Mixtures Of Persistent Organic Pollutants Research Articles

Applications of mixture methods in epidemiological studies investigating the health impact of persistent organic pollutants exposures: a scoping review.

Persistent organic pollutants (POPs) are environmental chemicals characterized by long half-lives in nature and human bodies, posing significant health risks. The concept of the exposome, encompassing all lifetime environmental exposures, underscores the importance of studying POP as mixtures rather than in isolation. The increasing body of evidence on the health impacts of POP mixtures necessitates the proper application of statisticalmethods. We aimed to summarize studies on the overall effects of POP mixtures, identify patterns in applications of mixture methods-statistical methods for investigating the association of mixtures-and highlight current challenges in synthesizing epidemiologic evidence of POP mixtures on health effects as illustrated through a case study. We conducted a systematic literature search on PubMed and Embase for epidemiological studies published between January 2011 and April 2023. We included 240 studies that met our eligibility criteria. 126 studies focused on per- and polyfluoroalkyl substances (PFAS) mixtures only, while 40 analyzed three or more classes of POPs in mixture analyses. We identified 23 unique mixture methods used to estimate the overall effects of POP mixtures, with Bayesian Kernel Machine Regression (BKMR), a type of response-surface modeling, being the most common. Additionally, 22.9% of studies used a combination of methods, including response-surface modeling, index modeling, dimension reduction, and latent variable models. The most extensively explored health outcome category was body weight and birth sizes (n = 43), and neurological outcomes (n = 41). In the case study of PFAS mixtures and birth weight, 12 studies showed negative associations, while 4 showed null results, and 2 showed positive associations. This scoping review consolidates the existing literature on the overall effects of POP mixtures using statistical methods. By providing a comprehensive overview, our study illuminates the present landscape of knowledge in this field and underscores the methodological hurdles prevalent in epidemiological studies focused on POP mixtures. Through this analysis, we aim to steer future research directions, fostering a more nuanced comprehension of the intricate dynamics involved in assessing the health effects of POP mixtures. Our work stands as a significant contribution to the ongoing exploration of the chemicalexposome.

Prospective study on the joint effect of persistent organic pollutants and glucose metabolism on chronic kidney disease: Modifying effects of lifestyle interventions

There is no evidence on the associations between persistent organic pollutants (POPs) and the incidence of chronic kidney disease (CKD) in the Chinese rural population. We aimed to investigate the individual and mixed effects of 22 POPs on the prevalence and incidence of CKD, and the joint effects of POPs and abnormal glucose metabolism as well as the modification effects of healthy lifestyle on these associations. A total of 2775 subjects, including 925 subjects with normal plasma glucose (NPG) and 925 subjects with prediabetes (PDM) and type 2 diabetes mellitus (T2DM), were enrolled from the Henan Rural Cohort Study. Logistic regression and quantile g-computation were performed to assess the individual and mixed effects of POPs on the risk of CKD. Joint effects of POPs and abnormal glucose metabolism status, as well as the modification effects of lifestyle on CKD were assessed. After 3-year follow-up, an increment of ln-o,p’-DDT was related to an elevated risk of CKD prevalence. Positive associations of p,p’-DDE and β-BHC with CKD incidence were observed (P < 0.05). In addition, participants with high levels of ∑POPs were associated elevated incidence risk of CKD (OR: 1.217, 95%CI: 1.008–1.469). One quartile increase in POPs mixture was associated with the increased incidence of CKD among T2DM patients (P < 0.05). Further, a higher risk of CKD was observed among PDM and T2DM patients with high levels of o,p’-DDT, p,p’-DDE, β-BHC, and ∑POPs than NPG subjects with low levels of pollutants. In addition, interactive effects of ∑POPs and lifestyle score on CKD incidence were found. Individual and mixed exposure to POPs increased the prevalence and incidence of CKD, and glucose metabolic status exacerbated the risk of CKD resulting from such exposures. Further, the modifying effects of lifestyle were observed, highlighting the importance of precision prevention for high-risk CKD population and healthy lifestyle intervention measures.

