Organophosphate Esters Exposure Research Articles

Association between organophosphate esters exposure and all-cause and cause-specific mortality: a national population-based cohort study

ABSTRACT Exposure to organophosphate esters (OPEs) is associated with several chronic diseases, but the relationship with mortality risk is unclear. Therefore, we used the National Health and Nutrition Examination Survey 2011–2018 data to evaluate these relationships. 6,869 participants aged 18 years or older were included. Survival status information was obtained through the National Death Index through 31 December 2019. Multivariable COX regression model was adopted to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationships of urinary OPEs metabolites with mortality risk. During an average of 5.0 years of follow-up, 406 deaths were documented. After adjusting for confounders, bis(2-chloroethyl) phosphate was associated with an increased risk of all-cause mortality [HR (95%CI) = 1.12(1.05–1.20)] and cardiovascular mortality [HR (95%CI) = 1.15(1.04–1.26)]. Our study found that exposure to OPEs was significantly associated with increased risks of all-cause and cardiovascular mortality. Consequently, controlling OPEs exposure is needed to alleviate the health-related burden.

Gestational organophosphate esters (OPEs) exposure in association with placental DNA methylation levels of peroxisome proliferator-activated receptors (PPARs) signaling pathway-related genes

BackgroundOrganophosphate esters (OPEs) exposure could affect offspring health. However, the underlying mechanisms are not well documented. ObjectivesBased on a birth cohort study, we aimed to investigate the associations among gestational OPEs exposure, placental DNA methylation levels of peroxisome proliferator-activated receptor (PPAR) signaling pathway-related genes, and fetal growth. MethodsWe measured the concentrations of eight OPE metabolites in maternal urine samples and neonatal anthropometric measurements in 733 mother-child pairs. In 327 placental samples, we assessed the DNA methylation levels of 14 genes which were involved in the PPARs signaling pathway and expressed in placenta. Multiple linear regression models were used to examine the associations of OPEs exposure with placental DNA methylation, and of OPEs and placental DNA methylation with neonatal anthropometric measurements. Causal mediation analyses were conducted to examine the potential mediating role of placental DNA methylation in the pathway between OPEs exposure and fetal growth. ResultsWe observed a general pattern of OPEs exposure being associated with hypermethylation of candidate genes, with statistically significant associations identified for several OPEs with RXRA, ACAA1, ACADL, ACADM, PLTP, and NR1H3 methylation. Further, gestational exposure to BCIPP, DPP, BBOEP, ∑NCl-OPEs, and ∑OPEs tended to be associated with lower anthropometric measurements, with more significant associations observed on arm circumference, and abdominal and back skinfold thickness. Notably, RXRA, ACAA1, ACOX1, CPT2, ACADM, and NR1H3 methylation tended to be associated with lower neonatal anthropometric measurements, especially for abdominal and back skinfold thickness. Moreover, mediation analyses showed that 19.42 % of the total effect of DPP on the back skinfold thickness was mediated by changes in RXRA methylation, and there was a significant indirect effect of RXRA methylation. ConclusionsGestational OPEs exposure could disrupt the placental DNA methylation levels of PPAR signaling pathway-related genes, which might contribute to the effect of OPEs on fetal growth.

Organophosphate Ester Flame Retardants and Plasticizers in Relation to Fetal Growth in the LIFECODES Fetal Growth Study.

Organophosphate esters (OPEs), used ubiquitously as flame retardants and plasticizers in consumer products, are suspected of having developmental toxicity. Our study aimed to estimate associations between prenatal exposure to OPEs and fetal growth, including both ultrasound (head circumference, abdominal circumference, femur length, and estimated fetal weight) and delivery [birth weight z-score, small-for-gestational age (SGA), and large-for-gestational age (LGA)] measures of growth. In the LIFECODES Fetal Growth Study (2008-2018), an enriched case-cohort of 900 babies born at the small and large ends of the growth spectrum, we quantified OPE biomarkers in three urine samples per pregnant participant and abstracted ultrasound and delivery measures of fetal growth from medical records. We estimated associations between pregnancy-averaged log-transformed OPE biomarkers and repeated ultrasound measures of fetal growth using linear mixed-effects models, and delivery measures of fetal growth using linear (birth weight) and logistic (SGA and LGA) regression models. Most OPE biomarkers were positively associated with at least one ultrasound measure of fetal growth, but associations with delivery measures were largely null. For example, an interquartile range (IQR; ) increase in bis(2-chloroethyl) phosphate concentration was associated with larger z-scores in head circumference [mean difference (difference): 0.09; 95% confidence interval (CI): 0.01, 0.17], abdominal circumference (difference: 0.10; 95% CI: 0.02, 0.18), femur length (difference: 0.11; 95% CI: 0.03, 0.19), and estimated fetal weight (difference: 0.13; 95% CI: 0.04, 0.22) but not birth weight (difference: 0.04; 95% CI: , 0.17). At delivery, an IQR () increase in diphenyl phosphate (DPHP) concentration was associated with an SGA birth (odds ratio: 1.46; 95% CI: 1.10, 1.94). In a large prospective cohort, gestational OPE exposures were associated with larger fetal size during pregnancy, but associations at delivery were null. DPHP concentrations were associated with heightened risk of an SGA birth. These findings suggest that OPE exposure may affect fetal development. https://doi.org/10.1289/EHP14647.

