Tablet-Based Cognitive and Eye Movement Measures as Accessible Tools for Schizophrenia Assessment: Multisite Usability Study.

BACKGROUND: Schizophrenia is a complex mental disorder characterized by significant cognitive and neurobiological alterations. Impairments in cognitive function and eye movement have been known to be promising biomarkers for schizophrenia. However, cognitive assessment methods require specialized expertise. To date, data on simplified measurement tools for assessing both cognitive function and eye movement in patients with schizophrenia are lacking. OBJECTIVE: This study aims to assess the efficacy of a novel tablet-based platform combining cognitive and eye movement measures for classifying schizophrenia. METHODS: Forty-four patients with schizophrenia, 67 healthy controls, and 41 patients with other psychiatric diagnoses participated in this study from 10 sites across Japan. A free-viewing eye movement task and 2 cognitive assessment tools (Codebreaker task from the THINC-integrated tool and the CognitiveFunctionTest app) were used for conducting assessments in a 12.9-inch iPad Pro. We performed comparative group and logistic regression analyses for evaluating the diagnostic efficacy of the 3 measures of interest. RESULTS: Cognitive and eye movement measures differed significantly between patients with schizophrenia and healthy controls (all 3 measures; P<.001). The Codebreaker task showed the highest classification effectiveness in distinguishing schizophrenia with an area under the receiver operating characteristic curve of 0.90. Combining cognitive and eye movement measures further improved accuracy with a maximum area under the receiver operating characteristic curve of 0.94. Cognitive measures were more effective in differentiating patients with schizophrenia from healthy controls, whereas eye movement measures better differentiated schizophrenia from other psychiatric conditions. CONCLUSIONS: This multisite study demonstrates the feasibility and effectiveness of a tablet-based app for assessing cognitive functioning and eye movements in patients with schizophrenia. Our results suggest the potential of tablet-based assessments of cognitive function and eye movement as simple and accessible evaluation tools, which may be useful for future clinical implementation.

An adverse outcome pathway-based approach to assess the neurotoxicity by combined exposure to current-use pesticides.

Exposure to multiple pesticides in daily life has become an important public health concern. However, the combined effects of pesticide mixtures have not been fully elucidated by the conventional toxicological testing used for individual chemicals. Grouping of chemicals by mode of action using common key events (KEs) in the adverse outcome pathway (AOP) as endpoints could be applied for efficient risk assessment of combined exposure to multiple chemicals. The purpose of this study was to investigate whether exposure to multiple pesticides has synergistic neurotoxic effects on mammalian nervous systems. According to the AOP-based approach, we evaluated the effects of 10 current-use pesticides (4 neonicotinoids, 4 pyrethroids and 2 phenylpyrazoles) on the common KEs in AOPs for neurotoxicity, such as KEs involving mitochondrial and proteolytic functions, in a mammalian neuronal cell model. Our data showed that several pyrethroids and phenylpyrazoles partly shared the effects on several common KEs, including decreases in mitochondrial membrane potential and proteasome activity and increases in autophagy activity. Furthermore, we also found that combined exposure to a type-I pyrethroid permethrin or a type-II pyrethroid deltamethrin and the phenylpyrazole fipronil decreased the cell viability and the benchmark doses much more than either single exposure, indicating that the pair exhibited synergistic effects, since the combination indexes were less than 1. These findings revealed that novel pairs of different classes of pesticides with similar effects on common KEs exhibited synergistic neurotoxicity and provide new insights into the risk assessment of combined exposure to multiple chemicals.

Combined effect of anthracene and polyethylene microplastics on swimming speed and cytochrome P4501A monooxygenase expression of Java medaka (Oryzias javanicus).

