKGROUND: The Healthy Eating Index (HEI)-2015 and Alternative Healthy Eating Index (AHEI)-2010 evaluate diet holistically in pregnancy. However, it remains unclear how individual index components interact to contribute to health. OBJECTIVES: To evaluate associations of HEI-2015 and AHEI-2010 components with gestational length using traditional and novel statistical methods in a prospective cohort. METHODS: Pregnant women completed a 3-mo food-frequency questionnaire (FFQ) at median 13 wk gestation to calculate the HEI-2015 or AHEI-2010. Covariate-adjusted linear regression models evaluated associations of HEI-2015 and AHEI-2010 total scores and individual components (one at a time and simultaneously adjusted) with gestational length. Covariate-adjusted weighted quantile sum regression models evaluated 1) associations of HEI-2015 or AHEI-2010 components as mixtures with gestational length and 2) contributions of components to these associations. RESULTS: Each 10-point increase in HEI-2015 and AHEI-2010 total score was associated with 0.11 (95% CI: -0.05, 0.27) and 0.14 (95% CI: 0.00, 0.28) wk longer gestation, respectively. In individual or simultaneously adjusted HEI-2015 models, higher intakes of seafood/plant proteins, total protein foods, greens/beans, and saturated fats but lower intakes of added sugars and refined grains were associated with longer gestational length. For the AHEI-2010, higher intake of nuts/legumes and lower intake of sugar-sweetened beverages (SSBs)/fruit juice were associated with longer gestational length. Jointly, 10% increases in HEI-2015 or AHEI-2010 mixtures were associated with 0.17 (95% CI: 0.001, 0.34) and 0.18 (95% CI: 0.05, 0.30) wk longer gestational length, respectively. Seafood/plant protein, total protein foods, dairy, greens/beans, and added sugars were the largest contributors to the HEI-2015 mixture. Nuts/legumes, SSBs/fruit juice, sodium, and DHA/EPA were the largest contributors to the AHEI-2010 mixture. Associations were less precise but consistent in women with spontaneous labors. CONCLUSIONS: Compared to traditional methods, associations of diet index mixtures with gestational length were more robust and identified unique contributors. Additional studies could consider interrogating these statistical approaches using other dietary indices and health outcomes.

Developmental Exposure to Polychlorinated Biphenyls Prevents Recovery from Noise-Induced Hearing Loss and Disrupts the Functional Organization of the Inferior Colliculus.

Exposure to combinations of environmental toxins is growing in prevalence; and therefore, understanding their interactions is of increasing societal importance. Here, we examined the mechanisms by which two environmental toxins, polychlorinated biphenyls (PCBs) and high-amplitude acoustic noise, interact to produce dysfunction in central auditory processing. PCBs are well established to impose negative developmental impacts on hearing. However, it is not known whether developmental exposure to this ototoxin alters the sensitivity to other ototoxic exposures later in life. Here, male mice were exposed to PCBs in utero, and later as adults were exposed to 45 min of high-intensity noise. We then examined the impacts of the two exposures on hearing and the organization of the auditory midbrain using two-photon imaging and analysis of the expression of mediators of oxidative stress. We observed that developmental exposure to PCBs blocked hearing recovery from acoustic trauma. In vivo two-photon imaging of the inferior colliculus (IC) revealed that this lack of recovery was associated with disruption of the tonotopic organization and reduction of inhibition in the auditory midbrain. In addition, expression analysis in the inferior colliculus revealed that reduced GABAergic inhibition was more prominent in animals with a lower capacity to mitigate oxidative stress. These data suggest that combined PCBs and noise exposure act nonlinearly to damage hearing and that this damage is associated with synaptic reorganization, and reduced capacity to limit oxidative stress. In addition, this work provides a new paradigm by which to understand nonlinear interactions between combinations of environmental toxins.SIGNIFICANCE STATEMENT Exposure to common environmental toxins is a large and growing problem in the population. This work provides a new mechanistic understanding of how the prenatal and postnatal developmental changes induced by polychlorinated biphenyls (PCBs) could negatively impact the resilience of the brain to noise-induced hearing loss (NIHL) later in adulthood. The use of state-of-the-art tools, including in vivo multiphoton microscopy of the midbrain helped in identifying the long-term central changes in the auditory system after the peripheral hearing damage induced by such environmental toxins. In addition, the novel combination of methods employed in this study will lead to additional advances in our understanding of mechanisms of central hearing loss in other contexts.

