Exploring autism spectrum disorder (ASD) and attention deficit disorder (ADD/ADHD) in children exposed to polybrominated biphenyl.

Background: Although the causes of attention-deficit/hyperactivity disorder (ADHD) and autism have not been identified, exposure to endocrine-disrupting chemicals, such as polybrominated biphenyl (PBB), during fetal development and early life has been suspected to impact neurological development. This study aims to investigate the association between prenatal and early life exposure to PBB and the development of ADHD and autism later in life. Methods: Data from the Michigan PBB Registry, a cohort of Michigan residents who had been exposed to PBB in a mass contamination event in 1973, was leveraged for this nested case-control analysis among two distinct samples: (1) Those who self-reported ADHD or autism diagnosis, and (2) mothers who reported their child's ADHD or autism diagnosis. PBB exposure was measured in participants of the PBB Registry, and the mother's PBB level was used in mother-reported analyses. Cases were matched with controls by sex and year of birth. Conditional logistic regression models were used to estimate the association between PBB level and case status. Results: PBB levels were higher among those who were exposed in early life compared with those exposed in utero (geometric mean: 0.300 ng/ml vs. 0.016 ng/ml). Among women in this cohort, a higher than expected proportion of self-reported ADHD diagnosis (11.11%), compared with population estimates. PBB was not associated with ADHD or autism in either self-reported or mother-reported analyses. Conclusions: This study adds to the sparse literature about prenatal and early life exposure to PBB-153 and ADHD and autism. Future studies should examine potential effect modification by sex.

Joint Effects of Indoor Air Pollution and Maternal Psychosocial Factors During Pregnancy on Trajectories of Early Childhood Psychopathology.

BACKGROUND: Prenatal indoor air pollution and maternal psychosocial factors have been associated with adverse psychopathology. We used environmental exposure mixture methodology to investigate joint effects of both exposure classes on child behavior trajectories. METHODS: For 360 children from the South African Drakenstein Child Health Study, we created trajectories of Child Behavior Checklist scores (24, 42, 60 months) using latent class linear mixed effects models. Indoor air pollutants and psychosocial factors were measured during pregnancy (2nd trimester). After adjusting for confounding, single-exposure effects (per natural log-1 unit increase) were assessed using polytomous logistic regression models; joint effects using self-organizing maps (SOM), and principal component (PC) analysis. RESULTS: Three trajectories were chosen for both internalizing and externalizing problems, with "high" (externalizing) or "increasing" (internalizing) being the most adverse trajectories. High externalizing trajectory was associated with increased particulate matter (PM10) exposure (OR [95%-CI]: 1.25 [1.01,1.55]) and SOM exposure profile most associated with smoking (2.67 [1.14,6.27]). Medium internalizing trajectory was associated with increased emotional intimate partner violence (2.66 [1.17,5.57]), increasing trajectory with increased benzene (1.24 [1.02,1.51]) and toluene (1.21 [1.02,1.44]) and the PC most correlated with benzene and toluene (1.25 [1.02, 1.54]). CONCLUSIONS: Prenatal exposure to environmental pollutants and psychosocial factors was associated with internalizing and externalizing child behavior trajectories. Understanding joint effects of adverse exposure mixtures will facilitate targeted interventions to prevent childhood psychopathology.

Joint effects of prenatal exposure to indoor air pollution and psychosocial factors on early life inflammation.

It is hypothesized that air pollution and stress impact the central nervous system through neuroinflammatory pathways Despite this, the association between prenatal exposure to indoor air pollution and psychosocial factors on inflammatory markers in infancy has been underexplored in epidemiology studies. This study investigates the individual and joint effects of prenatal exposure to indoor air pollution and psychosocial factors on early life inflammation (interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)). We analyzed data from the South African Drakenstein Child Health Study (N = 225). Indoor air pollution and psychosocial factor measurements were taken in the 2nd trimester of pregnancy. Circulating inflammatory markers (IL-1ß, Il-6, and TNF-α) were measured in serum in the infants at 6 weeks postnatal. Linear regression models were used to investigate associations between individual exposures and inflammatory markers. To investigate joint effects of environmental and psychosocial factors, Self-Organizing Maps (SOM) were used to create exposure profile clusters. These clusters were added to linear regression models to investigate the associations between exposure profiles and inflammatory markers. All models were adjusted for maternal age, maternal HIV status, and ancestry to control for confounding. Most indoor air pollutants were positively associated with inflammatory markers, particularly benzene and TNF-α in single pollutant models. No consistent patterns were found for psychosocial factors in single-exposure linear regression models. In joint effects analyses, the SOM profile with high indoor air pollution, low SES, and high maternal depressive symptoms were associated with higher inflammation. Indoor air pollutants were consistently associated with increased inflammation in both individual and joint effects models, particularly in combination with low SES and maternal depressive symptoms. The trend for individual psychosocial factors was not as clear, with mainly null associations. As we have observed pro- and anti-inflammatory effects, future research should investigate joint effects of these exposures on inflammation and their health effects.