Microplastics have been detected in a variety of aquatic ecosystems, and the combined effect of microplastics and chemical pollutants has become a matter of increasing concern. We conducted a 12-d co-exposure test of anthracene and spherical or fragmented polyethylene microplastics (size 200 µm) on Java medaka (Oryzias javanicus). The accumulation of anthracene in Java medaka muscle reached a plateau on day 5 in all anthracene exposure groups, and no significant differences were detected among the groups (ANT, 20.4 ± 5.5; ANT + SPPE-MP, 24.7 ± 2.7; ANT + FRPE-MP, 24.6 ± 4.7 µg/g). However, co-exposure to anthracene and spherical or fragmented polyethylene microplastics increased the duration of slow swimming in a swimming behavior test (control, 4.1 ± 1.4; ANT, 5.2 ± 2.8; ANT + SPPE-MP, 12.4 ± 3.7; ANT + FRPE-MP, 17.4 ± 5.1 min/30 min), and co-exposure to anthracene and fragmented polyethylene microplastics induced higher cytochrome P4501A monooxygenase (CYP1A) expression in Java medaka livers than the other anthracene exposure groups (ANT, 189 ± 74; ANT + SPPE-MP, 203 ± 75; ANT + FRPE-MP 272 ± 36% of control). Polyethylene microplastics appear to be weak vectors of anthracene at the size tested (200 µm), and the effect of shape (spherical or fragmented) on the vector effect was small. However, the presence of polyethylene microplastics could affect the swimming behavior and CYP1A expression in Java medaka.

Size effect of polystyrene microplastics on the accumulation of anthracene for Java medaka (Oryzias javanicus).

Pollution by microplastics in aquatic ecosystems is a worldwide problem, and the role of microplastics as vectors of pollutants has been a concern. Although small microplastics are thought to have a greater effect than large microplastics as vectors of pollutants, the impact of the size of microplastics on their ability to serve as vectors of pollutants has not been quantified. In this study, we conducted the 14-day experiment (7 days of exposure and 7 days of depuration) with polystyrene microplastics (2-µm or 10-µm diameter) and anthracene. On the last day of the exposure period, the concentration of anthracene in the muscle of Java medaka exposed to both anthracene and 2-µm polystyrene microplastics was the highest (47.4 ± 15.2 µg/g-muscle) of any group, followed by the group exposed to both anthracene and 10-µm polystyrene microplastics (23.0 ± 4.2 µg/g-muscle) and the group exposed to only anthracene (11.2 ± 2.2 µg/g-muscle). These results demonstrated that the size of microplastics was a critical determinant of their ability to serve as vectors of anthracene. The concentrations of anthracene and fine microplastics in the environment are sufficiently low that the effect of microplastics as vectors of anthracene may be observed only under experimental conditions that are unlikely to occur in the present environment. However, because pollution by plastics is expected to become more serious in the future, careful thought and proactive action will be needed to ensure that the impact of microplastics as vectors of pollutants does not become demonstrable under future environmental conditions.

Differences in microplastic degradation in the atmosphere and coastal water environment from two island nations: Japan and New Zealand.

Microplastics are subject to environmental forces that can change polymer organization on a molecular scale. However, it is not clear to what extent these changes occur in the environment and whether microplastics in the atmospheric and water environment differ. Here we identify structural differences between microplastics in the atmosphere and water environment from Japan and New Zealand, representing two archipelagos differing in their proximity to nearby countries and highly populated areas. We first highlight the propensity for smaller microplastics to arrive via air masses from the Asian continent to the Japan Sea coastal area, while New Zealand received larger, locally derived microplastics. Analyses of polyethylene in the Japanese atmosphere indicate that microplastics transported to the Japanese coastal areas were more crystalline than polyethylene particles in the water, suggesting that the plastics arriving by air were relatively more aged and brittle. By contrast, polypropylene particles in New Zealand waters were more degraded than the microplastic particles in the air. Due to the lack of abundance, both polyethylene and polypropylene could not be analyzed for both countries. Nevertheless, these findings show the structural variation in microplastics between environments in markedly different real-world locations, with implications for the toxic potential of these particles.

The Validation of Automated Social Skills Training in Members of the General Population Over 4 Weeks: Comparative Study.