A panel study on the association of organophosphate ester flame retardant exposure with thyroid function related hormones in healthy older adults

Objective: To explore the impact of whole blood organophosphate esters (OPEs) flame retardant exposure on thyroid function-related hormones in healthy older adults. Methods: In this panel study, five repeated population-based epidemiological surveys and biological sample collection were conducted from September 2018 to January 2019, with 76 healthy older adults aged 60-69 years in the Dianliu Community of Jinan, Shandong Province. Information on the sociodemographic characteristics, diet, and health status of the respondents was systematically gathered through questionnaires and physical examinations. Fasting venous blood was collected to determine the levels of OPEs, thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4). A linear mixed-effects model was used to analyze the impact of OPEs exposure on thyroid function-related hormones in healthy older adults. Results: Each of the 76 subjects participated in at least two follow-up visits, resulting in a total of 350 person visits. The age of the study participants was (65.07±2.76) years, with 38 participants of both sexes. A total of eight OPEs were included with a detection rate exceeding 50%, and the M (Q1, Q3) for ∑OPEs was 3.85 (2.33, 5.74) ng/ml, with alkyl-OPEs being the major type of OPEs with an M (Q1, Q3) of 1.27 (0.64, 2.50) ng/ml. The M (Q1, Q3) for TSH, T3, and T4 was 3.74 (2.55, 5.69) μIU/ml, 1.32 (1.10, 1.60) ng/ml, and 45.04 (36.96, 53.27) ng/ml, respectively. Linear mixed-effects model showed that TSH was significantly decreased by 9.93% (95%CI:-15.17%, -4.36%) and 11.14% (95%CI:-15.94%, -6.06%) in older adults for each quartile level increase in TnBP and TEHP exposures, respectively. Gender-stratified analysis indicated that TEHP exposure was negatively associated with TSH levels in male older adults, whereas a decrease in TSH levels among female older adults was associated with TnBP exposure. Conclusion: Exposure to whole blood OPEs is associated with decreased TSH levels among healthy older adults, with notable gender differences.

Estimated daily intake and cumulative risk assessment of organophosphate esters and associations with DNA damage among e-waste workers in Hong Kong

Organophosphate esters (OPEs) are extensively used as additives in various products, including electronic equipment, which becomes e-waste when obsolete. Nevertheless, no study has evaluated OPEs exposure levels and the related health risks among e-waste workers in Hong Kong. Therefore, 201 first-spot morning urine samples were collected from 101 e-waste workers and 100 office workers to compare eight urinary OPE metabolites (mOPEs) levels in these groups. The concentrations of six mOPEs were similar in e-waste workers and office workers, except for significantly higher levels of diphenyl phosphate (DPHP) in e-waste workers and bis(1-chloro-2propyl) phosphate (BCIPP) in office workers. Spearman correlation analysis showed that most non-chlorinated mOPEs were correlated with each other in e-waste workers (i.e., nine out of ten pairs, including di-p-cresyl phosphate (DpCP) and di-o-cresyl phosphate (DoCP), DpCP and bis(2-butoxyethyl) phosphate (BBOEP), DpCP and DPHP, DpCP and dibutyl phosphate (DBP), DoCP and BBOEP, DoCP and DPHP, DoCP and DBP, BBOEP and DPHP, DPHP and DBP), indicating that handling e-waste could be the exposure source of specific OPEs. The median values of estimated daily intake (EDI) and hazard quotient (HQ) suggested that the health risks from OPEs exposures were under the recommended thresholds. However, linear regression models, Quantile g-computation, and Bayesian kernel machine regression found that urinary mOPEs elevated 8-hydroxy-2-deoxyguanosine (8-OhdG) levels individually or as a mixture, in which DPHP contributed prominently. In conclusion, although e-waste might not elevate the internal OPEs levels among the participating Hong Kong e-waste workers, attention should be paid to the potential DNA damage stimulated by OPEs under the currently recommended thresholds.

