Urinary metabolite concentrations of phthalate and plasticizers in infancy and childhood in the UNC baby connectome project.

INTRODUCTION: Existing evidence suggests that exposure to phthalates is higher among younger age groups. However, limited knowledge exists on how phthalate exposure, as well as exposure to replacement plasticizers, di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) and di-2-ethylhexyl terephthalate (DEHTP), change from infancy through early childhood. METHODS: Urine samples were collected across the first 5 years of life from typically developing infants and young children enrolled between 2017 and 2020 in the longitudinal UNC Baby Connectome Project. From 438 urine samples among 187 participants, we quantified concentrations of monobutyl phthalate (MnBP), mono-3-carboxypropyl phthalate (MCPP), monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), and metabolites of di(2-ethylhexyl) phthalate (DEHP), diisonoyl phthalate (DiNP), DINCH and DEHTP. Specific gravity (SG) adjusted metabolite and molar sum concentrations were compared across age groups. Intraclass correlation coefficients (ICCs) were calculated among 122 participants with multiple urine specimens (373 samples). RESULTS: Most phthalate metabolites showed high detection frequencies (>80% of samples). Replacement plasticizers DINCH (58-60%) and DEHTP (>97%) were also commonly found. DiNP metabolites were less frequently detected (<10%). For some metabolites, SG-adjusted concentrations were inversely associated with age, with the highest concentrations found in the first year of life. ICCs revealed low to moderate reliability in metabolite measurements (ρ = 0.10-0.48) suggesting a high degree of within-individual variation in exposure among this age group. The first 6 months (compared to remaining age groups) showed an increased ratio of carboxylated metabolites of DEHP and DEHTP, compared to other common metabolites, but no clear age trends for DINCH metabolite ratios were observed. CONCLUSION: Metabolites of phthalates and replacements plasticizers were widely detected in infancy and early childhood, with the highest concentrations observed in the first year of life for several metabolites. Higher proportions of carboxylated metabolites of DEHP and DEHTP in younger age groups indicate potential differences in metabolism during infancy.

Family history of immune conditions and autism spectrum and developmental disorders: Findings from the study to explore early development.

Numerous studies have reported immune system disturbances in individuals with autism and their family members; however, there is considerable variability in findings with respect to the specific immune conditions involved, their timing, and the family members affected and little understanding of variation by autism subphenotype. Using data from the Study to Explore Early Development (SEED), a multi-site case-control study of children born 2003-2006 in the United States, we examined the role of family history of autoimmune diseases, asthma, and allergies in autism spectrum disorder (ASD) as well as other developmental disorders (DD). We investigated maternal immune conditions during the pregnancy period, as well as lifetime history of these conditions in several family members (mother, father, siblings, and study child). Logistic regression analyses included 663 children with ASD, 984 children with DD, and 915 controls ascertained from the general population (POP). Maternal history of eczema/psoriasis and asthma was associated with a 20%-40% increased odds of both ASD and DD. Risk estimates varied by specific ASD subphenotypes in association with these exposures. In addition, children with ASD were more likely to have a history of psoriasis/eczema or allergies than POP controls. No association was observed for paternal history or family history of these immune conditions for either ASD or DD. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes, and further suggest that associations may differ by ASD phenotype of the child. Autism Research 2019, 12: 123-135. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Using data from a large multi-site study in the US-the Study to Explore Early Development-we found that women with a history of eczema/psoriasis and asthma are more likely to have children with ASD or DD. In addition, children with ASD are more likely to have a history of psoriasis/eczema or allergies than typically developing children. These data support a link between maternal and child immune conditions and adverse neurodevelopmental outcomes.

Maternal Plasma Concentrations of Per- and polyfluoroalkyl Substances and Breastfeeding Duration in the Norwegian Mother and Child Cohort.