BACKGROUND: Social skills training by human trainers is a well-established method of teaching appropriate social and communication skills and strengthening social self-efficacy. Specifically, human social skills training is a fundamental approach to teaching and learning the rules of social interaction. However, it is cost-ineffective and offers low accessibility, since the number of professional trainers is limited. A conversational agent is a system that can communicate with a human being in a natural language. We proposed to overcome the limitations of current social skills training with conversational agents. Our system is capable of speech recognition, response selection, and speech synthesis and can also generate nonverbal behaviors. We developed a system that incorporated automated social skills training that completely adheres to the training model of Bellack et al through a conversational agent. OBJECTIVE: This study aimed to validate the training effect of a conversational agent-based social skills training system in members of the general population during a 4-week training session. We compare 2 groups (with and without training) and hypothesize that the trained group's social skills will improve. Furthermore, this study sought to clarify the effect size for future larger-scale evaluations, including a much larger group of different social pathological phenomena. METHODS: For the experiment, 26 healthy Japanese participants were separated into 2 groups, where we hypothesized that group 1 (system trained) will make greater improvement than group 2 (nontrained). System training was done as a 4-week intervention where the participants visit the examination room every week. Each training session included social skills training with a conversational agent for 3 basic skills. We evaluated the training effect using questionnaires in pre- and posttraining evaluations. In addition to the questionnaires, we conducted a performance test that required the social cognition and expression of participants in new role-play scenarios. Blind ratings by third-party trainers were made by watching recorded role-play videos. A nonparametric Wilcoxson Rank Sum test was performed for each variable. Improvement between pre- and posttraining evaluations was used to compare the 2 groups. Moreover, we compared the statistical significance from the questionnaires and ratings between the 2 groups. RESULTS: Of the 26 recruited participants, 18 completed this experiment: 9 in group 1 and 9 in group 2. Those in group 1 achieved significant improvement in generalized self-efficacy (P=.02; effect size r=0.53). We also found a significant decrease in state anxiety presence (P=.04; r=0.49), measured by the State-Trait Anxiety Inventory (STAI). For ratings by third-party trainers, speech clarity was significantly strengthened in group 1 (P=.03; r=0.30). CONCLUSIONS: Our findings reveal the usefulness of the automated social skills training after a 4-week training period. This study confirms a large effect size between groups on generalized self-efficacy, state anxiety presence, and speech clarity.

Hydroxylated benzo[c]phenanthrene metabolites cause osteoblast apoptosis and skeletal abnormalities in fish.

To study the toxicity of 3-hydroxybenzo[c]phenanthrene (3-OHBcP), a metabolite of benzo[c]phenanthrene (BcP), first we compared it with its parent compound, BcP, using an in ovo-nanoinjection method in Japanese medaka. Second, we examined the influence of 3-OHBcP on bone metabolism using goldfish. Third, the detailed mechanism of 3-OHBcP on bone metabolism was investigated using zebrafish and goldfish. The LC50s of BcP and 3-OHBcP in Japanese medaka were 5.7 nM and 0.003 nM, respectively, indicating that the metabolite was more than 1900 times as toxic as the parent compound. In addition, nanoinjected 3-OHBcP (0.001 nM) induced skeletal abnormalities. Therefore, fish scales with both osteoblasts and osteoclasts on the calcified bone matrix were examined to investigate the mechanisms of 3-OHBcP toxicity on bone metabolism. We found that scale regeneration in the BcP-injected goldfish was significantly inhibited as compared with that in control goldfish. Furthermore, 3-OHBcP was detected in the bile of BcP-injected goldfish, indicating that 3-OHBcP metabolized from BcP inhibited scale regeneration. Subsequently, the toxicity of BcP and 3-OHBcP to osteoblasts was examined using an in vitro assay with regenerating scales. The osteoblastic activity in the 3-OHBcP (10-10 to 10-7 M)-treated scales was significantly suppressed, while BcP (10-11 to 10-7 M)-treated scales did not affect osteoblastic activity. Osteoclastic activity was unchanged by either BcP or 3-OHBcP treatment at each concentration (10-11 to 10-7 M). The detailed toxicity of 3-OHBcP (10-9 M) in osteoblasts was then examined using gene expression analysis on a global scale with fish scales. Eight genes, including APAF1, CHEK2, and FOS, which are associated with apoptosis, were identified from the upregulated genes. This indicated that 3-OHBcP treatment induced apoptosis in fish scales. In situ detection of cell death by TUNEL methods was supported by gene expression analysis. This study is the first to demonstrate that 3-OHBcP, a metabolite of BcP, has greater toxicity than the parent compound, BcP.