Exposure to resorcinol bis (diphenyl phosphate) induces colonization of alien microorganisms with potential impacts on the gut microbiota and metabolic disruption in male zebrafish

Organophosphate esters (OPEs) have been demonstrated to induce various forms of toxicity in aquatic organisms. However, a scarcity of evidence impedes the conclusive determination of whether OPEs manifest sex-dependent toxic effects. Here, we investigated the effects of tris (1-chloro-2-propyl) phosphate (TCPP) and resorcinol bis (diphenyl phosphate) (RDP) on the intestines of both female and male zebrafish. The results indicated that, in comparison to TCPP, RDP induced more pronounced intestinal microstructural damage and oxidative stress, particularly in male zebrafish. 16S rRNA sequencing and metabolomics revealed significant alterations in the species richness and oxidative stress-related metabolites in the intestinal microbiota of zebrafish under exposure to both TCPP and RDP, manifesting gender-specific effects. Based on differential species analysis, we defined invasive species and applied invasion theory to analyze the reasons for changes in the male fish intestinal community. Correlation analysis demonstrated that alien species may have potential effects on metabolism. Overall, this study reveals a pronounced gender-dependent impact on both the intestinal microbiota and metabolic disruptions of zebrafish due to OPEs exposure and offers a novel perspective on the influence of pollutants on intestinal microbial communities and metabolism.

Flame Retardant Exposure in Vehicles Is Influenced by Use in Seat Foam and Temperature.

Flame retardants (FRs) are added to vehicles to meet flammability standards, such as US Federal Motor Vehicle Safety Standard FMVSS 302. However, an understanding of which FRs are being used, sources in the vehicle, and implications for human exposure is lacking. US participants (n = 101) owning a vehicle of model year 2015 or newer hung a silicone passive sampler on their rearview mirror for 7 days. Fifty-one of 101 participants collected a foam sample from a vehicle seat. Organophosphate esters (OPEs) were the most frequently detected FR class in the passive samplers. Among these, tris(1-chloro-isopropyl) phosphate (TCIPP) had a 99% detection frequency and was measured at levels ranging from 0.2 to 11,600 ng/g of sampler. TCIPP was also the dominant FR detected in the vehicle seat foam. Sampler FR concentrations were significantly correlated with average ambient temperature and were 2-5 times higher in the summer compared to winter. The presence of TCIPP in foam resulted in ∼4 times higher median air sampler concentrations in winter and ∼9 times higher in summer. These results suggest that FRs used in vehicle interiors, such as in seat foam, are a source of OPE exposure, which is increased in warmer temperatures.

Prenatal organophosphate esters exposure and neurodevelopment trajectory in infancy: Evidence from the Shanghai Maternal-Child Pairs Cohort

BackgroundConcerns remain about the neurotoxic properties of the ubiquitous organophosphate esters (OPEs), the replacement of the toxicant polybrominated diphenyl ethers. ObjectivesWe examined the associations of prenatal exposure to OPEs and their mixtures with early-life neurodevelopment trajectories. MethodsTotally 1276 mother-child pairs were recruited from the Shanghai Maternal-Child Pairs Cohort. A high-performance liquid chromatography-triple quadrupole mass spectrometer was used to measure the levels of 7 OPEs in cord serum. Ages and Stages Questionnaires was used to examine children's neuropsychological development at 2, 6, 12, and 24 months of age. Group-based trajectory models were applied to derive the neurodevelopmental trajectories. Multiple linear regression and logistic regression model were performed to assess the relationships between OPEs exposure and neurodevelopment and trajectories. Mixtures for widely detected OPEs (n = 4) were investigated using quantile-based g-computation. ResultsTributyl phosphate (TBP), tris (2-butoxy ethyl) phosphate (TBEP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and 2-ethylhexyl diphenyl phosphate (EHDPP), had detection rates >50 %. TDCPP had the highest median concentration (1.02 μg/L) in cord serum. EHDPP concentrations were negatively associated with scores in most domains at 12 months of age, with effect values (β) ranging from −1.89 to −0.57. EHDPP could negatively affect the total ASQ (OR = 1.07, 95 % CI: 1, 1.15) and gross-motor (OR = 1.09, 95 % CI: 1.02, 1.17) trajectory in infancy. Joint exposure to OPEs was associated with decreased scores in the total ASQ, gross-motor, fine-motor and problem-solving domain of 12-month-old infants, with β ranging from −5.93 to −1.25. In addition, the qgcomp models indicated significant positive associations between the concentrations of OPEs mixtures and risks of the persistently low group of the total ASQ, gross-motor and fine-motor development in early childhood. The impact of OPEs was more pronounced in boys. DiscussionOur findings suggested OPEs, especially EHDPP, had a persistently negative effect on neurodevelopment during the first 2 years.