BACKGROUND: Per- and polyfluoroalkyl substances (PFASs) have been widely produced, many of them persist in the environment, and have been associated with various health effects. Previous studies have identified inverse associations between perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS) and breastfeeding duration, but have been limited in investigation of other PFASs. METHODS: We measured the associations between plasma concentrations of 9 different PFASs and cessation of breastfeeding before 3 and 6 complete months using women from the Norwegian Mother and Child Cohort Study (MoBa). The study population includes 1716 primarily nulliparous women from two previous studies of MoBa participants, enrolled from 2003-2007. The association was measured using Cox proportional hazards model. Mixtures analyses were performed using Elastic net regularization to identify interactive effects and control for co-pollutant confounding. RESULTS: Concentrations of PFASs in this population were lower than concentrations in the previous studies on this topic. We found associations between increasing concentrations of perfluorononanoic acid (PFNA), perfluorodecaconic acid (PFDA), perfluoroundecanoic acid (PFUnDA) and decreased breastfeeding cessation (increased duration). The strongest associations were seen between PFDA and PFUnDA and cessation before 3 months: (both hazard ratios = 0.73, 95% confidence intervals: 0.62, 0.86). In our population, the other PFASs appeared to be unassociated with breastfeeding cessation. The mixtures analyses identified meaningful interactions between PFUnDA:PFDA, perfluorohexane sulfonate (PFHXS):PFOA and PFOA:PFOS. CONCLUSIONS: The identification of associations between previously unexamined PFASs concentrations and increased breastfeeding duration is novel and may be explained by differences in transplacental transfer rates.

Bayesian Correction for Exposure Misclassification and Evolution of Evidence in Two Studies of the Association Between Maternal Occupational Exposure to Asthmagens and Risk of Autism Spectrum Disorder.

PURPOSE OF REVIEW: Inference in epidemiologic studies is plagued by exposure misclassification. Several methods exist to correct for misclassification error. One approach is to use point estimates for the sensitivity (Sn) and specificity (Sp) of the tool used for exposure assessment. Unfortunately, we typically do not know the Sn and Sp with certainty. Bayesian methods for exposure misclassification correction allow us to model this uncertainty via distributions for Sn and Sp. These methods have been applied in epidemiologic literature, but are not considered a mainstream approach, especially in occupational epidemiology. RECENT FINDINGS: Here, we illustrate an occupational epidemiology application of a Bayesian approach to correct for the differential misclassification error generated by estimating occupational exposures from job codes using a job exposure matrix (JEM). We argue that analyses accounting for exposure misclassification should become more commonplace in the literature.

Menstrual cycle characteristics as determinants of plasma concentrations of perfluoroalkyl substances (PFASs) in the Norwegian Mother and Child Cohort (MoBa study).

INTRODUCTION: Perfluoroalkyl substances (PFASs) are fluorinated organic compounds that have been used in a variety of industrial and consumer applications. Menstruation is implicated as a possible route of elimination for PFASs in women. The overall purpose of this study was to examine menstrual cycle characteristics as determinants of plasma PFAS concentrations in women. METHODS: Our study sample consisted of 1977 pregnant women from the Norwegian Mother and Child Cohort (MoBa) study. The women were asked about menstrual cycle regularity in the year before the pregnancy and typical menstrual cycle length as well as other demographic and reproductive characteristics in a questionnaire completed during the pregnancy. Blood samples were collected around 17-18 weeks gestation and PFAS concentrations were measured in plasma. We examined the association between menstrual cycle characteristics and seven PFASs (perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), and perfluorooctane sulfonate (PFOS)) using multiple linear regression, adjusted for age, pre-pregnancy body mass index, smoking, education, income, parity, oral contraceptive use, inter-pregnancy interval, and breastfeeding duration. RESULTS: Irregular cycles were not associated with PFAS concentrations. Overall, we found no evidence of associations between menstrual cycle length and PFAS concentrations. In subgroup analyses we found some evidence, among parous women, of decreased PFHpS and PFOS with short menstrual cycles; we also found, among recent OC users (in the 12 months before the questionnaire) increased PFNA and PFUnDA with long cycle length. Limitations of our study include misclassification of menstrual cycle characteristics, small sample sizes in the sub-group analyses, and a lack of information on duration and volume of menses. CONCLUSIONS: In the entire study sample, we found little evidence of menstrual cycle characteristics as determinants of PFAS concentrations. However, we observed some associations between cycle length and PFAS concentrations with some select PFAS compounds in subgroup analyses.