Associations of serum persistent organic pollutant concentrations with incident diabetes in midlife women: The Study of Women’s Health Across the Nation Multi-Pollutant Study

BackgroundOrganochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that can negatively impact metabolic health through pathways including endocrine disruption. Few studies have evaluated diabetes risk associated with PBDEs. Little is known about the joint effect of exposure to POP mixtures on diabetes risk. ObjectivesWe investigated the relationship between POPs, individually and as mixtures, and diabetes development over 18 years (1999–2016) in midlife women. MethodsWe measured lipid-standardized serum concentrations of 34 PCBs, 19 OCPs, and 14 PBDEs in 1040 midlife women aged 45–56 years from the Study of Women’s Health Across the Nation. We tested the association between POPs measured in 1999/2000 and incident diabetes using Cox proportional hazards models. We evaluated diabetes risk associated with the overall POP mixture using Quantile-Based G-Computation (QBGC). ResultsFor most mixture components, single pollutant and mixtures analyses indicated null associations with diabetes risk, however results were inconsistent. After adjustment, hazard ratios (HRs) of developing diabetes (95% CI) associated with upper exposure tertiles (T2/T3) compared with the first tertile (T1), were 1.7 (1.0, 2.8) at T2 and 1.5 (0.84, 2.7) at T3 for hexachlorobenzene and 1.9 (1.1, 3.3) at T2 and 1.6 (0.88, 2.9) at T3 for PCB 123. A doubling of PBDE 47 was associated with 1.11 (1.00, 1.24) times the risk of T2D. QBGC identified no association for the overall joint effect of the POP mixture on diabetes (HR = 1.04 [0.53, 2.07]). ConclusionExposure to a mixture of PCBs, OCPs, and PBDEs was not associated with incident diabetes in midlife U.S. women, although some individual POPs demonstrated significant yet inconsistent associations with diabetes. Non-linear and non-monotonic dose-response dynamics deserve further exploration. More research is needed on the diabetogenic effects of PBDEs.

Impact of antenatal exposure to a mixture of persistent organic pollutants on intellectual development

ObjectiveStrong experimental evidence exists that several endocrine disrupting chemicals (EDCs) have neurobehavioral toxicity. However, evidence of associations between prenatal exposure and child's cognitive development is inconsistent. Moreover, toxicants are generally analyzed one by one without considering aggregate effects. We examined here the impact of a prenatal exposure to a mixture of persistent organic pollutants (POPs) on intellectual abilities in preschool children, and compared their effects to those described in the literature. MethodsSixty-two children were included in a longitudinal cohort. Four organochlorine pesticides, four polychlorinated biphenyls (PCBs) and seven perfluorinated compounds (PFCs) were measured in cord blood. Intellectual abilities were assessed at 6 years of age using the Wechsler Preschool and Primary Scale of Intelligence 4th ed. (WPPSI-IV). We examined the associations between a mixture of POPs and cognitive performances using principal components approach (PCA) and weighted quantile sum (WQS) regression taking sex difference into account. ResultsNo negative correlation was found when analyses were performed on boys and girls together. In sex-stratified analyses, lower scores in full scale intelligence quotient (FSIQ) and fluid reasoning index (FRI) were observed in boys most exposed to a mixture of POPs. Increase of the WQS index was also associated with lower verbal comprehension index (VCI) scores in girls only. No other negative correlation was found using both WQS and PCA models. ConclusionOur study suggests deleterious associations between antenatal exposure to a mixture of POPs and sex-specific cognitive level, clarifying some trends described in the literature.

Effects of an environmentally relevant mixture of organochlorine pesticide compounds on adipogenesis and adipocyte function in an immortalized human adipocyte model

Exposure to persistent organic pollutants (POPs), including organochlorine (OC) pesticide POPs, has been associated with the increased prevalence of obesity and type 2 diabetes. However, the underlying mechanisms through which exposure to these compounds may promote obesity and metabolic dysfunction remain an area of active investigation. To this end, the concentration dependent effects of an environmentally relevant mixture of OC pesticide POPs on adipocyte function was explored utilizing a translationally relevant immortalized human subcutaneous preadipocyte/adipocyte model. Briefly, immortalized human preadipocytes/adipocytes were exposed to a mixture of dichlorodiphenyldichloroethylene (DDE), trans-nonachlor, and oxychlordane (DTO) then key indices of preadipocyte/adipocyte function were assessed. Exposure to DTO did not alter adipogenesis. However, in mature adipocytes, exposure to DTO slightly increased fatty acid uptake whereas isoproterenol stimulated lipolysis, basal and insulin stimulated glucose uptake, mitochondrial membrane potential, and cellular ATP levels were all significantly decreased. DTO significantly increased Staphylococcus aureus infection induced increases in expression of pro-inflammatory cytokines IL-6, IL-1β, and Mcp-1 as well as the adipokine resistin. Taken together, the present data demonstrated exposure to an environmentally relevant mixture of OC pesticide compounds can alter mature adipocyte function in a translationally relevant human adipocyte model which further supports the adipose tissue as an effector site of OC pesticide POPs action.