Developmental exposure to polychlorinated biphenyls prevents recovery from noise-induced hearing loss and disrupts the functional organization of the inferior colliculus.

Exposure to combinations of environmental toxins is growing in prevalence, and therefore understanding their interactions is of increasing societal importance. Here, we examined the mechanisms by which two environmental toxins - polychlorinated biphenyls (PCBs) and high-amplitude acoustic noise - interact to produce dysfunction in central auditory processing. PCBs are well-established to impose negative developmental impacts on hearing. However, it is not known if developmental exposure to this ototoxin alters the sensitivity to other ototoxic exposures later in life. Here, male mice were exposed to PCBs in utero, and later as adults were exposed to 45 minutes of high-intensity noise. We then examined the impacts of the two exposures on hearing and the organization of the auditory midbrain using two-photon imaging and analysis of the expression of mediators of oxidative stress. We observed that developmental exposure to PCBs blocked hearing recovery from acoustic trauma. In vivo two-photon imaging of the inferior colliculus revealed that this lack of recovery was associated with disruption of the tonotopic organization and reduction of inhibition in the auditory midbrain. In addition, expression analysis in the inferior colliculus revealed that reduced GABAergic inhibition was more prominent in animals with a lower capacity to mitigate oxidative stress. These data suggest that combined PCBs and noise exposure act nonlinearly to damage hearing and that this damage is associated with synaptic reorganization, and reduced capacity to limit oxidative stress. In addition, this work provides a new paradigm by which to understand nonlinear interactions between combinations of environmental toxins. Significance statement: Exposure to common environmental toxins is a large and growing problem in the population. This work provides a new mechanistic understanding of how the pre-and postnatal developmental changes induced by polychlorinated biphenyls could negatively impact the resilience of the brain to noise-induced hearing loss later in adulthood. The use of state-of-the-art tools, including in vivo multiphoton microscopy of the midbrain helped in identifying the long-term central changes in the auditory system after the peripheral hearing damage induced by such environmental toxins. In addition, the novel combination of methods employed in this study will lead to additional advances in our understanding of mechanisms of central hearing loss in other contexts.

Birth Outcomes in Relation to Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Stress in the Environmental Influences on Child Health Outcomes (ECHO) Program.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress. OBJECTIVES: We estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships. METHODS: We included 3,339 participants from 11 prospective prenatal cohorts in the Environmental influences on the Child Health Outcomes (ECHO) program to estimate the associations of five PFAS and birth outcomes. We stratified by perceived stress scale scores to examine effect modification and used Bayesian Weighted Sums to estimate mixtures of PFAS. RESULTS: We observed reduced birth size with increased concentrations of all PFAS. For a 1-unit higher log-normalized exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), we observed lower birthweight-for-gestational-age z-scores of ß=-0.15 [95% confidence interval (CI): -0.27, -0.03], ß=-0.14 (95% CI: -0.28, -0.002), ß=-0.22 (95% CI: -0.23, -0.10), ß=-0.06 (95% CI: -0.18, 0.06), and ß=-0.25 (95% CI: -0.37, -0.14), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age: ORPFNA=0.56 (95% CI: 0.38, 0.83), ORPFDA=0.52 (95% CI: 0.35, 0.77). For a 1-unit increase in log-normalized concentration of summed PFAS, we observed a lower birthweight-for-gestational-age z-score [-0.28; 95% highest posterior density (HPD): -0.44, -0.14] and decreased odds of large-for-gestational-age (OR=0.49; 95% HPD: 0.29, 0.82). Perfluorodecanoic acid (PFDA) explained the highest percentage (40%) of the summed effect in both models. Associations were not modified by maternal perceived stress. DISCUSSION: Our large, multi-cohort study of PFAS and adverse birth outcomes found a negative association between prenatal PFAS and birthweight-for-gestational-age, and the associations were not different in groups with high vs. low perceived stress. This study can help inform policy to reduce exposures in the environment and humans. https://doi.org/10.1289/EHP10723.