Oral contraceptive use as a determinant of plasma concentrations of perfluoroalkyl substances among women in the Norwegian Mother and Child Cohort (MoBa) study.

OBJECTIVE: Because oral contraceptives (OC) tends to lessen menstrual fluid loss - a route of excretion for perfluoroalkyl substances (PFASs) - we hypothesized that such use would be positively associated with PFAS concentrations. METHODS: This analysis was based on the Norwegian Mother and Child Cohort (MoBa) study. We included 1090 women from two previous substudies of women enrolled from 2003 to 2007. Characteristics of OC use were obtained at baseline: use in the past 12months, duration and recency of use, age at first use. We examined log-transformed plasma concentrations of seven PFASs (perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), and perfluorooctane sulfonate (PFOS)). Linear regression analyses, adjusted for maternal age, menstrual cycle length, parity, and education, were used to examine whether OC use characteristics were determinants of PFAS concentrations. RESULTS: Except for PFDA and PFUnDA, women who used OCs in the 12months preceding the baseline interview had 12.9-35.7% higher PFAS concentrations than never OC users. To a lesser extent, past OC use was positively associated with PFASs (estimates ranged from 7.2-32.1%). Compared with never users, using OCs for 10 or more years was associated with increased PFAS concentrations, except for PFDA and PFUnDA (estimates for other PFASs ranged from 18.9-46.2%). We observed little effect of age at first OC use. CONCLUSIONS: This analysis shows that characteristics of OC use, and duration of use in particular, may be important considerations when investigating relationships between women's reproductive outcomes and PFASs.

Prenatal Alcohol Exposure in Relation to Autism Spectrum Disorder: Findings from the Study to Explore Early Development (SEED).

BACKGROUND: Prenatal alcohol exposure can affect neurodevelopment, but few studies have examined associations with autism spectrum disorder (ASD). METHODS: We assessed the association between maternal alcohol use and ASD in the Study to Explore Early Development, a multi-site case-control study of children born between September 2003 and August 2006 in the US Regression analyses included 684 children with research clinician-confirmed ASD, 869 children with non-ASD developmental delays or disorders (DDs), and 962 controls ascertained from the general population (POP). Maternal alcohol exposure during each month from 3 months prior to conception until delivery was assessed by self-report. RESULTS: Mothers of POP children were more likely to report any prenatal alcohol use than mothers of children with ASD or DD. In trimester one, 21.2% of mothers of POP children reported alcohol use compared with 18.1% and 18.2% of mothers of children with ASD or DD, respectively (adjusted OR for ASD vs. POP 0.8, 95% confidence interval 0.6, 1.1). During preconception and the first month of pregnancy, one to two drinks on average per week was inversely associated with ASD risk. CONCLUSIONS: These results do not support an adverse association between low-level alcohol exposure and ASD, although these findings were based on retrospective self-reported alcohol use. Unmeasured confounding or exposure misclassification may explain inverse associations with one to two drinks per week. Pregnant or potentially pregnant women should continue to follow recommendations to avoid alcohol use because of other known effects on infant health and neurodevelopment.

Prenatal phthalate exposures and child temperament at 12 and 24 months.

INTRODUCTION: Gestational phthalate exposures have been adversely associated with attention, externalizing, and internalizing behaviors in childhood. Early childhood temperament may be a marker of later behavioral patterns. We therefore sought to determine whether gestational phthalate exposures were associated with infant and toddler temperament. METHODS: The Mount Sinai Children's Environmental Health Study is a prospective cohort study of children born between May 1998 and July 2001 in New York City (N=404). Phthalate metabolites were measured in spot urine samples collected from pregnant women in their third trimester. Child temperament was assessed by parental report at 12-months using the Infant Behavior Questionnaire (IBQ) (N=204) and at 24-months using the Toddler Behavior Assessment Questionnaire (TBAQ) (N=279). We used multiple linear regression to evaluate associations between urinary phthalate metabolites and eleven temperament domains. RESULTS: Phthalate biomarker concentrations were weakly associated with lower gross motor activity levels as well as higher duration of orienting at the 12-month assessment. Mono(3-carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP) and the sum of metabolites of di(2-ethylhexyl) phthalate (∑DEHP) were associated with lower levels of smiling and laughing at 12 months. At 24-months, social fear and lower pleasure was linked to higher concentrations of MCPP and MBzP, and higher ∑DEHP was weakly associated with increased anger levels at 24-months. CONCLUSIONS: Though we observed some weak associations between biomarkers of prenatal exposure to phthalates and temperament at 12- and 24-months, overall phthalates biomarkers were not strongly associated with alterations in temperament.