Joint effects of air pollution and neighborhood socioeconomic status on cognitive decline - Mediation by depression, high cholesterol levels, and high blood pressure.

Air pollution and neighborhood socioeconomic status (N-SES) are associated with adverse cardiovascular health and neuropsychiatric functioning in older adults. This study examines the degree to which the joint effects of air pollution and N-SES on the cognitive decline are mediated by high cholesterol levels, high blood pressure (HBP), and depression. In the Emory Healthy Aging Study, 14,390 participants aged 50+ years from Metro Atlanta, GA, were assessed for subjective cognitive decline using the cognitive function instrument (CFI). Information on the prior diagnosis of high cholesterol, HBP, and depression was collected through the Health History Questionnaire. Participants' census tracts were assigned 3-year average concentrations of 12 air pollutants and 16 N-SES characteristics. We used the unsupervised clustering algorithm Self-Organizing Maps (SOM) to create 6 exposure clusters based on the joint distribution of air pollution and N-SES in each census tract. Linear regression analysis was used to estimate the effects of the SOM cluster indicator on CFI, adjusting for age, race/ethnicity, education, and neighborhood residential stability. The proportion of the association mediated by high cholesterol levels, HBP, and depression was calculated by comparing the total and direct effects of SOM clusters on CFI. Depression mediated up to 87 % of the association between SOM clusters and CFI. For example, participants living in the high N-SES and high air pollution cluster had CFI scores 0.05 (95 %-CI:0.01,0.09) points higher on average compared to those from the high N-SES and low air pollution cluster; after adjusting for depression, this association was attenuated to 0.01 (95 %-CI:-0.04,0.05). HBP mediated up to 8 % of the association between SOM clusters and CFI and high cholesterol up to 5 %. Air pollution and N-SES associated cognitive decline was partially mediated by depression. Only a small portion (<10 %) of the association was mediated by HBP and high cholesterol.

In-utero exposure to polybrominated biphenyl (PBB) and menstrual cycle function in adulthood.

BACKGROUND: There is evidence that in-utero exposure to PBBs, and similar chemicals, are associated with several adverse reproductive health outcomes including altered pubertal timing. However, less is known about the effects of in-utero exposure to PBBs on menstrual cycle function and reproductive hormone levels in adulthood. METHODS: For this menstrual cycle study, we recruited reproductive-aged women in the Michigan PBB Registry who were not pregnant, lactating, or taking hormonal medications (2004-2014). A total of 41 women who were born after the PBB contamination incident (1973-1974) and were prenatally exposed to PBBs, were included in this analysis. We estimated in-utero PBB exposure using maternal serum PBB measurements taken after exposure and extrapolated to time of pregnancy using a PBB elimination model. Women were followed for up to 6 months during which they provided daily urine samples and completed daily diaries. The urine samples were assayed for estrone 3-glucuronide (E13G), pregnanediol 3-glucuronide (Pd3G), and follicle stimulating hormone (FSH). RESULTS: Women in our study were, on average, 27.5 (SD:5.3) years old and contributed 4.9 (SD:1.9) menstrual cycles of follow-up. Compared to women with low in-utero PBB exposure (≤1 ppb), women with medium (>1.0-3.0 ppb) and high (>3.0 ppb) exposure had higher maximum 3-day mean Pd3G levels during the luteal phase. Specifically, the age- and creatinine-adjusted maximum 3-day mean luteal phase Pd3G levels (95% CI) in increasing categories of in-utero PBB exposure were 9.2 (4.6,13.9), 14.8 (11.6,18.0), and 16.1 (12.9,19.3) µg/mg creatinine. There were no meaningful differences in average cycle length, follicular or luteal phase cycle length, bleed length, or creatinine-adjusted E13G or FSH levels by category of in-utero PBB exposure. CONCLUSION: Higher exposure to PBB in-utero was associated with increased progesterone levels across the luteal phase, however, most other menstrual cycle characteristics were largely unassociated with in-utero PBB exposure. Given our modest sample size, our results require cautious interpretation.

Polybrominated biphenyls (PBBs) and prevalence of autoimmune disorders among members of the Michigan PBB registry.