Organophosphate ester flame retardants and plasticizers affect the phenotype and function of HepG2 liver cells.

Exposure to the organophosphate esters (OPEs), used as flame retardants and plasticizers, is associated with a variety of adverse health effects including an increase in the incidence of fatty liver diseases. The goal of this study was to investigate the effects of six OPEs, all detected in Canadian house dust, on the phenotype and function of HepG2 liver cells. We used high-content imaging to investigate the effects of these OPEs on cell survival, mitochondria, oxidative stress, lipid droplets, and lysosomes. Effects on the autophagy/lipophagy pathway were evaluated using confocal microscopy. The triaryl OPEs (isopropylated triphenylphosphate [IPPP], tris(methylphenyl) phosphate [TMPP], and triphenyl phosphate [TPHP]) were more cytotoxic than non-triaryl OPEs (tris(2-butoxyethyl) phosphate [TBOEP],tris(1-chloro-2-propyl) phosphate [TCIPP], and tris(1,3-dichloro-2-propyl) phosphate [TDCIPP]). Exposure to most OPEs increased total mitochondria, reduced reactive oxygen species, and increased total lipid droplet areas and lysosomal intensity. Potency ranking was done using the lowest benchmark concentration/administered equivalent dose method and toxicological prioritization index analyses to integrate all phenotypic endpoints. IPPP, TBOEP, and TPHP ranked as the most potent OPEs, whereas TMPP, TCIPP, and TDCIPP were relatively less bioactive. Confocal microscopic analysis demonstrated that IPPP reduced the colocalization of lipid droplets (PLIN2), lysosomes (LAMP1), and autophagosomes (p62), disrupting autophagy. In contrast, TBOEP rescued cells from bafilomycin A1-induced inhibition of autophagy and/or increased autophagic flux. Together, these data demonstrate that OPEs have adverse effects on HepG2 cells. Further, OPE-induced dysregulation of autophagy may contribute to the association between OPE exposure and adverse effects on liver lipid homeostasis.

Trimester-specific effect of maternal co-exposure to organophosphate esters and phthalates on preschooler cognitive development: The moderating role of gestational vitamin D status

Organophosphate esters (OPEs) and phthalate acid esters (PAEs) are prevalent endocrine-disrupting chemicals (EDCs). Humans are often exposed to OPEs and PAEs simultaneously through multiple routes. Given that fetal stage is a critical period for neurodevelopment, it is necessary to know whether gestational co-exposure to OPEs and PAEs affects fetal neurodevelopment. However, accessible epidemiological studies are limited. The present study included 2, 120 pregnant women from the Ma'anshan Birth Cohort (MABC) study. The concentrations of tris (2-chloroethyl) phosphate (TCEP), 6 OPE metabolites and 7 PAE metabolites were measured in the first, second and third trimester using ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS). Cognitive development of preschooler was assessed based on the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (WPPSI-IV) of the Chinese version. Generalized estimating equations (GEEs), restricted cubic spline (RCS) and generalized additive models (GAMs) were employed to explore the associations between individual OPE exposure and preschooler cognitive development. The quantile-based g-computation (QGC) method was used to estimate the joint effect of PAEs and OPEs exposure on cognitive development. GEEs revealed significant adverse associations between diphenyl phosphate (DPHP) (β: −0.58, 95% CI: −1.14, −0.01), bis (2-butoxyethyl) phosphate(BBOEP) (β: −0.44, 95% CI: −0.85, −0.02), bis(1-chloro-2-propyl) phosphate (BCIPP) (β: −0.81, 95%CI: −1.43, −0.20) and full-scale intelligence quotient (FSIQ) in the first trimester; additionally, TCEP and bis(2-ethylhexyl) phosphate (BEHP) in the second trimester, as well as DPHP in the third trimester, were negatively associated with cognitive development. Through the QGC analyses, mixture exposure in the first trimester was negatively associated with FSIQ scores (β: −1.70, 95% CI: −3.06, −0.34), mono-butyl phthalate (MBP), BCIPP, and DPHP might be the dominant contributors after controlling for other OPEs and PAEs congeners. Additionally, the effect of OPEs and PAEs mixture on cognitive development might be driven by vitamin D deficiency.