Parental exposures to occupational asthmagens and risk of autism spectrum disorder in a Danish population-based case-control study.

BACKGROUND: Environmental exposures and immune conditions during pregnancy could influence development of autism spectrum disorder (ASD) in offspring. However, few studies have examined immune-triggering exposures in relation to ASD. We evaluated the association between parental workplace exposures to risk factors for asthma ("asthmagens") and ASD. METHODS: We conducted a population-based case-control study in the Danish population using register linkage. Our study population consisted of 11,869 ASD cases and 48,046 controls born from 1993 through 2007. Cases were identified by ICD-10 codes in the Danish Psychiatric Central Register. ASD cases and controls were linked to parental Danish International Standard Classification of Occupations (DISCO-88) job codes. Parental occupational asthmagen exposure was estimated by linking DISCO-88 codes to an asthma-specific job-exposure matrix. RESULTS: Our maternal analyses included 6706 case mothers and 29,359 control mothers employed during the pregnancy period. We found a weak inverse association between ASD and any maternal occupational asthmagen exposure, adjusting for sociodemographic covariates (adjusted OR: 0.92, 95% CI: 0.86-0.99). In adjusted analyses, including 7647 cases and 31,947 controls with employed fathers, paternal occupational asthmagen exposure was not associated with ASD (adjusted OR: 0.98, 95% CI: 0.92-1.05). CONCLUSIONS: We found a weak inverse association between maternal occupational asthmagen exposure and ASD, and a null association between paternal occupational exposure and ASD. We suggest that unmeasured confounding negatively biased the estimate, but that this unmeasured confounding is likely not strong enough to bring the effect above the null. Overall, our results were consistent with no positive association between parental asthmagen exposure and ASD in the children.

Maternal Exposure to Occupational Asthmagens During Pregnancy and Autism Spectrum Disorder in the Study to Explore Early Development.

Maternal immune activity has been linked to children with autism spectrum disorder (ASD). We examined maternal occupational exposure to asthma-causing agents during pregnancy in relation to ASD risk. Our sample included 463 ASD cases and 710 general population controls from the Study to Explore Early Development whose mothers reported at least one job during pregnancy. Asthmagen exposure was estimated from a published job-exposure matrix. The adjusted odds ratio for ASD comparing asthmagen-exposed to unexposed was 1.39 (95 % CI 0.96-2.02). Maternal workplace asthmagen exposure was not associated with ASD risk in this study, but this result does not exclude some involvement of maternal exposure to asthma-causing agents in ASD.

Demographic profile of families and children in the Study to Explore Early Development (SEED): Case-control study of autism spectrum disorder.

BACKGROUND: The Study to Explore Early Development (SEED) is designed to enhance knowledge of autism spectrum disorder characteristics and etiologies. OBJECTIVE: This paper describes the demographic profile of enrolled families and examines sociodemographic differences between children with autism spectrum disorder and children with other developmental problems or who are typically developing. METHODS: This multi-site case-control study used health, education, and birth certificate records to identify and enroll children aged 2-5 years into one of three groups: 1) cases (children with autism spectrum disorder), 2) developmental delay or disorder controls, or 3) general population controls. Study group classification was based on sampling source, prior diagnoses, and study screening tests and developmental evaluations. The child's primary caregiver provided demographic characteristics through a telephone (or occasionally face-to-face) interview. Groups were compared using ANOVA, chi-squared test, or multinomial logistic regression as appropriate. RESULTS: Of 2768 study children, sizeable proportions were born to mothers of non-White race (31.7%), Hispanic ethnicity (11.4%), and foreign birth (17.6%); 33.0% of households had incomes below the US median. The autism spectrum disorder and population control groups differed significantly on nearly all sociodemographic parameters. In contrast, the autism spectrum disorder and developmental delay or disorder groups had generally similar sociodemographic characteristics. CONCLUSIONS: SEED enrolled a sociodemographically diverse sample, which will allow further, in-depth exploration of sociodemographic differences between study groups and provide novel opportunities to explore sociodemographic influences on etiologic risk factor associations with autism spectrum disorder and phenotypic subtypes.