BACKGROUND: Polybrominated biphenyls (PBBs), a class of endocrine disrupting chemicals, were the main chemicals present in one of the largest industrial accidents in the United States. We investigated the association between serum PBB-153 levels and autoimmune disorders among members of the Michigan PBB Registry. METHODS: Eight hundred and ninety-five members of the registry had both a serum PBB-153 measurement and had completed one or more questionnaires about autoimmune disorders. Autoimmune disorders were examined collectively and within specific organ systems. Sex-stratified unadjusted and adjusted log-binomial models were used to examine the association between tertiles of serum PBB-153 levels and autoimmune disorders. Models were adjusted by lifestage at exposure (in utero, childhood, adulthood), smoking history (never, past, current), and total serum lipid levels (continuous). We utilized cubic spline models to investigate non-linearity between serum PBB-153 levels and the prevalence of autoimmune disorders. RESULTS: Approximately 12.9% and 20.7% of male and female participants reported having one or more autoimmune disorders, respectively. After adjustment for potential confounders, we observed no association between PBB-153 tertiles and the composite classification of 'any autoimmune disorder' in either sex. We observed some evidence for an association between serum PBB-153 levels and rheumatoid arthritis in males and females; however, this was not statistically significant in females. We also observed some evidence for an association between serum PBB-153 levels and neurological- and thyroid-related autoimmune disorders in females, but again this was not statistically significant. Additionally, we identified dose-response curves for serum PBB-153 levels and the prevalence of autoimmune disorders that differed by lifestage of exposure and sex. CONCLUSIONS: We observed some evidence that increasing serum PBB-153 levels were associated with three specified autoimmune disorders. Studies focusing on these three autoimmune disorders and the potential non-linear trend differences by lifestage of exposure warrant further investigation.

Assessing Metabolic Differences Associated with Exposure to Polybrominated Biphenyl and Polychlorinated Biphenyls in the Michigan PBB Registry.

BACKGROUND: Polybrominated biphenyls (PBB) and polychlorinated biphenyls (PCB) are persistent organic pollutants with potential endocrine-disrupting effects linked to adverse health outcomes. OBJECTIVES: In this study, we utilize high-resolution metabolomics (HRM) to identify internal exposure and biological responses underlying PCB and multigenerational PBB exposure for participants enrolled in the Michigan PBB Registry. METHODS: HRM profiling was conducted on plasma samples collected from 2013 to 2014 from a subset of participants enrolled in the Michigan PBB Registry, including 369 directly exposed individuals (F0) who were alive when PBB mixtures were accidentally introduced into the food chain and 129 participants exposed to PBB in utero or through breastfeeding, if applicable (F1). Metabolome-wide association studies were performed for PBB-153 separately for each generation and ΣPCB (PCB-118, PCB-138, PCB-153, and PCB-180) in the two generations combined, as both had direct PCB exposure. Metabolite and metabolic pathway alterations were evaluated following a well-established untargeted HRM workflow. RESULTS: Mean levels were 1.75 ng/mL [standard deviation (SD): 13.9] for PBB-153 and 1.04 ng/mL (SD: 0.788) for ΣPCB. Sixty-two and 26 metabolic features were significantly associated with PBB-153 in F0 and F1 [false discovery rate (FDR) p<0.2], respectively. There were 2,861 features associated with ΣPCB (FDR p<0.2). Metabolic pathway enrichment analysis using a bioinformatics tool revealed perturbations associated with ΣPCB in numerous oxidative stress and inflammation pathways (e.g., carnitine shuttle, glycosphingolipid, and vitamin B9 metabolism). Metabolic perturbations associated with PBB-153 in F0 were related to oxidative stress (e.g., pentose phosphate and vitamin C metabolism) and in F1 were related to energy production (e.g., pyrimidine, amino sugars, and lysine metabolism). Using authentic chemical standards, we confirmed the chemical identity of 29 metabolites associated with ΣPCB levels (level 1 evidence). CONCLUSIONS: Our results demonstrate that serum PBB-153 is associated with alterations in inflammation and oxidative stress-related pathways, which differed when stratified by generation. We also found that ΣPCB was associated with the downregulation of important neurotransmitters, serotonin, and 4-aminobutanoate. These findings provide novel insights for future investigations of molecular mechanisms underlying PBB and PCB exposure on health. https://doi.org/10.1289/EHP12657.

Sensitive periods for exposure to indoor air pollutants and psychosocial factors in association with symptoms of psychopathology at school-age in a South African birth cohort.

