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.

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 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.

Impact of sedentary behavior and emotional support on prenatal psychological distress and birth outcomes during the COVID-19 pandemic.

Abstract. BACKGROUND: Studies have reported mixed findings regarding the impact of the coronavirus disease 2019 (COVID-19) pandemic on pregnant women and birth outcomes. This study used a quasi-experimental design to account for potential confounding by sociodemographic characteristics. METHODS: Data were drawn from 16 prenatal cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) program. Women exposed to the pandemic (delivered between 12 March 2020 and 30 May 2021) (n = 501) were propensity-score matched on maternal age, race and ethnicity, and child assigned sex at birth with 501 women who delivered before 11 March 2020. Participants reported on perceived stress, depressive symptoms, sedentary behavior, and emotional support during pregnancy. Infant gestational age (GA) at birth and birthweight were gathered from medical record abstraction or maternal report. RESULTS: After adjusting for propensity matching and covariates (maternal education, public assistance, employment status, prepregnancy body mass index), results showed a small effect of pandemic exposure on shorter GA at birth, but no effect on birthweight adjusted for GA. Women who were pregnant during the pandemic reported higher levels of prenatal stress and depressive symptoms, but neither mediated the association between pandemic exposure and GA. Sedentary behavior and emotional support were each associated with prenatal stress and depressive symptoms in opposite directions, but no moderation effects were revealed. CONCLUSIONS: There was no strong evidence for an association between pandemic exposure and adverse birth outcomes. Furthermore, results highlight the importance of reducing maternal sedentary behavior and encouraging emotional support for optimizing maternal health regardless of pandemic conditions.

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.

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.

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 maternal anthropometrics with newborn anogenital distance and the 2:4 digit ratio.

STUDY QUESTION: Are maternal anthropometrics associated with anogenital distance (AGD) and 2:4 digit ratio (2:4D) in newborns? SUMMARY ANSWER: Select maternal anthropometrics indicative of obesity or increased adiposity are associated with elongated AGD in daughters. WHAT IS KNOWN ALREADY: Excessive maternal weight or adiposity before or in early pregnancy may impact child reproductive, and other hormonally mediated, development. AGD and 2:4D are proposed markers of in utero reproductive development. STUDY DESIGN, SIZE, DURATION: This study includes 450 mother/newborn dyads participating in the Illinois Kids Development Study (I-KIDS), a prospective pregnancy cohort from Champaign-Urbana, IL, USA. Participants included in the current study enrolled between 2013 and 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: Most mothers in this study were college-educated (82%) and non-Hispanic White (80%), and 55% were under- or normal weight before pregnancy. Pregnant women aged 18-40 years reported pre-pregnancy weight and height to calculate pre-pregnancy BMI. At 8-15 weeks gestation, we measured waist and hip circumference, and evaluated weight, % body fat, visceral fat level, % muscle and BMI using bioelectrical impedance analysis. Within 24 h of birth, we measured newborn 2nd and 4th left/right digits to calculate the 2:4D. In daughters, we measured AGDAF (anus to fourchette) and AGDAC (anus to clitoris). In sons, we measured AGDAS (anus to scrotum) and AGDAP (anus to base of the penis). MAIN RESULTS AND THE ROLE OF CHANCE: Select maternal anthropometrics were positively associated with AGD in newborn daughters, but not sons. For example, AGDAC was 0.73 mm (95% CI: 0.15, 1.32) longer for every interquartile range (IQR) increase in pre-pregnancy BMI and 0.88 mm (95% CI: 0.18, 1.58) longer for every IQR increase in hip circumference, whereas AGDAF was 0.51 mm (95% CI: 0.03, 1.00) and 0.56 mm (95% CI: 0.03, 1.09) longer for every IQR increase in hip and waist circumference, respectively. Quartile analyses generally supported linear associations, but additional strong associations emerged in Q4 (versus Q1) of maternal % body fat and visceral fat levels with AGDAC. In quartile analyses, we observed only a few modest associations of maternal anthropometrics with 2:4D, which differed by hand (left versus right) and newborn sex. Although there is always the possibility of spurious findings, the associations for both measures of female AGD were consistent across multiple maternal anthropometric measures, which strengthens our conclusions. LIMITATIONS, REASONS FOR CAUTION: Our study sample was racially and ethnically homogenous, educated and relatively healthy, so our study may not be generalizable to other populations. Additionally, we may not have been powered to identify some sex-specific associations, especially for 2:4D. WIDER IMPLICATIONS OF THE FINDINGS: Increased maternal weight and adiposity before and in early pregnancy may lengthen the female AGD, which warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S): This publication was made possible by the National Institute for Environmental Health Sciences (NIH/NIEHS) grants ES024795 and ES022848, the National Institute of Child Health and Human Development grant R03HD100775, the U.S. Environmental Protection Agency grant RD83543401 and National Institute of Health Office of the Director grant OD023272. Its contents are solely the responsibility of the grantee and do not necessarily represent the official views of the US EPA or NIH. Furthermore, the US EPA does not endorse the purchase of any commercial products or services mentioned in the publication. This project was also supported by the USDA National Institute of Food and Agriculture and Michigan AgBioResearch. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Exposure to Contemporary and Emerging Chemicals in Commerce among Pregnant Women in the United States: The Environmental influences on Child Health Outcome (ECHO) Program.