Prenatal environmental tobacco smoke exposure alters children's cognitive control circuitry: A preliminary study.

BACKGROUND AND OBJECTIVES: Prenatal exposure to environmental tobacco smoke (ETS) is associated with increased attention problems in children, however, the effects of such exposure on children's brain structure and function have not been studied. Herein, we probed effects of prenatal ETS on children's cognitive control circuitry and behavior. METHODS: Forty-one children (7-9 years) recruited from a prospective longitudinal birth cohort of non-smoking mothers completed structural and task-functional magnetic resonance imaging to evaluate effects of maternal ETS exposure, measured by maternal prenatal urinary cotinine. Attention problems and externalizing behaviors were measured by parent report on the Child Behavior Checklist. RESULTS: Compared to non-exposed children, exposed children had smaller left and right thalamic and inferior frontal gyrus (IFG) volumes, with large effect sizes (p-FDR < .05, Cohen's D range from 0.79 to 1.07), and increased activation in IFG during the resolution of cognitive conflict measured with the Simon Spatial Incompatibility Task (38 voxels; peak t(25) = 5.25, p-FWE = .005). Reduced thalamic volume was associated with increased IFG activation and attention problems, reflecting poor cognitive control. Mediation analyses showed a trend toward left thalamic volume mediating the association between exposure and attention problems (p = .05). CONCLUSIONS: Our findings suggest that maternal ETS exposure during pregnancy has deleterious effects on the structure and function of cognitive control circuitry which in turn affects attentional capacity in school-age children. These findings are consistent with prior findings documenting the effects of active maternal smoking on chidlren's neurodevleoment, pointing to the neurotixicity of nicotine regardless of exposure pathway.

Correlation between Polycyclic Aromatic Hydrocarbons in Wharf Roach (Ligia spp.) and Environmental Components of the Intertidal and Supralittoral Zone along the Japanese Coast.

Polycyclic aromatic hydrocarbon (PAH) concentrations in wharf roach (Ligia spp.), as an environmental indicator, and in environmental components of the intertidal and supralittoral zones were determined, and the PAH exposure pathways in wharf roach were estimated. Wharf roaches, mussels, and environmental media (water, soil and sand, and drifting seaweed) were collected from 12 sites in Japan along coastal areas of the Sea of Japan. PAH concentrations in wharf roaches were higher than those in mussels (median total of 15 PAHs: 48.5 and 39.9 ng/g-dry weight (dw), respectively) except for samples from Ishikawa (wharf roach: 47.9 ng/g-dw; mussel: 132 ng/g-dw). The highest total PAH concentration in wharf roach was from Akita (96.0 ng/g-dw), followed by a sample from Niigata (85.2 ng/g-dw). Diagnostic ratio analysis showed that nearly all PAHs in soil and sand were of petrogenic origin. Based on a correlation analysis of PAH concentrations between wharf roach and the environmental components, wharf roach exposure to three- and four-ring PAHs was likely from food (drifting seaweed) and from soil and sand, whereas exposure to four- and five-ring PAHs was from several environmental components. These findings suggest that the wharf roach can be used to monitor PAH pollution in the supralittoral zone and in the intertidal zone.

Oral administration of melatonin contained in drinking water increased bone strength in naturally aged mice.