Background: Gestation and the first few months of life are important periods for brain development. During these periods, exposure to environmental toxicants and psychosocial stressors are particularly harmful and may impact brain development. Specifically, exposure to indoor air pollutants (IAP) and psychosocial factors (PF) during these sensitive periods has been shown to predict childhood psychopathology. Objectives: This study aims to investigate sensitive periods for the individual and joint effects of IAP and PF on childhood psychopathology at 6.5 years. Methods: We analyzed data from the Drakenstein Child Health Study (N=599), a South African birth cohort. Exposure to IAP and PF was measured during the second trimester of pregnancy and 4 months postpartum. The outcome of childhood psychopathology was assessed at 6.5 years old using the Childhood Behavior Checklist (CBCL). We investigated individual effects of either pre-or postnatal exposure to IAP and PF on CBCL scores using adjusted linear regression models, and joint effects of these exposures using quantile g-computation and self-organizing maps (SOM). To identify possible sensitive periods, we used a structured life course modeling approach (SLCMA) as well as exposure mixture methods (quantile g-computation and SOM). Results: Prenatal exposure to IAP or PFs, as well as the total prenatal mixture assessed using quantile g-computation, were associated with increased psychopathology. SLCMA and SOM models also indicated that the prenatal period is a sensitive period for IAP exposure on childhood psychopathology. Depression and alcohol were associated in both the pre-and postnatal period, while CO was associated with the postnatal period. Discussion: Pregnancy may be a sensitive period for the effect of indoor air pollution on childhood psychopathology. Exposure to maternal depression and alcohol in both periods was also associated with psychopathology. Determining sensitive periods of exposure is vital to ensure effective interventions to reduce childhood psychopathology.

Joint Effects of Indoor Air Pollution and Maternal Psychosocial Factors During Pregnancy on Trajectories of Early Childhood Psychopathology.

Background: Prenatal indoor air pollution and maternal psychosocial factors have been associated with adverse psychopathology. We used environmental exposure mixture methodology to investigate joint effects of both exposure classes on child behavior trajectories. Methods: For 360 children from the South African Drakenstein Child Health Study, we created trajectories of Child Behavior Checklist scores (24, 42, 60 months) using latent class linear mixed effects models. Indoor air pollutants and psychosocial factors were measured during pregnancy (2 nd trimester). After adjusting for confounding, single-exposure effects (per natural log-1 unit increase) were assessed using polytomous logistic regression models; joint effects using self-organizing maps (SOM), and principal component (PC) analysis. Results: High externalizing trajectory was associated with increased particulate matter (PM 10 ) exposure (OR [95%-CI]: 1.25 [1.01,1.55]) and SOM exposure profile most associated with smoking (2.67 [1.14,6.27]). Medium internalizing trajectory was associated with increased emotional intimate partner violence (2.66 [1.17,5.57]), increasing trajectory with increased benzene (1.24 [1.02,1.51]) and toluene (1.21 [1.02,1.44]) and the PC most correlated with benzene and toluene (1.25 [1.02, 1.54]). Conclusions: Prenatal exposure to environmental pollutants and psychosocial factors was associated with internalizing and externalizing child behavior trajectories. Understanding joint effects of adverse exposure mixtures will facilitate targeted interventions to prevent childhood psychopathology.

Elimination of PBB-153; findings from a cohort of Michigan adults.

BACKGROUND: An industrial accident led to the widespread contamination of polybrominated biphenyl (PBB), a flame retardant, into the food system in Michigan in the 1970's. PBB continues to be detected in Michiganders' blood some forty years later. It is necessary to understand the elimination rate and half-life of PBB because it may provide clues on how to hasten the elimination of it from the human body. METHODS: Serum samples were taken from young adult and adult participants of the Michigan PBB registry from 1974 to 2019. A single compartment model was assumed for the elimination rate for PBB-153 in young adults and adults (≥16 years). Generalized linear mixed models were used to estimate the average elimination rate of PBB-153 and allowed for a random intercept and slope for the time between measurements. Models were adjusted for age at exposure, body mass index (BMI) at initial measurement, and smoking. Models were also stratified by demographic characteristics. RESULTS: In total, 1974 participants contributed 4768 samples over a forty-year span. The median initial PBB-153 level was 1.542 parts per billion (ppb) (Range: 0.001-1442.48 ppb). The adjusted median participant-specific half-life for PBB-153 was 12.23 years. The half-life of PBB-153 was lengthened by higher initial PBB level (∼1.5 years), younger age at exposure (∼5.4 years), higher BMI (∼1.0 years), and increased gravidity (∼7.3 years). Additionally, the half-life of PBB-153 was shortened by smoking status (∼-2.8 years) and breastfeeding (∼-3.5 years). CONCLUSIONS: Consistent with previous studies, PBB-153 has been demonstrated to have a long half-life in the human body and may be modified by some demographic characteristics. These updated estimates of half-life will further support evaluation of health effects associated with PBB exposure. Investigations into mechanisms to accelerate elimination and reduce body burdens of PBB-153, especially those related to body weight, are needed.