Environmental risk scores of persistent organic pollutants associate with higher ALS risk and shorter survival in a new Michigan case/control cohort

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal, progressive neurogenerative disease caused by combined genetic susceptibilities and environmental exposures. Identifying and validating these exposures are of paramount importance to modify disease...

Prepandemic personal concentrations of per- and polyfluoroalkyl substances (PFAS) and other pollutants: Specific and combined effects on the incidence of COVID-19 disease and SARS-CoV-2 infection

ObjectiveTo investigate the specific and combined effects of personal concentrations of some per- and polyfluoroalkyl substances (PFAS), other persistent organic pollutants (POPs), and chemical elements –measured in individuals’ blood several years before the pandemic– on the development of SARS-CoV-2 infection and COVID-19 disease in the general population. MethodsWe conducted a prospective cohort study in 240 individuals from the general population of Barcelona. PFAS, other POPs, and chemical elements were measured in plasma, serum, and whole blood samples, respectively, collected in 2016–2017. PFAS were analyzed by liquid chromatography-triple quadrupole mass spectrometry. SARS-CoV-2 infection was detected by rRT-PCR in nasopharyngeal swabs and/or antibody serology in blood samples collected in 2020–2021. ResultsNo individual PFAS nor their mixtures were significantly associated with SARS-CoV-2 seropositivity or COVID-19 disease. Previously identified mixtures of POPs and elements (Porta et al., 2023) remained significantly associated with seropositivity and COVID-19 when adjusted for PFAS (all OR > 4 or p < 0.05). Nine chemicals comprised mixtures associated with COVID-19: thallium, ruthenium, lead, benzo[b]fluoranthene, DDD, other DDT-related compounds, manganese, tantalum, and aluminium. And nine chemicals comprised the mixtures more consistently associated with SARS-CoV-2 seropositivity: thallium, ruthenium, lead, benzo[b]fluoranthene, DDD, gold, and (protectively) selenium, indium, and iron. ConclusionsThe PFAS studied were not associated with SARS-CoV-2 seropositivity or COVID-19. The results confirm the associations between personal blood concentrations of some POPs and chemical elements and the risk of COVID-19 and SARS-CoV-2 infection in what remains the only prospective and population-based cohort study on the topic. Mixtures of POPs and chemical elements may contribute to explain the heterogeneity in the risks of SARS-CoV-2 infection and COVID-19 in the general population.

&lt;i&gt;Danio rerio&lt;/i&gt; as a model for studying reproductive risks associated with human exposure to polychlorinated biphenils: a systematic review

This review presents the findings of a comprehensive investigation that involved a systematic search, critical analysis, and synthesis of scientific evidence regarding the impact of a broad range of persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), on the reproductive functions, postembryonic survival, and morphofunctional development of offspring in the aquarium fish species Danio rerio, commonly known as Zebrafish. These fish are extensively utilized in experimental studies to simulate carcinogenic, mutagenic, and general toxic effects.&#x0D; The literature search was conducted using Web of Science, Scopus, PubMed, and eLIBRARY.RU databases following the PRISMA 2020 recommendations. A total of 613 articles were identified, out of which 14 were selected for detailed analysis. Among them, 11 focused on assessing the impact of PCB exposure on the reproductive system of Danio rerio. Additionally, 8 articles reported on the results of studying the effects of parental exposure to PCBs on the viability and postembryonic development of their offspring. The adverse effects of PCBs, either alone or in combination with other POPs, have been studied to a lesser extent in male Danio rerio compared to females. Furthermore, the transmission of morphological and functional disorders to subsequent generations resulting from separate parental exposure to PCBs in both sexes, as well as the dose-response relationship, have not been adequately assessed based on the published works. Moreover, developmental disorders in offspring have mostly been studied for the first generation following parental exposure to mixtures of POPs and PCBs. The lack of such information hinders a proper evaluation of the transgenerational risk inheritance phenomenon, specifically regarding the transmission of morphological and functional disorders associated with progenitor exposure to PCBs and other environmental endocrine-disrupting pollutants.&#x0D; The findings of this analysis can be used for planning experimental quantitative assessments, predicting, and preventing impairments to human reproductive health, and safeguarding the well-being of future generations.