Melatonin has recently been found to be a possible new regulator of bone metabolism. However, the influence of melatonin in natural age-related osteoporosis has not been fully elucidated yet, although there have been some reports regarding postmenopausal osteoporosis with melatonin treatments. The present study investigated the effects of long-term melatonin administration during the aging process on bone metabolism. Using quantitative computed tomography methods, we found that the total bone density of both the femur metaphysis and diaphysis decreased significantly in 20-month-old male mice. In the metaphysis, both trabecular bone mass and Polar-Strength Strain Index (SSI), which is an index of bone strength, decreased significantly. Judging from bone histomorphometry analysis, trabecular bone in 20-month-old male mice decreases significantly with age and is small and sparse, as compared to that of 4-month-old male mice. Loss of trabecular bone is one possible cause of loss of bone strength in the femoral bone. In the metaphysis, the melatonin administration group had significantly higher trabecular bone density than the non-administration group. The Polar-SSI, cortical area, and periosteal circumference in the diaphysis was also significantly higher with melatonin treatments. Since the melatonin receptor, MT2, was detected in both osteoblasts and osteoclasts of the femoral bone of male mice, we expect that melatonin acts on osteoblasts and osteoclasts to maintain the bone strength of the diaphysis and metaphysis. Thus, melatonin is a potential drug for natural age-related osteoporosis.

Exposure to per- and polyfluorinated alkyl substances in pregnant Brazilian women and its association with fetal growth.

Research pertaining to exposure of humans to per- and polyfluorinated alkyl substances (PFASs) has received considerable public and regulatory attention in recent years. Although several studies have reported exposure to PFASs by populations in North America and western Europe, such information is still scarce in Latin America, including Brazil. In this study, concentrations of thirteen PFASs were determined in whole blood collected during the second trimester from 252 pregnant Brazilian women. This is a nested case-control study within the Brazilian Ribeirao Preto and Sao Luiz Birth Cohort Study (BRISA) with selected birth outcomes cases (n = 63) and matched controls (n = 189). PFASs concentrations were associated with conditions including preeclampsia, birth weight (BW), preterm birth, and intrauterine growth restriction (IUGR). Among PFASs measured, perfluorooctane sulfonate (PFOS) was found at the highest concentration (range: 1.06-106 ng mL-1 with a median value of 3.41 ng mL-1) which was followed by perfluorooctanoic acid (PFOA, range: 0.11-2.77 ng mL-1 with a median value of 0.20 ng mL-1). A significant positive association of PFOS and PFOA concentrations with fetal growth restriction (p < 0.05) was found. This is the first study to assess whole blood concentrations of PFASs and their effect on fetal growth in pregnant Brazilian women.

Toxicities of Polycyclic Aromatic Hydrocarbons for Aquatic Animals.

Polycyclic aromatic hydrocarbons (PAHs) are organic compounds that are widely distributed in the air, water, and soil. Recently, the amount of PAHs derived from fuels and from incomplete combustion processes is increasing. In the aquatic environment, oil spills directly cause PAH pollution and affect marine organisms. Oil spills correlate very well with the major shipping routes. Furthermore, accidental oil spills can seriously impact the marine environment toxicologically. Here, we describe PAH toxicities and related bioaccumulation properties in aquatic animals, including invertebrates. Recent studies have revealed the toxicity of PAHs, including endocrine disruption and tissue-specific toxicity, although researchers have mainly focused on the carcinogenic toxicity of PAHs. We summarize the toxicity of PAHs regarding these aspects. Additionally, the bioaccumulation properties of PAHs for organisms, including invertebrates, are important factors when considering PAH toxicity. In this review, we describe the bioaccumulation properties of PAHs in aquatic animals. Recently, microplastics have been the most concerning environmental problem in the aquatic ecosystem, and the vector effect of microplastics for lipophilic compounds is an emerging environmental issue. Here, we describe the correlation between PAHs and microplastics. Thus, we concluded that PAHs have a toxicity for aquatic animals, indicating that we should emphasize the prevention of aquatic PAH pollution.

Persistent organic pollutants and gestational diabetes: A multi-center prospective cohort study of healthy US women.