Depression and Anxiety Are Associated With Cardiovascular Health in Young Adults.

Background Cardiovascular health (CVH) declines in young adulthood, and mood disorders commonly emerge during this life stage. This study examined the association between depression, anxiety, and CVH metrics among young adults. Methods and Results We conducted a cross-sectional analysis of participants aged 18 to 34 years who completed the Emory Healthy Aging Study Health History Questionnaire (n=875). We classified participants as having poor, intermediate, or ideal levels of the 8 CVH metrics using definitions set forth by the American Heart Association with adaptions when necessary. We defined depression and anxiety as absent, mild, or moderate to severe using standard cutoffs for Patient Health Questionnaire and General Anxiety Disorder scales. We used multivariable regression to examine the association between depression and anxiety and CVH, adjusting for age, sex, race and ethnicity, income, and education. The mean participant age was 28.3 years, and the majority identified as women (724; 82.7%); 129 (14.7%) participants had moderate to severe anxiety, and 128 (14.6%) participants had moderate to severe depression. Compared with those without anxiety, participants with moderate to severe anxiety were less likely to meet ideal levels of physical activity (adjusted prevalence ratio [aPR], 0.60 [95% CI, 0.44-0.82]), smoking (aPR, 0.90 [95% CI, 0.82-0.99]), and body mass index (aPR, 0.79 [95% CI, 0.66-0.95]). Participants with moderate to severe depression were less likely than those without depression to meet ideal levels of physical activity (aPR, 0.48 [95% CI, 0.34-0.69]), body mass index (aPR, 0.75 [95% CI, 0.61-0.91]), sleep (aPR, 0.79 [95% CI, 0.66-0.94]), and blood pressure (aPR, 0.92 [95% CI, 0.86-0.99]). Conclusions Anxiety and depression are associated with less ideal CVH in young adults. Interventions targeting CVH behaviors such as physical activity, diet, and sleep may improve both mood and CVH.

Birth outcomes associated with paternal polybrominated and polychlorinated biphenyl exposure.

In 1973-74, a polybrominated biphenyl (PBB) flame retardant mixture was shipped to Michigan livestock feed mills in place of a nutritional supplement and contaminated the food supply. Following the accident, the Michigan PBB Registry was established to study the long-term health effects of halogenated compounds and is now led by a community-academic partnership. PBB exposure is associated with altered DNA methylation in sperm, which may lead to adverse birth outcomes in children whose fathers have increased levels of serum PBB or polychlorinated biphenyl (PCB). Paternal PBB and PCB levels of men enrolled in the Michigan PBB Registry (n = 155) were analyzed against matched offspring birthweight and gestational age (n = 336). Birthweight and gestational age were dichotomized at the 25th percentile and 37 weeks, respectively, and paternal PBB and PCB levels were examined as continuous measures and divided into tertiles. Associations of offspring birthweight and gestational age with paternal PBB and PCB serum concentrations were modeled using multivariable linear spline and log-risk regression, adjusting for family clustering, paternal health and lifestyle factors, maternal PBB, and PCB serum concentrations, sex, and offspring gestational age (for birthweight). Fathers in the middle and upper PBB and PCB tertiles had increased risks for lowest quartile birthweight compared to the first tertile, with adjusted risk ratios (aRR) = 1.67 (95% CI: 0.93, 2.99) and aRR = 2.06 (95% CI: 1.12, 3.79) for PBB, and aRR = 1.47 (95% CI: 0.79, 2.75) and aRR = 1.34 (95% CI: 0.70, 2.54) for PCB, respectively. Elevated paternal PBB levels were not associated with an increased risk for preterm birth, while PCB levels were associated with a small, but not significant, decrease in gestational age, ß = -0.37 (95% CI: -0.76, 0.03) weeks per log unit increase PCB. The findings suggest that increased paternal PBB and PCB levels negatively impact offspring birthweight, and paternal PCB levels may negatively impact gestational age.

The complex relationship of air pollution and neighborhood socioeconomic status and their association with cognitive decline.