The effects of pollutant mixture released from grafted adipose tissues on fatty acid and lipid metabolism in the skeletal muscles, kidney, heart, and lungs of male mice

Persistent organic pollutants (POPs) accumulated in the adipose tissue can affect the fatty acid and lipid metabolism in the body. Gas chromatography-mass spectrometry (GC-MS) metabolomics analysis was carried out to study the metabolic changes induced by internal exposure to the POPs in mouse skeletal muscle (soleus, plantaris, and gastrocnemius), kidney, heart, and lungs. Male donor mice were injected with a mixture of 10 POPs at concentrations of 0 × and 5 × lowest-observed-adverse-effect level (LOAEL). Their adipose tissue (AT) containing the POP was then grafted onto the host mice and the metabolic change of the host mice was monitored for 3 or 21 days. The metabolites related to fatty acid and lipid metabolism were studied. For the host mice engrafted with POP-containing fat pad, there was dysregulation of the fatty acids and glycerides observed in all the organs studied 3 days after the graft. However, there was no longer a significant change in the metabolites 21 days after the graft. The difference in significant values and metabolite regulation in each of the skeletal muscles showed that the POP mixture affects different types of skeletal muscle in a heterogeneous manner. Fold change analysis showed that certain metabolites in the kidney of host mice exposed to POPs for 3 days were greatly affected. Using multivariate analysis, apart from the plantaris, most treated groups exposed to POPs for 3 days are well distinguished from the control groups. However, for host mice exposed to POPs for 21 days, apart from the kidney and heart, groups are not well-distinguished from the control group. This study helps bring new insight into the effects of the pollutants mixture released from AT on fatty acid and lipid metabolism at different periods and how the dysregulation of metabolites might result in diseases associated with the organs.

Prenatal exposure to multiple persistent organic pollutants in association with adiposity markers and blood pressure in preadolescents

BackgroundSeveral studies have reported that prenatal exposure to some persistent organic pollutants (POPs) is associated with higher adiposity in childhood. Few studies have assessed whether this finding persists into adolescence, and few have considered exposure to POPs as a mixture. This study aims to assess the association between prenatal exposure to multiple POPs and adiposity markers and blood pressure in preadolescents. MethodsThis study included 1667 mother-child pairs enrolled in the PELAGIE (France) and the INMA (Spain) mother-child cohorts. Three polychlorobiphenyls (PCB 138, 153 and 180, treated as a sum of PCBs) and three organochlorine pesticides (p,p′-Dichlorodiphenyldichloroethylene [p,p′-DDE], β-hexachlorocyclohexane [β-HCH], and hexachlorobenzene [HCB]) were assessed in maternal or cord serum. Body mass index z-score (zBMI), abdominal obesity (waist-to-height ratio > 0.5), percentage of fat mass, and blood pressure (mmHg) were measured at around 12 years of age. Single-exposure associations were studied using linear or logistic regressions, and the POP mixture effect was evaluated using quantile G-computation (qgComp) and Bayesian Kernel Machine Regression (BKMR). All models were adjusted for potential confounders and performed for boys and girls together and separately. ResultsPrenatal exposure to the POP mixture was associated with higher zBMI (beta [95 % CI] of the qgComp = 0.15 [0.07; 0.24]) and percentage of fat mass (0.83 [0.31; 1.35]), with no evidence of sex-specific association. These mixture effects were also statistically significant using BKMR. These associations were driven mainly by exposure to HCB and, to a lesser extent, to β-HCH. In addition, the single-exposure models showed an association between β-HCH and p,p′-DDE and higher systolic blood pressure, especially in girls (p,p′-DDE for girls = 1.00 [0.15; 1.86]). No significant associations were found for PCBs. ConclusionThis study suggests that prenatal exposure to POPs, particularly organochlorine pesticides, remains associated with unfavorable cardiometabolic health up to the age of 12.