BACKGROUND: Persistent organic pollutants (POPs) are linked with insulin resistance and type-2 diabetes (T2D) in the general population. However, their associations with gestational diabetes (GDM) are inconsistent. OBJECTIVE: We prospectively evaluated the associations of POPs measured in early pregnancy with GDM risk. We also assessed whether pre-pregnancy BMI (ppBMI) and family history of T2D modify this risk. METHODS: In NICHD Fetal Growth Study, Singletons, we measured plasma concentration of 76 POPs, including 11 organochlorine pesticides (OCPs), 9 polybrominated diphenylethers (PBDEs), 44 polychlorinated biphenyls (PCBs), and 11 per-and polyfluoroalkyl substances (PFAS) among 2334 healthy non-obese women at 8-13 weeks of gestation. GDM was diagnosed by Carpenter and Coustan criteria. We constructed chemical networks using a weighted-correlation algorithm and examined the associations of individual chemical and chemical networks with GDM using multivariate Poisson regression with robust variance. RESULTS: Higher concentrations of PCBs with six or more chlorine atoms were associated with increased risk of GDM in the overall cohort (risk ratios [RRs] range: 1.08-1.13 per 1-standard deviation [SD] increment) and among women with a family history of T2D (RRs range: 1.08-1.48 per 1-SD increment) or normal ppBMI (RRs range: 1.08-1.22 per 1-SD increment). Similar associations were observed for the chemical network comprised of PCBs with ≥6 chlorine atoms and the summary measure of total PCBs and non-dioxin like PCBs (138, 153, 170, 180). Furthermore, four PFAS congeners - perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluoroheptanoic acid (PFHpA), and perfluorododecanoic acid (PFDoDA) - showed significant positive associations with GDM among women with a family history of T2D (RRs range:1.22-3.18 per 1-SD increment), whereas BDE47 and BDE153 showed significant positive associations among women without a family history of T2D. CONCLUSIONS: Environmentally relevant levels of heavily chlorinated PCBs and some PFAS and PBDEs were positively associated with GDM with suggestive effect modifications by family history of T2D and body adiposity status.

Preconception seminal plasma concentrations of endocrine disrupting chemicals in relation to semen quality parameters among male partners planning for pregnancy.

BACKGROUND: Some non-persistent endocrine disruptors (EDCs) are adversely associated with semen quality and few studies have measured those EDCs in seminal plasma. OBJECTIVE: To find an association between EDCs in seminal plasma and semen quality parameters. METHODS: Five chemical classes of non-persistent EDCs were quantified in seminal plasma from 339 male partners who participated in a prospective pregnancy study. Bisphenols, benzophenone UV-filters, antimicrobials and phthalate diesters and their monoester metabolites were measured using high performance liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Semen samples underwent next day analysis using a standardized protocol for the quantification of 35 endpoints. Linear mixed-effects models of EDCs that were log transformed and rescaled by their standard deviations or dichotomized at the 75th percentile for each exposure and outcomes with covariate adjustment were performed. EDCs in seminal plasma were also assessed relative to clinical reference values of semen quality endpoints using logistic regression or generalized estimating equations. RESULTS: The most consistent findings supporting adverse associations between seminal EDCs and semen quality were observed for some phthalate metabolites. For example, seminal plasma mono-ethyl, mono-n-butyl, mono-2-isobutyl and mono-benzyl phthalate concentrations were associated with decreased odds of having semen volume above clinical reference values (mEP: aOR=0.46; 95%CI= 0.32, 0.66; mBP: aOR=0.40; 95%CI= 0.28, 0.57; miBP: aOR=0.39; 95%CI= 0.27, 0.56), and mBzP: aOR= 0.34; 95%CI= 0.24, 0.49). CONCLUSIONS: Environmentally relevant concentrations of specific phthalates in seminal plasma were associated with diminished semen volume, sperm motility, viability, and morphological alterations in sperm heads such that semen volume and sperm viability fall below reference values.

Endocrine disruptors and neonatal anthropometry, NICHD Fetal Growth Studies - Singletons.