Bioaccumulation and Potential Endocrine Disruption Risk of Legacy and Emerging Organophosphate Esters in Cetaceans from the Northern South China Sea.

Despite the increasing health risks shown by the continuous detection of organophosphate esters (OPEs) in biota in recent years, information on the occurrence and potential risks of OPEs in marine mammals remains limited. This study conducted the first investigation into the body burdens and potential risks of 10 traditional OPEs (tOPEs) and five emerging OPEs (eOPEs) in 10 cetacean species (n = 84) from the northern South China Sea (NSCS) during 2005-2021. All OPEs, except for 2-ethylhexyl diphenyl phosphate (EHDPHP), were detected in these cetaceans, indicating their widespread occurrence in the NSCS. Although the levels of the ∑10tOPEs in humpback dolphins remained stable from 2005 to 2021, the concentrations of the ∑5eOPEs showed a significant increase, suggesting a growing demand for these new-generation OPEs in South China. Dolphins in proximity to urban regions generally exhibited higher OPE concentrations than those from rural areas, mirroring the environmental trends of OPEs occurring in this area. All OPE congeners, except for EHDPHP, in humpback dolphins exhibited a maternal transfer ratio >1, indicating that the dolphin placenta may not be an efficient barrier for OPEs. The observed significant correlations between levels of OPEs and hormones (triiodothyronine, thyroxine, and testosterone) in humpback dolphins indicated that OPE exposures might have endocrine disruption effects on the dolphin population.

Impact of Exposure to a Mixture of Organophosphate Esters on Adrenal Cell Phenotype, Lipidome, and Function.

Organophosphate esters (OPEs) are used primarily as flame retardants and plasticizers. Previously, we reported that adrenal cells are important targets of individual OPEs. However, real-life exposures are to complex mixtures of these chemicals. To address this, we exposed H295R human adrenal cells to varying dilutions (1/1000K to 1/3K) of a Canadian household dust-based OPE mixture for 48 hours and evaluated effects on phenotypic, lipidomic, and functional parameters. Using a high-content screening approach, we assessed phenotypic markers at mixture concentrations at which there was greater than 70% cell survival; the most striking effect of the OPE mixture was a 2.5-fold increase in the total area of lipid droplets. We then determined the response of specific lipid species to OPE exposures with novel, nontargeted lipidomic analysis of isolated lipid droplets. These data revealed that house dust OPEs induced concentration-dependent alterations in the composition of lipid droplets, particularly affecting the triglyceride, diglyceride, phosphatidylcholine, and cholesterol ester subclasses. The steroid-producing function of adrenal cells in the presence or absence of a steroidogenic stimulus, forskolin, was determined. While the production of 17β-estradiol remained unaffected, a slight decrease in testosterone production was observed after stimulation. Conversely, a 2-fold increase in both basal and stimulated cortisol and aldosterone production was observed. Thus, exposure to a house dust-based mixture of OPEs exerts endocrine-disrupting effects on adrenal cells, highlighting the importance of assessing the effects of environmentally relevant mixtures.

Uptake, accumulation and translocation mechanisms of organophosphate esters in cucumber (Cucumis sativus) following foliar exposure