Beyond crosswalks: reliability of exposure assessment following automated coding of free-text job descriptions for occupational epidemiology.

Epidemiologists typically collect narrative descriptions of occupational histories because these are less prone than self-reported exposures to recall bias of exposure to a specific hazard. However, the task of coding these narratives can be daunting and prohibitively time-consuming in some settings. The aim of this manuscript is to evaluate the performance of a computer algorithm to translate the narrative description of occupational codes into standard classification of jobs (2010 Standard Occupational Classification) in an epidemiological context. The fundamental question we address is whether exposure assignment resulting from manual (presumed gold standard) coding of the narratives is materially different from that arising from the application of automated coding. We pursued our work through three motivating examples: assessment of physical demands in Women's Health Initiative observational study, evaluation of predictors of exposure to coal tar pitch volatiles in the US Occupational Safety and Health Administration's (OSHA) Integrated Management Information System, and assessment of exposure to agents known to cause occupational asthma in a pregnancy cohort. In these diverse settings, we demonstrate that automated coding of occupations results in assignment of exposures that are in reasonable agreement with results that can be obtained through manual coding. The correlation between physical demand scores based on manual and automated job classification schemes was reasonable (r = 0.5). The agreement between predictive probability of exceeding the OSHA's permissible exposure level for polycyclic aromatic hydrocarbons, using coal tar pitch volatiles as a surrogate, based on manual and automated coding of jobs was modest (Kendall rank correlation = 0.29). In the case of binary assignment of exposure to asthmagens, we observed that fair to excellent agreement in classifications can be reached, depending on presence of ambiguity in assigned job classification (κ = 0.5-0.8). Thus, the success of automated coding appears to depend on the setting and type of exposure that is being assessed. Our overall recommendation is that automated translation of short narrative descriptions of jobs for exposure assessment is feasible in some settings and essential for large cohorts, especially if combined with manual coding to both assess reliability of coding and to further refine the coding algorithm.

An inducible nuclear body in the Drosophila germinal vesicle.

When living egg chambers of Drosophila are isolated in a saline solution and gently squashed between a microscope slide and coverslip, prominent nuclear bodies (1 - 20 mm diameter) can be seen inside the oocyte nucleus or germinal vesicle (GV).  These bodies do not pre-exist within the GV and are not seen in material that is fixed in paraformaldehyde before squashing.  Instead, they form spontaneously within minutes after an egg chamber is damaged and the cytoplasm is exposed to the isolation medium.  Electron microscopy shows that the bodies lack an investing membrane and consist of closely packed, irregular particles 30-50 nm in diameter.  We used GFP-tagged proteins from the Carnegie Protein Trap Library to identify 22 proteins that are either enriched in the bodies or excluded from them.  We were unable to discern common features of proteins that are concentrated in the bodies, such as isoelectric point, molecular weight, or biological process.  Induced bodies are formed in GVs of flies that are null for coilin or WDR79, proteins that are required for formation of Cajal bodies (CBs).  We performed fluorescence recovery after photobleaching (FRAP) experiments on five GFP-tagged proteins that are enriched in the bodies.  Four of the proteins regained the full pre-bleach fluorescence intensity, indicating that the contents of the bodies are in dynamic equilibrium with the surrounding nucleoplasm.  Induced nuclear bodies presumably form as a result of unusual physico-chemical changes in the Drosophila GV.  We suggest that their behavior serves as a useful model for self-assembly of nuclear bodies in general, and we discuss the possibility that similar bodies may occur normally in cells of other organisms.