BACKGROUND: Intrauterine exposure to endocrine disrupting chemicals (EDCs) has been equivocally associated with birth weight, length and head circumference with limited attention to anthropometric endpoints such as umbilical circumference and limb lengths. OBJECTIVE: To explore 76 prenatal maternal plasma EDC concentrations in a healthy obstetric cohort and 7 neonatal anthropometric endpoints by maternal race/ethnicity. METHODS: The study cohort comprised 2106 (564 White, 549 Black, 590 Hispanic, 403 Asian) healthy pregnant women recruited from 12 U.S. clinical sites between 2009 and 2012 who were followed through delivery. Neonates underwent standardized anthropometric assessment (weight, length, head and umbilical circumference, and mid- upper arm and thigh length). Plasma EDC concentrations were quantified using high resolution gas chromatography-high resolution mass spectrometry and liquid chromatography-tandem mass spectrometry. EDCs were log-transformed and rescaled by their deviations (SD) when modeled relative to neonatal endpoints using linear regression adjusting for age, education, pre-pregnancy body mass index (BMI), serum cotinine, serum lipids for lipophilic chemicals, and a race/ethnicity interaction term; p-values had false discovery rate correction (<0.05). RESULTS: The cohort comprised women aged 28 (SD = 5) years with normal BMIs (23.6 kg/m2, SD = 3). Maternal EDC concentrations varied by self-identified race/ethnicity and neonatal outcomes, though no specific EDC was consistently associated with neonatal anthropometric outcomes across racial/ethnic groups. For the overall cohort, perfluorooctanoic acid was negatively associated with birth length per SD increase in concentration (ß = -0.23 cm; 95% CI -0.35, -0.10), while perfluorohexanesulfonic acid was negatively associated with umbilical circumference (ß = -0.26 cm; 95% CI -0.40, -0.13), perfluorodecanoic acid with arm length (-0.09 cm; 95% CI -0.14, -0.04), and PCBs congeners 118/106 (-0.12 cm; 95% CI -0.20, -0.04) and 146/161 (-0.14 cm; 95% CI -0.23, -0.05) with thigh length, as were 7 other poly-and-perfluorinated alkyl substances (PFASs). CONCLUSIONS: Among healthy pregnant women with low risk antenatal profiles and relatively low EDC concentrations, reductions in umbilical circumference and bone lengths may be a sensitive marker of intrauterine EDC exposure, particularly for PFAS.

Advanced data mining approaches in the assessment of urinary concentrations of bisphenols, chlorophenols, parabens and benzophenones in Brazilian children and their association to DNA damage.

Human exposure to endocrine disrupting chemicals (EDCs) has received considerable attention over the last three decades. However, little is known about the influence of co-exposure to multiple EDCs on effect-biomarkers such as oxidative stress in Brazilian children. In this study, concentrations of 40 EDCs were determined in urine samples collected from 300 Brazilian children of ages 6-14 years and data were analyzed by advanced data mining techniques. Oxidative DNA damage was evaluated from the urinary concentrations of 8-hydroxy-2'-deoxyguanosine (8OHDG). Fourteen EDCs, including bisphenol A (BPA), methyl paraben (MeP), ethyl paraben (EtP), propyl paraben (PrP), 3,4-dihydroxy benzoic acid (3,4-DHB), methyl-protocatechuic acid (OH-MeP), ethyl-protocatechuic acid (OH-EtP), triclosan (TCS), triclocarban (TCC), 2-hydroxy-4-methoxybenzophenone (BP3), 2,4-dihydroxybenzophenone (BP1), bisphenol A bis(2,3-dihydroxypropyl) glycidyl ether (BADGE·2H2O), 2,4-dichlorophenol (2,4-DCP), and 2,5-dichlorophenol (2,5-DCP) were found in >50% of the urine samples analyzed. The highest geometric mean concentrations were found for MeP (43.1 ng/mL), PrP (3.12 ng/mL), 3,4-DHB (42.2 ng/mL), TCS (8.26 ng/mL), BP3 (3.71 ng/mL), and BP1 (4.85 ng/mL), and exposures to most of which were associated with personal care product (PCP) use. Statistically significant associations were found between urinary concentrations of 8OHDG and BPA, MeP, 3,4-DHB, OH-MeP, OH-EtP, TCS, BP3, 2,4-DCP, and 2,5-DCP. After clustering the data on the basis of i) 14 EDCs (exposure levels), ii) demography (age, gender and geographic location), and iii) 8OHDG (effect), two distinct clusters of samples were identified. 8OHDG concentration was the most critical parameter that differentiated the two clusters, followed by OH-EtP. When 8OHDG was removed from the dataset, predictability of exposure variables increased in the order of: OH-EtP > OH-MeP > 3,4-DHB > BPA > 2,4-DCP > MeP > TCS > EtP > BP1 > 2,5-DCP. Our results showed that co-exposure to OH-EtP, OH-MeP, 3,4-DHB, BPA, 2,4-DCP, MeP, TCS, EtP, BP1, and 2,5-DCP was associated with DNA damage in children. This is the first study to report exposure of Brazilian children to a wide range of EDCs and the data mining approach further strengthened our findings of chemical co-exposures and biomarkers of effect.