Associations of prenatal exposure to a mixture of persistent organic pollutants with social traits and cognitive and adaptive function in early childhood: Findings from the EARLI study

BackgroundLiterature suggests that maternal exposure to persistent organic pollutants (POPs) may influence child neurodevelopment. Evidence linking prenatal POPs and autism spectrum disorder has been inconclusive and few studies have examined the mixture effect of the POPs on autism-related traits. ObjectiveTo evaluate the associations between prenatal exposure to a mixture of POPs and autism-related traits in children from the Early Autism Risk Longitudinal Investigation study. MethodsMaternal serum concentrations of 17 POPs (11 polychlorinated biphenyls [PCBs], 4 polybrominated diphenyls [PBDEs], and 2 persistent pesticides) in 154 samples collected during pregnancy were included in this analysis. We examined the independent associations of the natural log-transformed POPs with social, cognitive, and behavioral traits at 36 months of age, including Social Responsiveness Scale (SRS), Mullen Scales of Early Learning-Early Learning Composite (MSEL-ELC), and Vineland Adaptive Behavior Scales (VABS) scores, using linear regression models. We applied Bayesian kernel machine regression and quantile g-computation to examine the joint effect and interactions of the POPs. ResultsHigher ln-PBDE47 was associated with greater deficits in social reciprocity (higher SRS score) (β = 6.39, 95% CI: 1.12, 11.65) whereas higher ln-p,p’-DDE was associated with lower social deficits (β = −8.34, 95% CI: −15.32, −1.37). Positive associations were observed between PCB180 and PCB187 and cognitive (MSEL-ELC) scores (β = 5.68, 95% CI: 0.18, 11.17; β = 4.65, 95% CI: 0.14, 9.17, respectively). Adaptive functioning (VABS) scores were positively associated with PCB170, PCB180, PCB187, PCB196/203, and p,p’-DDE. In the mixture analyses, we did not observe an overall mixture effect of POPs on the quantitative traits. Potential interactions between PBDE99 and other PBDEs were identified in association with MSEL-ELC scores. ConclusionsWe observed independent effects of PCB180, PCB187, PBDE47, and p,p’ DDE with ASD-related quantitative traits and potential interactions between PBDEs. Our findings highlight the importance of assessing the effect of POPs as a mixture.

A Realistic Mixture of Persistent Organic Pollutants Affects Zebrafish Development, Behavior, and Specifically Eye Formation by Inhibiting the Condensin I Complex.

Persistent organic pollutants (POPs) are posing major environmental and health threats due to their stability, ubiquity, and bioaccumulation. Most of the numerous studies of these compounds deal with single chemicals, although real exposures always consist of mixtures. Thus, using different tests, we screened the effects on zebrafish larvae caused by exposure to an environmentally relevant POP mixture. Our mixture consisted of 29 chemicals as found in the blood of a Scandinavian human population. Larvae exposed to this POP mix at realistic concentrations, or sub-mixtures thereof, presented growth retardation, edemas, retarded swim bladder inflation, hyperactive swimming behavior, and other striking malformations such as microphthalmia. The most deleterious compounds in the mixture belong to the per- and polyfluorinated acids class, although chlorinated and brominated compounds modulated the effects. Analyzing the changes in transcriptome caused by POP exposure, we observed an increase of insulin signaling and identified genes involved in brain and eye development, leading us to propose that the impaired function of the condensin I complex caused the observed eye defect. Our findings contribute to the understanding of POP mixtures, their consequences, and potential threats to human and animal populations, indicating that more mechanistic, monitoring, and long-term studies are imperative.

Establishment of killer whale (Orcinus orca) primary fibroblast cell cultures and their transcriptomic responses to pollutant exposure