Organophosphate esters (OPEs) have been frequently detected in crops. However, few studies have focused on the uptake and translocation of OPEs in plants following foliar exposure. Herein, to investigate the foliar uptake, accumulation and translocation mechanisms of OPEs in plant, the cucumber (Cucumis sativus) was selected as a model plant for OPEs exposure via foliar application under control conditions. The results showed that the content of OPEs in the leaf cuticle was higher than that in the mesophyll on exposed leaf. Significant positive correlations were observed between the content of OPEs in the leaf cuticle and their log Kow and log Kcw values (P < 0.01), suggesting that OPEs with high hydrophobicity could not easily move from the cuticle to the mesophyll. The moderately hydrophobic OPEs, such as tris (2-chloroisopropyl) phosphate (TCPP, log Kow = 2.59), were more likely to move not only from the cuticle to the mesophyll but also from the mesophyll to the phloem. The majority of the transported OPEs accumulated in younger leaves (32–45 %), indicating that younger tissue was the primary target organ for OPEs accumulation after foliar exposure. Compared to chlorinated OPEs (except TCPP) and aryl OPEs, alkyl OPEs exhibited the strongest transport capacity in cucumber seedling due to their high hydrophilicity. Interestingly, tri-p-cresyl phosphate was found to be more prone to translocation compared to tri-m-cresyl phosphate and tri-o-cresyl phosphate, despite having same molecular weight and similar log Kow value. These results can contribute to our understanding of foliar uptake and translocation mechanism of OPEs by plant.

Prenatal exposures to organophosphate ester metabolites and early motor development in the MADRES cohort

Organophosphate esters (OPEs) are increasingly considered neurotoxicants which may impact gross and fine motor development. We evaluated associations between prenatal OPE exposures and infant motor development. Third trimester urinary concentrations of nine OPE metabolites were measured in 329 mother-infant dyads participating in the Maternal And Developmental Risks from Environmental and Social Stressors (MADRES) cohort. Child gross and fine motor development at 6, 9, 12, and 18-months were assessed with the Ages and Stages Questionnaire-3 (ASQ-3) and operationalized in models using dichotomous instrument-specific cutoffs for typical motor development. Five OPE metabolites with >60% detection were specific-gravity-adjusted, natural log-transformed, and modeled continuously, while four metabolites with <60% detection were modeled dichotomously (detected/not-detected). We fit mixed effects logistic regression between OPE metabolites and fine/gross motor development and assessed sex-specific effects using a statistical interaction term and sex-stratified models. Among children, 31% and 23% had gross and fine motor scores, respectively, below the ASQ-3 at-risk cutoffs at least once across infancy. A doubling in prenatal diphenyl phosphate (DPHP) exposure was associated with 26% increased odds of potential fine motor delays (ORfine = 1.26, 95% CI: 1.02, 1.57, p = 0.04). We also observed significant interactions by infant sex for associations of detected dipropyl phosphate (DPRP) with gross motor development (pinteraction = 0.048) and detected bis(1-chloro-2-propyl) phosphate (BCIPP) with fine motor development (pinteraction = 0.02). Females had greater odds of potential motor delays for both detected DPRP (females vs males ORgross (95% CI) = 1.48 (0.71, 3.09), p = 0.30 vs 0.27 (0.06, 1.29), p = 0.10) and detected BCIPP (females vs males ORfine (95% CI) = 2.72 (1.27, 5.85), p = 0.01 vs 0.76 (0.31, 1.90), p = 0.56). There were no other significant associations between other metabolites and motor development, despite similar patterns. We found evidence of adverse effects of prenatal OPE exposures on infant motor development with greater adverse effects among female infants with some OPE metabolites.

Reproductive hormones, organophosphate esters and semen quality: Exploring associations and mediation effects among men from an infertility clinic

Accumulating evidence indicates that organophosphate esters (OPEs) exposure may affect semen quality. As a crucial factor in male reproduction, reproductive hormones might be linked organophosphate esters (OPEs) exposure and semen quality. This study aimed to explore the mediating role of reproductive hormones on the association between OPEs exposure and semen quality. Five serum reproductive hormones, semen quality, and 16 urinary OPE metabolites were measured among 491 reproductive-aged men from a reproductive center. The associations of urinary OPE metabolites with reproductive hormones and semen quality were assessed using multivariable linear regression models, and the mediating role of reproductive hormones was evaluated by mediation analyses. We found that follicle stimulating hormone (FSH) was positively associated with diphenyl phosphate (DPHP) that in turn was negatively associated with sperm total count. In addition, inverse associations were exhibited between serum FSH and sperm concentration, sperm total count, total motility, and progressive motility (all Ptrend <0.05). Mediation analysis further showed that FSH mediated 13.7% of the inverse association of DPHP and sperm total count. Although further investigations are required, our results suggest that FSH was an intermediate mechanism in the associations between OPEs exposure and impaired semen quality.