Prenatal chemical exposures can influence maternal and child health; however, few industrial chemicals are routinely biomonitored. We assessed an extensive panel of contemporary and emerging chemicals in 171 pregnant women across the United States (U.S.) and Puerto Rico in the Environmental influences on Child Health Outcomes (ECHO) Program. We simultaneously measured urinary concentrations of 89 analytes (103 total chemicals representing 73 parent compounds) in nine chemical groups: bactericides, benzophenones, bisphenols, fungicides and herbicides, insecticides, organophosphate esters (OPEs), parabens, phthalates/alternative plasticizers, and polycyclic aromatic hydrocarbons (PAHs). We estimated associations of creatinine-adjusted concentrations with sociodemographic and specimen characteristics. Among our diverse prenatal population (60% non-Hispanic Black or Hispanic), we detected 73 of 89 analytes in ≥1 participant and 36 in >50% of participants. Five analytes not currently included in the U.S. biomonitoring were detected in ≥90% of samples: benzophenone-1, thiamethoxam, mono-2-(propyl-6-carboxy-hexyl) phthalate, monocarboxy isooctyl phthalate, and monohydroxy-iso-decyl phthalate. Many analyte concentrations were higher among women of Hispanic ethnicity compared to those of non-Hispanic White women. Concentrations of certain chemicals decreased with the calendar year, whereas concentrations of their replacements increased. Our largest study to date identified widespread exposures to prevalent and understudied chemicals in a diverse sample of pregnant women in the U.S.

Maternal diet quality moderates associations between parabens and birth outcomes.

BACKGROUND/OBJECTIVE: Maternal paraben exposure and diet quality are both independently associated with birth outcomes, but whether these interact is unknown. We assessed sex-specific associations of parabens with birth outcomes and differences by maternal diet quality. METHODS: Illinois pregnant women (n = 458) provided five first-morning urines collected at 8-40 weeks gestation, which we pooled for quantification of ethylparaben, methylparaben, and propylparaben concentrations. We collected/measured gestational age at delivery, birth weight, body length, and head circumference within 24 h of birth, and calculated sex-specific birth weight-for-gestational-age z-scores and weight/length ratio. Women completed three-month food frequency questionnaires in early and mid-to-late pregnancy, which we used to calculate the Alternative Healthy Eating Index (AHEI)-2010. Linear regression models evaluated sex-specific associations of parabens with birth outcomes, and differences in associations by average pregnancy AHEI-2010. RESULTS: In this predominately non-Hispanic white, college-educated sample, maternal urinary paraben concentrations were only modestly inversely associated with head circumference and gestational length. However, methylparaben and propylparaben were inversely associated with birth weight, birth weight z-scores, body length, and weight/length ratio in female, but not male newborns. For example, each 2-fold increase in methylparaben concentrations was associated with -46.61 g (95% CI: -74.70, -18.51) lower birth weight, -0.09 (95% CI: -0.15, -0.03) lower birth weight z-scores, -0.21 cm (95% CI: -0.34, -0.07) shorter body length, and -0.64 g/cm (95% CI: -1.10, -0.19) smaller weight/length ratio in females. These inverse associations were more prominent in females of mothers with poorer diets (AHEI-2010 < median), but attenuated in those with healthier diets (AHEI-2010 ≥ median). In newborn males of mothers with healthier diets, moderate inverse associations emerged for propylparaben with gestational length and head circumference. CONCLUSIONS: Maternal diet may moderate associations of parabens with birth size in a sex-specific manner. Additional studies may consider understanding the inflammatory and metabolic mechanisms underlying these findings.