BACKGROUND: Air pollution and neighborhood socioeconomic status (nSES) have been shown to affect cognitive decline in older adults. In previous studies, nSES acts as both a confounder and an effect modifier between air pollution and cognitive decline. OBJECTIVES: This study aims to examine the individual and joint effects of air pollution and nSES on cognitive decline on adults 50 years and older in Metro Atlanta, USA. METHODS: Perceived memory and cognitive decline was assessed in 11,897 participants aged 50+ years from the Emory Healthy Aging Study (EHAS) using the cognitive function instrument (CFI). Three-year average air pollution concentrations for 12 pollutants and 16 nSES characteristics were matched to participants using census tracts. Individual exposure linear regression and LASSO models explore individual exposure effects. Environmental mixture modeling methods including, self-organizing maps (SOM), Bayesian kernel machine regression (BKMR), and quantile-based G-computation explore joint effects, and effect modification between air pollutants and nSES characteristics on cognitive decline. RESULTS: Participants living in areas with higher air pollution concentrations and lower nSES experienced higher CFI scores (beta: 0.121; 95 % CI: 0.076, 0.167) compared to participants living in areas with low air pollution and high nSES. Additionally, the BKMR model showed a significant overall mixture effect on cognitive decline, suggesting synergy between air pollution and nSES. These joint effects explain protective effects observed in single-pollutant linear regression models, even after adjustment for confounding by nSES (e.g., an IQR increase in CO was associated with a 0.038-point lower (95 % CI: -0.06, -0.01) CFI score). DISCUSSION: Observed protective effects of single air pollutants on cognitive decline can be explained by joint effects and effect modification of air pollutants and nSES. Researchers must consider nSES as an effect modifier if not a co-exposure to better understand the complex relationships between air pollution and nSES in urban settings.

Neighborhood characteristics as confounders and effect modifiers for the association between air pollution exposure and subjective cognitive functioning.

BACKGROUND: Air pollution has been associated with cognitive function in the elderly. Previous studies have not evaluated the simultaneous effect of neighborhood-level socioeconomic status (N-SES), which can be an essential source of bias. OBJECTIVES: We explored N-SES as a confounder and effect modifier in a cross-sectional study of air pollution and subjective cognitive function. METHODS: We included 12,058 participants age 50+ years from the Emory Healthy Aging Study in Metro Atlanta using the Cognitive Function Instrument (CFI) score as our outcome, with higher scores representing worse subjective cognitive function. We estimated 9-year average ambient carbon monoxide (CO), nitrogen oxides (NOx), and fine particulate matter (PM2.5) concentrations at residential addresses using a fusion of dispersion and chemical transport models. We collected census-tract level N-SES indicators and created two composite measures via principal component analysis and k-means clustering. Associations between pollutants and CFI and effect modification by N-SES were estimated via linear regression models adjusted for age, education, race and N-SES. RESULTS: N-SES confounded the association between air pollution and CFI, independent of individual characteristics. We found significant effect modifications by N-SES for the association between air pollution and CFI (p-values<0.001) suggesting that effects of air pollution differ depending on N-SES. Participants living in areas with low N-SES were most vulnerable to air pollution. In the lowest N-SES urban areas, interquartile range (IQR) increases in CO, NOx, and PM2.5 were associated with 5.4% (95%-confidence interval, -0.2,11.3), 4.9% (-0.4,10.4), and 9.8% (2.2,18.0) changes in CFI, respectively. In lowest N-SES suburban areas, IQR increases in CO, NOx, and PM2.5 were associated with higher changes in CFI, namely 13.0% (0.9,26.5), 13.0% (-0.1,27.8), and 17.3% (2.5,34.2), respectively. DISCUSSION: N-SES is an important confounder and effect modifier in our study. This finding could have implications for studying health effects of air pollution and identifying susceptible populations.

The association between alcohol intake and fecundability during menstrual cycle phases.