Determinants of organophosphate esters exposure in pregnant women from East China

Organophosphate esters (OPEs) have been broadly used in various industrial and consumer products, resulting in global distribution and human exposure. Gestational exposure to OPEs may adversely affect the health of both pregnant women and their offspring. To better understand OPE exposure in pregnant women, our study determined eight urinary metabolites of major OPEs in pregnant women (n = 733) recruited at 12–16 weeks of gestation from Shanghai, China, and explored the determinants of OPE exposure among various sociodemographic characteristics, lifestyles, and dietary factors. Urinary metabolites of OPEs, including bis (1,3-dichloro-2-propyl) phosphate (BDCPP), bis (2-chloroethyl) phosphate (BCEP), bis (1-chloro-2-propyl) phosphate (BCIPP), dicresyl phosphate (DCP), diphenyl phosphate (DPP), dibutyl phosphate (DBP), bis (2-ethylhexyl) phosphate (BEHP), and bis (2-butoxyethyl) phosphate (BBOEP), exhibited a detection rate ranging from 69.30% to 99.32%. Multivariate linear regression models indicated that pregnant women who were multiparous, had a higher family income per capita, worked in white-collar jobs, and took nutritional supplements such as milk powder and fish oil tended to have higher urinary OPE metabolite concentrations. Besides, independent of sociodemographic characteristics and lifestyle factors, consumption of more aquatic products, soy products, pork, and puffed food, as well as drinking of purified tap water versus tap water, were associated with increased urinary OPEs metabolite concentrations. Our study demonstrated that OPE exposure was ubiquitous in pregnant women from Shanghai, and provided new insights into the potential factors influencing OPE exposure during pregnancy.

Gas–particle partitioning of organophosphate esters in indoor and outdoor air and its implications for individual exposure

The extensive utilization of organophosphate esters (OPEs) has resulted in their widespread presence in the environment, raising concerns about potential human health risks. In this study, 13 OPEs were analyzed in both gas and particle phases as well as in indoor and outdoor atmospheric environments. Moreover, human exposure to OPEs were investigated within a university environment, focusing on forehead contact and individual PM2.5 inhalation. The results showed similar distribution patterns of OPEs indoors and outdoors, although higher concentrations were found indoors. The average atmospheric concentration of ∑OPEs (combining particle and gaseous OPEs) was 1575 pg/m3 in the outdoor environment and 6574 pg/m3 ∑OPEs in the indoor microenvironments. The overwhelming majority of OPEs exhibit a pronounced propensity to adsorb onto PM2.5 particles. Notably, the concentration of OPEs on the forehead differed significantly from that in the atmospheric environment, whereas individual PM2.5 exposure was consistent with the concentration of indoor PM2.5. Intriguingly, some OPEs with high octanol–water partition coefficient (log Kow) were not detected in the environment but found on human foreheads. Gas-particle partitioning was predicted using the Harner–Bidleman and Li–Ma–Yang models and the results were in agreement with the monitoring data for approximately half of the OPE monomers. Correlations between OPEs exposure and gas-particle partitioning were found to be more significant for novel OPEs. No non-cancer risk to humans through individual exposure to OPEs was identified via forehead exposure or inhalation. The previously unreported relationship between individual exposure and the environmental occurrence of traditional and novel OPEs demonstrated in this study highlights the importance of evaluating the potential health risks associated with actual OPE exposure.

Patterns of urinary organophosphate ester metabolite trajectories in children: the HOME Study.

Organophosphate esters (OPEs) have replaced flame retardant polybrominated diphenyl ethers as flame retardants in consumer products, but few longitudinal studies have characterized childhood OPE exposure. We aimed to examine the exposure pattern of urinary OPE metabolites in children. We quantified three urinary OPE metabolites five times in children (1, 2, 3, 5, 8 years) from 312 mother-child pairs in the Health Outcomes and Measures of the Environment (HOME) Study, a prospective pregnancy and birth cohort in Cincinnati, Ohio, USA. We examined the associations of average maternal OPE metabolite concentrations with OPE metabolite concentrations in childhood, characterized childhood OPE trajectories with latent class growth analysis (LCGA), and examined factors related to trajectory membership. Bis(2-chloroethyl) phosphate (BCEP) had the lowest median concentrations over time (0.66-0.97 mg/L) while the median concentrations of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) increased with age (1.44-3.80 mg/L). The median concentrations of diphenyl phosphate (DPHP) fluctuated between 1.96 and 2.69 mg/L. Intraclass correlation coefficients for urinary metabolites measured at five time points indicated high variability within individuals (0.13-0.24). Average maternal urinary BCEP and BDCIPP were associated with concentrations in early childhood. Maternal education, the birth year of the child, and having a carpet in the main activity room were associated with BCEP and BDCIPP trajectory while none of the factors were associated with DPHP trajectory. The trajectory analysis showed different patterns of urinary OPE metabolite concentrations, suggesting the need to collect multiple samples to adequately reflect OPE exposure. In this well-established cohort, we evaluated the patterns of urinary OPE metabolites in children ages 1-8 years. The number of repeated measures over childhood has not been achieved in prior studies. Our results suggested the high variability of urinary OPE metabolites within individuals. Maternal metabolite concentrations during pregnancy were related to child concentrations at ages 1-3 years. BCEP, BDCIPP, and DPHP demonstrated different trajectories in children, which suggests that multiple samples may be required to capture OPE exposure patterns in childhood.