Perspectives of peripartum people on opportunities for personal and collective action to reduce exposure to everyday chemicals: Focus groups to inform exposure report-back.

Participants in biomonitoring studies who receive personal exposure reports seek information to reduce exposures. Many chemical exposures are driven by systems-level policies rather than individual actions; therefore, change requires engagement in collective action. Participants' perceptions of collective action and use of report-back to support engagement remain unclear. We conducted virtual focus groups during summer 2020 in a diverse group of peripartum people from cohorts in the Environmental influences on Child Health Outcomes (ECHO) Program (N = 18). We assessed baseline exposure and collective action experience, and report-back preferences. Participants were motivated to protect the health of their families and communities despite significant time and cognitive burdens. They requested time-conscious tactics and accessible information to enable action to reduce individual and collective exposures. Participant input informed the design of digital report-back in the cohorts. This study highlights opportunities to shift responsibility from individuals to policymakers to reduce chemical exposures at the systems level.

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.

A framework for assessing the impact of chemical exposures on neurodevelopment in ECHO: Opportunities and challenges.

The Environmental influences on Child Health Outcomes (ECHO) Program is a research initiative funded by the National Institutes of Health that capitalizes on existing cohort studies to investigate the impact of early life environmental factors on child health and development from infancy through adolescence. In the initial stage of the program, extant data from 70 existing cohort studies are being uploaded to a database that will be publicly available to researchers. This new database will represent an unprecedented opportunity for researchers to combine data across existing cohorts to address associations between prenatal chemical exposures and child neurodevelopment. Data elements collected by ECHO cohorts were determined via a series of surveys administered by the ECHO Data Analysis Center. The most common chemical classes quantified in multiple cohorts include organophosphate pesticides, polychlorinated biphenyls, polybrominated diphenyl ethers, environmental phenols (including bisphenol A), phthalates, and metals. For each of these chemicals, at least four ECHO cohorts also collected behavioral data during infancy/early childhood using the Child Behavior Checklist. For these chemicals and this neurodevelopmental assessment (as an example), existing data from multiple ECHO cohorts could be pooled to address research questions requiring larger sample sizes than previously available. In addition to summarizing the data that will be available, the article also describes some of the challenges inherent in combining existing data across cohorts, as well as the gaps that could be filled by the additional data collection in the ECHO Program going forward.

Endocrine disrupting chemical exposure and maladaptive behavior during adolescence.

BACKGROUND: Studies suggest that exposure to endocrine disrupting chemicals (EDCs), including phthalates, phenols, and parabens may influence childhood behavior, but the relationship during adolescence has not been assessed. OBJECTIVE: We investigated the association between urinary biomarker concentrations of potential EDCs, including some phthalate and bisphenol A replacement chemicals, and behavior in adolescents. METHODS: Participants were from the New Bedford Cohort (NBC), a prospective birth cohort of residents near the New Bedford Harbor Superfund site in Massachusetts. We measured urinary concentrations of 16 phthalate metabolites or replacements, 8 phenols, and 4 parabens in 205 NBC adolescents and estimated associations between select EDCs and adolescent behavior assessed with the Behavior Assessment System for Children, Second Edition -Teacher Rating Scale (BASC-2). Of note, up to 32 of the 205 in our assessment had missing outcome information imputed. RESULTS: Increased urinary concentrations of the sum of 11 antiandrogenic phthalate metabolites were associated with an increase in maladaptive behaviors (Externalizing Behavior, Behavioral Symptoms Index, and Developmental Social Disorders or DSD), and a decrease in Adaptive Skills. For example, a doubling of urinary concentrations of antiandrogenic phthalate metabolites was associated with an increased risk of Externalizing Behavior (RR=1.04; 95% CI: 1.01-1.08). While associations were generally stronger in males, sex differences were not statistically significant. Urine concentrations of phenols and parabens were not associated with adverse behavior. CONCLUSION: Our findings support the importance of exposure to antiandrogenic phthalates during adolescence as a potential correlate of maladaptive behaviors including Externalizing Behavior, DSD behaviors, and decrements in Adaptive Skills.

Licorice root components mimic estrogens in an object location task but not an object recognition task.