STUDY QUESTION: Is increased alcohol intake in different phases of the menstrual cycle associated with fecundability in women? SUMMARY ANSWER: Heavy intake (>6 drinks/week) of alcoholic beverages in the luteal phase and ovulatory subphase was associated with reduced odds of conception; moderate intake (3-6 drinks/week) during the luteal phase was also associated with reduced fecundability. WHAT IS KNOWN ALREADY: Despite strong indications for increased risk of infertility among drinking women with intention to conceive, inconsistencies in previous results point to possible residual confounding, and have not thoroughly investigated timing of drinking and other drinking patterns during the menstrual cycle. STUDY DESIGN, SIZE, DURATION: Participants in The Mount Sinai Study of Women Office Workers (MSSWOW), a prospective cohort study of fertility, were recruited and followed between 1990 and 1994, and completed daily diaries reporting their alcohol intake (type and number of drinks) for a maximum of 19 months of follow-up (N = 413). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were between 19 and 41 years of age. After completion of baseline surveys, they were asked to record their alcoholic beverage intake as number of drinks of beer, wine, and liquor per day, in addition to other exposures such as caffeine and smoking. Furthermore, they submitted urine samples each month to assess pregnancy. Menstrual cycle phases were calculated using the Knaus-Ognio approach. Discrete survival analysis methods were employed to estimate the association between categories of alcohol intake in each phase of menstrual cycle and fecundability. MAIN RESULTS AND THE ROLE OF CHANCE: In the luteal phase, both moderate drinking (3-6 drinks/week, Fecundability Odds Ratio (FOR)=0.56, CI: 0.31, 0.98) and heavy drinking (>6 drinks/week, FOR = 0.51, CI: 0.29, 0.89) were associated with a reduction in fecundability, compared to non-drinkers. For the follicular phase, heavy drinking in the ovulatory sub-phase (FOR = 0.39, CI: 0.19, 0.72) was similarly associated with reduced fecundability, compared to non-drinkers. For the pre-ovulatory sub-phase, heavy drinking (>6 drinks/week, FOR = 0.54, CI: 0.29, 0.97) was associated with reduction in fecundability, but this association was inconsistent when subjected to sensitivity tests. Each extra day of binge drinking was associated with 19% (FOR = 0.81, CI: 0.63, 0.98), and 41% (FOR = 0.59, CI: 0.33, 0.93) reduction in fecundability for the luteal phase and ovulatory sub-phase respectively, but no association was observed in the pre-ovulatory sub-phase. No meaningful differences in fecundability between beverages were observed in any menstrual phase. LIMITATIONS, REASONS FOR CAUTION: Patterns of alcohol intake in this cohort suggest a lower average alcohol intake compared to more recent national averages for the same demographic group. Sample sizes were small for some subgroups, resulting in limited power to examine specific beverage types in different phases of the menstrual cycle, or to assess interaction. In addition, the influence of male partner alcohol intake was not assessed, the data relied on self-report, and residual confounding (e.g. unmeasured behaviors correlated with alcohol intake) is a possibility. WIDER IMPLICATIONS OF THE FINDINGS: Results suggest an inverse association between alcohol and fecundability, and support the relevance of menstrual cycle phases in this link. More specifically, moderate to heavy drinking during the luteal phase, and heavy drinking in the ovulatory window, could disturb the delicate sequence of hormonal events, affecting chances of a successful conception. STUDY FUNDING/COMPETING INTEREST(S): Authors declare no conflict of interest. This work was supported by the National Institutes of Health grant, R01-HD24618. TRIAL REGISTRATION NUMBER: N/A.

Association Between Business Travel, Health-Related Behaviors, and Adiposity.

OBJECTIVE: To evaluate the associations between frequency of business travel and health behaviors and adiposity. METHODS: Retrospective cross-sectional analysis of de-identified electronic medical records from 795 corporate physical exams. RESULTS: Business travel frequency demonstrates a curvilinear relationship with body mass index and body composition in men and women, with domestic and international travel. Linear and quadratic term beta coefficients indicate stronger associations between the sum of domestic and international travel and BMI, body fat percentage, and visceral adipose tissue in women than men, after accounting for age, exercise, and sleep. Based on our male sample population, international travel frequency has a greater influence on adiposity than summed (mostly domestic) travel. CONCLUSIONS: Frequent business travel adversely affects body composition, with differences by gender and type of travel.

Urinary and salivary endocrine measurements to complement Tanner staging in studies of pubertal development.

BACKGROUND: Many studies investigating pubertal development use Tanner staging to assess maturation. Endocrine markers in urine and saliva may provide an objective, sensitive, and non-invasive method for assessing development. OBJECTIVE: Our objective was to examine whether changes in endocrine levels can indicate the onset of pubertal development prior to changes in self-rated Tanner stage. METHODS: Thirty-five girls and 42 boys aged 7 to 15 years were enrolled in the Growth and Puberty (GAP) study, a longitudinal pilot study conducted from 2007-2009 involving children of women enrolled in the Agricultural Health Study (AHS) in Iowa. We collected saliva and urine samples and assessed pubertal development by self-rated Tanner staging (pubic hair, breast development (girls), genital development (boys)) at three visits over six months. We measured dehydroepiandrosterone (DHEA) in saliva and creatinine-adjusted luteinizing hormone (LH), testosterone, follicle stimulating hormone (FSH), estrone 3-glucuronide (E13G) and pregnanediol 3-glucuronide (Pd3G) concentrations in first morning urine. We evaluated the relationships over time between Tanner stage and each biomarker using repeated measures analysis. RESULTS: Among girls still reporting Tanner breast stage 1 at the final visit, FSH levels increased over the 6-month follow-up period and were no longer lower than higher stage girls at the end of follow-up. We observed a similar pattern for testosterone in boys. By visit 3, boys still reporting Tanner genital stage 1 or pubic hair stage 1 had attained DHEA levels that were comparable to those among boys reporting Tanner stages 2 or 3. CONCLUSIONS: Increasing concentrations of FSH in girls and DHEA and testosterone in boys over a 6-month period revealed the start of the pubertal process prior to changes in self-rated Tanner stage. Repeated, non-invasive endocrine measures may complement the more subjective assessment of physical markers in studies determining pubertal onset.