Characterizing changes in behaviors associated with chemical exposures during the COVID-19 pandemic.

The COVID-19 pandemic-and its associated restrictions-have changed many behaviors that can influence environmental exposures including chemicals found in commercial products, packaging and those resulting from pollution. The pandemic also constitutes a stressful life event, leading to symptoms of acute traumatic stress. Data indicate that the combination of environmental exposure and psychological stress jointly contribute to adverse child health outcomes. Within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort, a national consortium initiated to understand the effects of environmental exposures on child health and development, our objective was to assess whether there were pandemic-related changes in behavior that may be associated with environmental exposures. A total of 1535 participants from nine cohorts completed a survey via RedCap from December 2020 through May 2021. The questionnaire identified behavioral changes associated with the COVID-19 pandemic in expected directions, providing evidence of construct validity. Behavior changes reported by at least a quarter of the respondents include eating less fast food and using fewer ultra-processed foods, hair products, and cosmetics. At least a quarter of respondents reported eating more home cooked meals and using more antibacterial soaps, liquid soaps, hand sanitizers, antibacterial and bleach cleaners. Most frequent predictors of behavior change included Hispanic ethnicity and older age (35 years and older). Respondents experiencing greater COVID-related stress altered their behaviors more than those not reporting stress. These findings highlight that behavior change associated with the pandemic, and pandemic-related psychological stress often co-occur. Thus, prevention strategies and campaigns that limit environmental exposures, support stress reduction, and facilitate behavioral change may lead to the largest health benefits in the context of a pandemic. Analyzing biomarker data in these participants will be helpful to determine if behavior changes reported associate with measured changes in exposure.

Urinary oxidative stress biomarkers are associated with preterm birth: an Environmental Influences on Child Health Outcomes program study.

BACKGROUND: Preterm birth is the leading cause of infant morbidity and mortality worldwide. Elevated levels of oxidative stress have been associated with an increased risk of delivering before term. However, most studies testing this hypothesis have been conducted in racially and demographically homogenous study populations, which do not reflect the diversity within the United States. OBJECTIVE: We leveraged 4 cohorts participating in the Environmental Influences on Child Health Outcomes Program to conduct the largest study to date examining biomarkers of oxidative stress and preterm birth (N=1916). Furthermore, we hypothesized that elevated oxidative stress would be associated with higher odds of preterm birth, particularly preterm birth of spontaneous origin. STUDY DESIGN: This study was a pooled analysis and meta-analysis of 4 birth cohorts spanning multiple geographic regions in the mainland United States and Puerto Rico (208 preterm births and 1708 full-term births). Of note, 8-iso-prostaglandin-F2α, 2,3-dinor-5,6-dihydro-8-iso-prostaglandin-F2α (F2-IsoP-M; the major 8-iso-prostaglandin-F2α metabolite), and prostaglandin-F2α were measured in urine samples obtained during the second and third trimesters of pregnancy. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals for the associations between averaged biomarker concentrations for each participant and all preterm births, spontaneous preterm births, nonspontaneous preterm births (births of medically indicated or unknown origin), and categories of preterm birth (early, moderate, and late). Individual oxidative stress biomarkers were examined in separate models. RESULTS: Approximately 11% of our analytical sample was born before term. Relative to full-term births, an interquartile range increase in averaged concentrations of F2-IsoP-M was associated with higher odds of all preterm births (odds ratio, 1.29; 95% confidence interval, 1.11-1.51), with a stronger association observed for spontaneous preterm birth (odds ratio, 1.47; 95% confidence interval, 1.16-1.90). An interquartile range increase in averaged concentrations of 8-iso-prostaglandin-F2α was similarly associated with higher odds of all preterm births (odds ratio, 1.19; 95% confidence interval, 0.94-1.50). The results from our meta-analysis were similar to those from the pooled combined cohort analysis. CONCLUSION: Here, oxidative stress, as measured by 8-iso-prostaglandin-F2α, F2-IsoP-M, and prostaglandin-F2α in urine, was associated with increased odds of preterm birth, particularly preterm birth of spontaneous origin and delivery before 34 completed weeks of gestation.