This study investigated the efficacy of components of licorice root to alter performance on two different recognition tasks, a hippocampus-sensitive metric change in object location (MCOL) task and a striatum-sensitive double object recognition (DOR) task. Isoliquiritigenin (ISL), licorice root extract (LRE), and whole licorice root powder (LRP) were assessed. Young adult female rats were ovariectomized (OVX) and exposed to ISL, LRE or LRP at 0.075%, 0.5% or 5% respectively in the diet. An estradiol group was included as a positive control based on our prior findings. Rats were allowed to explore two objects for three 5-min study trials (separated by 3-min intervals) before a fourth 5-min test trial where the objects were moved closer together (MCOL task) or replaced with two new objects (DOR task). Rats typically habituate to the objects across the three study trials. An increase in object exploration time in the test trial suggests the rat detected the change. Estradiol improved MCOL performance and impaired DOR performance, similar to previously shown effects of estradiol and other estrogens, which tend to improve learning and memory on hippocampus-sensitive tasks and impair striatum-sensitive cognition. LRP had no effect on recognition while exposure to ISL and LRE improved MCOL performance. Exposure to ISL, LRE and LRP failed to attenuate DOR, contrary to effects of estradiol shown here and to previous reports in young-adult OVX rats. These findings suggest components of licorice root may prove to be effective therapies targeting memory enhancement without unintended deleterious cognitive effects.

Systematic reviews and meta-analyses of human and animal evidence of prenatal diethylhexyl phthalate exposure and changes in male anogenital distance.

Male reproductive alterations found in animals and humans following in utero phthalate exposure include decreased anogenital distance (AGD) and other reproductive-tract malformations. The aim of this investigation was to conduct systematic reviews of human and animal evidence of the effect of in utero exposure to diethylhexyl phthalate (DEHP) on anogenital distance (AGD) in males. PubMed, Embase, and Toxline were searched for relevant human and experimental animal studies on August 15, 2016. Search results were screened for relevance, and studies that met the inclusion criteria were evaluated for quality and data extracted for analysis. Confidence in the human and animal bodies of evidence was assessed and hazard conclusions reached by integrating evidence streams. The search yielded 6 relevant human studies and 19 animal studies. Meta-analysis of 5 human observational prospective cohort studies showed that increased maternal urinary concentrations of DEHP metabolites were associated with decreased AGD in boys (-4.07 [CI, -6.49 to -1.66] % decrease per log10 rise in DEHP metabolites). Meta-analysis and meta-regression of the 19 experimental animal studies found reduced AGD with DEHP treatment, with a dose-response gradient, and with heterogeneity explained by species and strain. There is a moderate level of evidence from human investigations and a high level of data from animal studies that in utero exposure to DEHP decreases AGD. Based upon the available human and animal evidence, and consideration of mechanistic data, DEHP is presumed to be a reproductive hazard to humans on the basis of effects on AGD.

Polybrominated diphenyl ether (PBDE) neurotoxicity: a systematic review and meta-analysis of animal evidence.

A recent systematic review (SR) and meta-analysis of human studies found an association between prenatal serum polybrominated diphenyl ethers (PBDE) concentrations and a decrease in the IQ of children. A SR of experimental developmental animal PBDE-mediated neurotoxicity studies was performed in the present study. Outcomes assessed included measures related to learning, memory, and attention, which parallel the intelligence-related outcomes evaluated in the human studies SR. PubMed, Embase, and Toxline were searched for relevant experimental non-human mammalian studies. Evaluation of risk of bias (RoB) and overall body of evidence followed guidance developed by the National Toxicology Program. Animal studies using varying designs and outcomes were available for BDEs 47, 99, 153, 203, 206, and 209 and the technical mixture DE-71. Study reporting of methods and results was often incomplete leading to concerns regarding RoB. A meta-analysis of 6 Morris water maze studies showed evidence of a significant increase in last trial latency (effect size of 25.8 [CI, 20.3 to 31.2]) in PBDE-exposed animals with low heterogeneity. For most endpoints, there were unexplained inconsistencies across studies and no consistent evidence of a dose-response relationship. There is a "moderate" level of evidence that exposure to BDEs 47, 99, and 209 affects learning. For other PBDEs and other endpoints, the level of evidence was "low" or "very low". The meta-analysis led to stronger conclusions than that based upon a qualitative review of the evidence. The SR also identified RoB concerns that might be remedied by better study reporting.

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.

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.