Prenatal exposure to mixtures of persistent endocrine disrupting chemicals and early menarche in a population-based cohort of British girls.

Exposure to endocrine disrupting chemicals (EDCs) is ubiquitous. EDC exposure, especially during critical periods of development like the prenatal window, may interfere with the body's endocrine system, which can affect growth and developmental outcomes such as puberty. Most studies have examined one EDC at a time in relation to disease; however, humans are exposed to many EDCs. By studying mixtures, the human experience can be more closely replicated. We investigated the association of prenatal exposure to persistent EDCs (poly- and perfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), and organochlorine pesticides (OCPs)) as mixtures with early menarche among female offspring in a nested case-control study within the Avon Longitudinal Study of Parents and Children (ALSPAC) recruited in the United Kingdom in 1991-1992. Concentrations of 52 EDCs were quantified in maternal serum samples collected during pregnancy. Daughter's age at menarche was ascertained through mailed questionnaires sent annually. We used repeated holdout weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) to examine the association between prenatal exposure to multiple EDCs and early menarche (<11.5 (n = 218) vs. ≥11.5 years (n = 230)) for each chemical class separately (PFAS, PCBs, and OCPs) and for all three classes combined. Models adjusted for maternal age at menarche, maternal education, parity, pre-pregnancy body mass index, maternal age, prenatal smoking, and gestational week at sample collection. Mixture models showed null associations between prenatal exposure to EDC mixtures and early menarche. Using WQS regression, the odds ratio for early menarche for a one-decile increase in chemical concentrations for all three classes combined was 0.89 (95% CI: 0.76, 1.05); using BKMR, the odds ratio when all exposures were at the 60th percentile compared to the median was 0.98 (95% CI: 0.91, 1.05). Results suggest the overall effect of prenatal exposure to persistent EDC mixtures is not associated with early menarche.

Genome-wide DNA methylation differences and polychlorinated biphenyl (PCB) exposure in a US population.

Exposure to polychlorinated biphenyls (PCBs), an endocrine-disrupting compound, is ubiquitous despite decades-old bans on the manufacture and use of PCBs. Increased exposure to PCBs is associated with adverse health consequences throughout life, including type 2 diabetes and cancer. PCB exposure is also associated with alterations in epigenetic marks and gene transcription, which could lead to adverse health outcomes, but many of these are population-specific. To further investigate the association between PCB and epigenetic marks, DNA methylation was measured at 787,684 CpG sites in 641 peripheral blood samples from the Michigan Polybrominated Biphenyl (PBB) Registry. 1345 CpGs were associated with increased total PCB level after controlling for age, sex, and 24 surrogate variables (FDR < 0.05). These CpGs were enriched in active promoter and transcription associated regions (p < 0.05), and in regions around the binding sites for transcription factors involved in xenobiotic metabolism and immune function (FDR < 0.05). PCB exposure also associated with proportions of CD4T, NK, and granulocyte cell types, and with the neutrophil to lymphocyte ratio (NLR) (p < 0.05), and the estimated effect sizes of PCB on the epigenome were correlated with the effect sizes previously reported in an epigenome-wide study of C-reactive protein (r = 0.29; p = 2.22e-5), supporting previous studies on the association between PCB and immune dysfunction. These results indicate that PCB exposure is associated with differences in epigenetic marks in active regions of the genome, and future work should investigate whether these may mediate the association between PCB and health consequences.

Sex-specific DNA methylation differences in people exposed to polybrominated biphenyl.

Aim: Michigan residents were exposed to polybrominated biphenyls (PBBs) when it was accidentally added to the food supply. Highly exposed individuals report sex-specific health problems, but the underlying biological mechanism behind these different health risks is not known. Materials and methods: DNA methylation in blood from 381 women and 277 men with PBB exposure was analyzed with the MethylationEPIC BeadChip. Results: 675 CpGs were associated with PBBs levels in males, while only 17 CpGs were associated in females (false discovery rate <0.05). No CpGs were associated in both sexes. These CpGs were enriched in different functional regions and transcription factor binding sites in each sex. Conclusion: Exposure to PBBs may have sex-specific effects on the epigenome that may underlie sex-specific adverse health outcomes.