Cross-cultural applicability of eye-tracking in assessing attention to emotional faces in preschool-aged children.

Humans show an attention bias toward emotional versus neutral information, which is considered an adaptive pattern of information processing. Deviations from this pattern have been observed in children with socially withdrawn behaviors, with most research being conducted in controlled settings among children from urban areas. The goal of the current study was to examine the cross-cultural applicability of two eye-tracking-based measures in assessing attention biases and their relations to children's symptoms of socially withdrawn behaviors in two independent and diverse samples of preschool children. The cross-cultural comparison was conducted between the Navajo Birth Cohort study (NBCS), an indigenous cohort with relatively low socioeconomic status (SES), and the Illinois Kids Development study (IKIDS), a primarily Non-Hispanic White and high SES cohort. Children in both cohorts completed eye-tracking tasks with pictures of emotional faces, and mothers reported on children's symptoms of socially withdrawn behaviors. Results showed that general patterns of attention biases were mostly the same across samples, reflecting heightened attention toward emotional versus neutral faces. The differences across two samples mostly involved the magnitude of attention biases. NBCS children were slower to disengage from happy faces when these emotional faces were paired with neutral faces. Additionally, socially withdrawn children in the NBCS sample showed a pattern of attentional avoidance for emotional faces. The comparability of overall patterns of attention biases provides initial support for the cross-cultural applicability of the eye-tracking measures and demonstrates the robustness of these methods across clinical and community settings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Associations of individual and cumulative urinary phthalate and replacement biomarkers with gestational weight gain through late pregnancy.

BACKGROUND/AIMS: Phthalates and their replacements are endocrine/metabolic disruptors that may impact gestational weight gain (GWG) - a pregnancy health indicator. We investigated overall and fetal sex-specific associations of individual and cumulative phthalate/replacement biomarkers with GWG. METHODS: Illinois women (n = 299) self-reported their weight pre-pregnancy and at their final obstetric appointment before delivery (median 38 weeks). We calculated pre-pregnancy body mass index and gestational age-specific GWG z-scores (GWGz). We quantified 19 phthalate/replacement metabolites (representing 10 parent compounds) in pools of up-to-five first-morning urine samples, collected approximately monthly between 8 and 40 weeks gestation. We used linear regression, quantile-based g-computation (QGComp), and weighted quantile sum regression (WQSR) to evaluate associations of ten biomarkers (individual metabolites or parent molar-sums) individually or as mixtures (in interquartile range intervals) with GWGz. We evaluated associations in all women and stratified by fetal sex. RESULTS: Individually, sums of metabolites of di(2-ethylhexyl) phthalate (Æ©DEHP), di(isononyl) cyclohexane-1,2-dicarboxylate (Æ©DiNCH), and di(2-ethylhexyl) terephthalate (Æ©DEHTP) had consistent inverse associations with GWGz, and some associations were fetal sex-specific. When evaluating phthalates/replacements as a mixture, QGComp identified Æ©DEHP, Æ©DEHTP, and mono-(3-carboxypropyl) phthalate, along with sum of di(isononyl) phthalate metabolites (Æ©DiNP) and monobenzyl phthalate as notable contributors to lower and higher GWGz, respectively, resulting in a marginal inverse joint association in all women (ß: -0.29; 95% CI: -0.70, 0.12). In women carrying females, Æ©DEHP contributed to the marginal inverse joint association (ß: -0.54; 95% CI: -1.09, 0.03). However, there was no overall association in women carrying males (ß: 0.00; 95% CI: -0.60, 0.59), which was explained by approximately equal negative (driven by Æ©DEHTP) and positive (driven by Æ©DiNP) partial associations. WQSR analyses consistently replicated these QGComp findings. CONCLUSIONS: Biomarkers of phthalates/replacements were fetal sex-specifically associated with GWGz. Because Æ©DEHTP contributed substantively to mixture associations, additional studies in pregnant women may be needed around this plasticizer replacement.