Modeling environment through a general exposome factor in two independent adolescent cohorts.

Exposures to perinatal, familial, social, and physical environmental stimuli can have substantial effects on human development. We aimed to generate a single measure that capture's the complex network structure of the environment (ie, exposome) using multi-level data (participant's report, parent report, and geocoded measures) of environmental exposures (primarily from the psychosocial environment) in two independent adolescent cohorts: The Adolescent Brain Cognitive Development Study (ABCD Study, N = 11 235; mean age, 10.9 years; 47.7% females) and an age- and sex-matched sample from the Philadelphia Neurodevelopmental Cohort (PNC, N = 4993). We conducted a series of data-driven iterative factor analyses and bifactor modeling in the ABCD Study, reducing dimensionality from 348 variables tapping to environment to six orthogonal exposome subfactors and a general (adverse) exposome factor. The general exposome factor was associated with overall psychopathology (B = 0.28, 95% CI, 0.26-0.3) and key health-related outcomes: obesity (odds ratio [OR] , 1.4; 95% CI, 1.3-1.5) and advanced pubertal development (OR, 1.3; 95% CI, 1.2-1.5). A similar approach in PNC reduced dimensionality of environment from 29 variables to 4 exposome subfactors and a general exposome factor. PNC analyses yielded consistent associations of the general exposome factor with psychopathology (B = 0.15; 95% CI, 0.13-0.17), obesity (OR, 1.4; 95% CI, 1.3-1.6), and advanced pubertal development (OR, 1.3; 95% CI, 1-1.6). In both cohorts, inclusion of exposome factors greatly increased variance explained in overall psychopathology compared with models relying solely on demographics and parental education (from <4% to >38% in ABCD; from <4% to >18.5% in PNC). Findings suggest that a general exposome factor capturing multi-level environmental exposures can be derived and can consistently explain variance in youth's mental and general health.

Ascertainment Bias in a Historic Cohort Study of Residents in an Asbestos Manufacturing Community.

This paper describes follow-up for a cohort of 4530 residents living in the asbestos manufacturing community of Ambler, PA, U.S. in 1930. Using re-identified census data, cause and date of death data obtained from the genealogic website Ancestry.com, along with geospatial analysis, we explored relationships among demographic characteristics, occupational, paraoccupational and environmental asbestos exposures. We identified death data for 2430/4530 individuals. Exposure differed significantly according to race, gender, age, and recency of immigration to the U.S. Notably, there was a significant difference in the availability of year of death information for non-white vs. white individuals (odds ratio (OR) = 0.62 p-value < 0.001), females (OR = 0.53, p-value < 0.001), first-generation immigrants (OR = 0.67, p-value = 0.001), second-generation immigrants (OR = 0.31, p-value < 0.001) vs. non-immigrants, individuals aged less than 20 (OR = 0.31 p-value < 0.001) and individuals aged 20 to 59 (OR = 0.63, p-value < 0.001) vs. older individuals. Similarly, the cause of death was less often available for non-white individuals (OR = 0.42, p-value <0.001), first-generation immigrants and (OR = 0.71, p-value = 0.009), second-generation immigrants (OR = 0.49, p-value < 0.001), individuals aged less than 20 (OR = 0.028 p-value < 0.001), and individuals aged 20 to 59 (OR = 0.26, p-value < 0.001). These results identified ascertainment bias that is important to consider in analyses that investigate occupational, para-occupational and environmental asbestos exposure as risk factors for mortality in this historic cohort. While this study attempts to describe methods for assessing itemized asbestos exposure profiles for a community in 1930 using Ancestry.com and other publicly accessible databases, it also highlights how historic cohort studies likely underestimate the impact of asbestos exposure on vulnerable populations. Future work will aim to assess mortality patterns in this cohort.

All-trans Retinoic Acid Disrupts Development in Ex Vivo Cultured Fetal Rat Testes. II: Modulation of Mono-(2-ethylhexyl) Phthalate Toxicity.

Humans are universally exposed to low levels of phthalate esters (phthalates), which are used to plasticize polyvinyl chloride. Phthalates exert adverse effects on the development of seminiferous cords in the fetal testis through unknown toxicity pathways. To investigate the hypothesis that phthalates alter seminiferous cord development by disrupting retinoic acid (RA) signaling in the fetal testis, gestational day 15 fetal rat testes were exposed for 1-3 days to 10-6 M all-trans retinoic acid (ATRA) alone or in combination with 10-6-10-4 M mono-(2-ethylhexyl) phthalate (MEHP) in ex vivo culture. As previously reported, exogenous ATRA reduced seminiferous cord number. This effect was attenuated in a concentration-dependent fashion by MEHP co-exposure. ATRA and MEHP-exposed testes were depleted of DDX4-positive germ cells but not Sertoli cells. MEHP alone enhanced the expression of the RA receptor target Rbp1 and the ovary development-associated genes Wnt4 and Nr0b1, and suppressed expression of the Leydig cell marker, Star, and the germ cell markers, Ddx4 and Pou5f1. In co-exposures, MEHP predominantly enhanced the gene expression effects of ATRA, but the Wnt4 and Nr0b1 concentration-responses were nonlinear. Similarly, ATRA increased the number of cells expressing the granulosa cell marker FOXL2 in testis cultures, but this induction was attenuated by addition of MEHP. These results indicate that MEHP can both enhance and inhibit actions of ATRA during fetal testis development and provide evidence that RA signaling is a target for phthalate toxicity in the fetal testis.

Role of the Inducible Adhesin CpAls7 in Binding of Candida parapsilosis to the Extracellular Matrix under Fluid Shear.

The yeast Candida parapsilosis is an increasingly common cause of systemic fungal infections among immunocompromised individuals, including premature infants. Adhesion to host surfaces is an important step in pathogenesis, but this process has not been extensively studied in this organism. A microfluidics assay was developed to test the ability of C. parapsilosis to adhere to immobilized host extracellular matrix proteins under physiological fluid shear conditions. Growth in mammalian tissue culture medium at 37°C for 3 to 6 h led to the induction of an adhesive phenotype at shear forces of 1 to 5 dynes/cm2 in some isolates of C. parapsilosis Glutamic acid, proline, and calcium appeared to be the minimally necessary requirements for increased adhesion in these assays. To determine whether genes homologous to the ALS gene family of C. albicans were important for the adhesive phenotype, the expression levels of 5 homologous C. parapsilosis genes were quantified by using quantitative PCR (qPCR) under conditions leading to increased adhesion. CPAR2_404800 (CpALS7) and CPAR2_404780 showed increased expression levels compared to those in control yeast. The extent of adhesion was variable among different isolates, and linear regression identified the expression of CpALS7 but not CPAR2_404780 as having a strong positive correlation with adhesion. A homozygous CpALS7 deletion strain was deficient in adhesion, whereas the expression of CpALS7 in Saccharomyces cerevisiae resulted in increased adhesion. Together, these data provide strong evidence that CpAls7 aids in the adherence of C. parapsilosis to the extracellular matrix under shear forces and support its previously reported role in virulence.