Urinary concentrations of organophosphate esters and associated health outcomes in Korean firefighters

Although firefighters are at an increased risk of occupational exposure to chemicals, such as flame retardants, research on the exposure of Korean firefighters to organophosphate esters (OPEs)—a group of emerging flame retardants—remains limited. Therefore, in the present study, OPE metabolite concentrations in the urine samples of 149 former and current Korean firefighters were measured. Based on the data obtained, the estimated daily intakes (EDIs) of OPEs were calculated. Subsequently, the association between the urinary concentrations of OPE metabolites and the potential determinants of OPE exposure and health outcomes (e.g., obesity and serum lipids) was investigated. We found that bis(1-chloro-2-propyl) phosphate (BCIPP) and bis(2-chloroethyl) phosphate (BCEP) were the most prevalent urinary OPE metabolites, with median concentrations of 2.33 and 1.80 ng/mL, respectively; these concentrations were higher than those reported previously in other countries, such as the USA and China. Moreover, their parent compounds—tris(1-chloro-2-propyl) phosphate (TCIPP) and tris(2-chloroethyl) phosphate (TCEP)—exhibited EDIs of 126 and 94.8 ng/kg bw/day, respectively. Unlike the high detection rate of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) in other populations, its detection rate in this study was low (6.7%), suggesting regional differences in the exposure pattern of OPEs among countries. Furthermore, occupational characteristics, such as recent participation in firefighting activity, were identified as determinants of the urinary concentrations of OPE metabolites. Total OPE metabolites were inversely associated with body mass index and positively associated with high-density lipoprotein cholesterol. Overall, our findings demonstrate that Korean firefighters are highly exposed to several occupation-related OPEs. Further prospective studies will help elucidate the potential health implications of occupational exposure to OPEs among firefighters.

Machine learning reveals common transcriptomic signatures across rat brain and placenta following developmental organophosphate ester exposure.

Toxicogenomics is a critical area of inquiry for hazard identification and to identify both mechanisms of action and potential markers of exposure to toxic compounds. However, data generated by these experiments are highly dimensional and present challenges to standard statistical approaches, requiring strict correction for multiple comparisons. This stringency often fails to detect meaningful changes to low expression genes and/or eliminate genes with small but consistent changes particularly in tissues where slight changes in expression can have important functional differences, such as brain. Machine learning offers an alternative analytical approach for "omics" data that effectively sidesteps the challenges of analyzing highly dimensional data. Using 3 rat RNA transcriptome sets, we utilized an ensemble machine learning approach to predict developmental exposure to a mixture of organophosphate esters (OPEs) in brain (newborn cortex and day 10 hippocampus) and late gestation placenta of male and female rats, and identified genes that informed predictor performance. OPE exposure had sex specific effects on hippocampal transcriptome, and significantly impacted genes associated with mitochondrial transcriptional regulation and cation transport in females, including voltage-gated potassium and calcium channels and subunits. To establish if this holds for other tissues, RNAseq data from cortex and placenta, both previously published and analyzed via a more traditional pipeline, were reanalyzed with the ensemble machine learning methodology. Significant enrichment for pathways of oxidative phosphorylation and electron transport chain was found, suggesting a transcriptomic signature of OPE exposure impacting mitochondrial metabolism across tissue types and developmental epoch. Here we show how machine learning can complement more traditional analytical approaches to identify vulnerable "signature" pathways disrupted by chemical exposures and biomarkers of exposure.