Parabens in human urine from several Asian countries, Greece, and the United States.

Parabens, esters of para-hydroxybenzoic acid, are commonly used as antimicrobial preservatives in cosmetics and personal care products. Although several studies report exposure of humans to parabens in Western countries, little is known about exposure of humans to parabens in Asian countries. In this study, we determined concentrations of six parabens in spot urine samples collected from nine countries and estimated daily intakes (DI) and potential health risks of parabens. Ethyl-paraben, methyl-paraben, and propyl-paraben were detected frequently at 100, 98.0, and 80.3%, respectively, with representative median concentrations of 0.68, 7.02, and 1.21 ng/mL, respectively, for all nine countries. Urine samples from females (total median concentration: 32.3 ng/mL) contained significantly higher concentrations of parabens than did those from males (5.46 ng/mL). Urine samples from Korea (total median paraben concentration: 227 ng/mL) had the highest concentrations, which were one to two orders of magnitude higher than those found in other countries (3.67-29.1 ng/mL). The estimated DI of parabens (on the basis of concentrations measured in urine) varied widely, and several samples had propyl-paraben exposures above the acceptable DI. Our results suggest that paraben exposure is ubiquitous in Asian countries, and further assessment of potential health risk of these chemicals is needed.

Male urinary biomarkers of antimicrobial exposure and bi-directional associations with semen quality parameters.

Antimicrobials including parabens, triclosan, and triclocarban have endocrine disrupting properties. Among 501 male partners of couples planning to become pregnant, preconception urinary biomarkers of parabens, triclosan and triclocarban exposure were quantified in spot urine samples. Men also provided two fresh semen samples collected approximately one month to undergo 24-h semen quality analysis. Linear mixed-effects models, adjusted for creatinine, race, age and body mass index, were utilized to assess the relationship between log transformed chemical concentrations rescaled by their standard deviations and semen parameters. Methyl, ethyl and butyl parabens, were associated with diminished sperm count and several sperm motility parameters. Hydroxylated paraben metabolites and triclosan were significantly positively associated with select semen quality parameters. Overall, our findings suggest that specific urinary parabens found in consumer goods (methyl, ethyl and butyl parabens) may adversely impact sperm quality parameters among reproductive-age male partners of couples trying for pregnancy.

Endocrine disrupting chemicals in seminal plasma and couple fecundity.

Growing evidence supports the importance of men's exposure to non-persistent endocrine disruptors (EDCs) and couple fecundability, as measured by time-to-pregnancy (TTP). This evolving literature contrasts with the largely equivocal findings reported for women's exposures and fecundity. While most evidence relies upon urinary concentrations, quantification of EDCs in seminal plasma may be more informative about potential toxicity arising within the testes. We analyzed 5 chemical classes of non-persistent EDCs in seminal plasma for 339 male partners of couples who were recruited prior to conception and who were followed daily until pregnant or after one year of trying. Benzophenones, bisphenols, parabens, and phthalate metabolites and phthalate diesters were measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) except for phthalate diesters, which were analyzed using gas chromatography-mass spectrometry. Cox regression with discrete-time was used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs) for each chemical to estimate the probability of pregnancy. While most EDCs were detected in seminal plasma, concentrations were lower than urinary concentrations previously analyzed for the cohort. None of the EDCs were significantly associated with fecundability even after covariate adjustment, though benzophenones consistently yielded FORs <1.0 (ranging from 0.72 to 0.91) in couple-adjusted models suggestive of diminished fecundity (longer TTP). The findings underscore that a range of EDCs can be quantified in seminal plasma, but the lower concentrations may require a large cohort for assessing couple fecundability, as well as the need to consider other fecundity outcomes such as semen quality.