Populations of killer whale (Orcinus orca) contain some of the most polluted animals on Earth. Yet, the knowledge on effects of chemical pollutants is limited in this species. Cell cultures and in vitro exposure experiments are pertinent tools to study effects of pollutants in free-ranging marine mammals. To investigate transcriptional responses to pollutants in killer whale cells, we collected skin biopsies of killer whales from the Northern Norwegian fjords and successfully established primary fibroblast cell cultures from the dermis of 4 out of 5 of them. Cells from the individual with the highest cell yield were exposed to three different concentrations of a mixture of persistent organic pollutants (POPs) that reflects the composition of the 10 most abundant POPs found in Norwegian killer whales (p,p’-DDE, trans-nonachlor, PCB52, 99, 101, 118, 138, 153, 180, 187). Transcriptional responses of 13 selected target genes were studied using digital droplet PCR, and whole transcriptome responses were investigated utilizing RNA sequencing. Among the target genes analysed, CYP1A1 was significantly downregulated in the cells exposed to medium (11.6 µM) and high (116 µM) concentrations of the pollutant mixture, while seven genes involved in endocrine functions showed a non-significant tendency to be upregulated at the highest exposure concentration. Bioinformatic analyses of RNA-seq data indicated that 13 and 43 genes were differentially expressed in the cells exposed to low and high concentrations of the mixture, respectively, in comparison to solvent control. Subsequent pathway and functional analyses of the differentially expressed genes indicated that the enriched pathways were mainly related to lipid metabolism, myogenesis and glucocorticoid receptor regulation. The current study results support previous correlative studies and provide cause-effect relationships, which is highly relevant for chemical and environmental management.

Luteolin protects against adipogenic and lipogenic potency induced by human relevant mixtures of persistent organic pollutants (POPs) in the 3T3-L1 model.

Human exposure to persistent organic pollutants (POPs) may contribute to obesogenic effects. We have previously shown that POP mixtures modelled on blood levels relevant to the Scandinavian population induces adipogenic effects in the mouse 3T3-L1 cell line. Luteolin is a flavone that has shown anti-lipogenic and anti-adipogenic effects on adipogenesis in in vitro models. In this study, luteolin has been applied to inhibit adipocyte formation and intracellular lipid content increase induced by a human relevant mixture of POPs. 3T3-L1 cells were exposed to a POP mixture consisting of 29 chemicals, including amongst others polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), perfluoroalkylated acids (PFAAs), and polybrominated diphenyl ethers (PBDEs). Rosiglitazone was applied as a positive lipogenic control. Luteolin was tested between 0.5 and 10μM. High content analysis was used to assess changes in adipocyte formation and intracellular lipid content in the 3T3-L1 cell line. Luteolin significantly reduced POP-induced adipocyte formation at 2, 5 and 10μM, and lipid accumulation at 10μM. Interestingly, luteolin did not affect rosiglitazone induced adipo- and lipogenic effects, suggesting differences in mechanisms of action. In conclusion, this in vitro study shows that dietary polyphenols such as luteolin may protect against POP induced adipo- and lipogenic effects.

Impact of mixtures of persistent organic pollutants on breast cancer aggressiveness

Impact of mixtures of persistent organic pollutants on breast cancer aggressiveness

Exposure to persistent organic pollutants alters the serum metabolome in non-obese diabetic mice

IntroductionAutoimmune disorders such as type 1 diabetes (T1D) are believed to be caused by the interplay between several genetic and environmental factors. Elucidation of the role of environmental factors in metabolic and immune dysfunction leading to autoimmune disease is not yet well characterized.ObjectivesHere we investigated the impact of exposure to a mixture of persistent organic pollutants (POPs) on the metabolome in non-obese diabetic (NOD) mice, an experimental model of T1D. The mixture contained organochlorides, organobromides, and per- and polyfluoroalkyl substances (PFAS).MethodsAnalysis of molecular lipids (lipidomics) and bile acids in serum samples was performed by UPLC-Q-TOF/MS, while polar metabolites were analyzed by GC-Q-TOF/MS.ResultsExperimental exposure to the POP mixture in these mice led to several metabolic changes, which were similar to those previously reported as associated with PFAS exposure, as well as risk of T1D in human studies. This included an increase in the levels of sugar derivatives, triacylglycerols and lithocholic acid, and a decrease in long chain fatty acids and several lipid classes, including phosphatidylcholines, lysophosphatidylcholines and sphingomyelins.ConclusionTaken together, our study demonstrates that exposure to POPs results in an altered metabolic signature previously associated with autoimmunity.

Impact of mixtures of persistent organic pollutants on breast cancer aggressiveness

IntroductionBreast cancer (BC) is frequent with a poor prognosis in case of metastasis. The role of the environment has been poorly evaluated in its progression. We searched to assess whether a mixture of pollutants could be responsible of BC aggressiveness. MethodsPatients undergoing surgery for their BC were prospectively included in the METAPOP cohort. Forty-two POPs were extracted, among them 17 dioxins (PCDD/F), 16 polychlorobiphenyls (PCB), 8 polybromodiphenylethers (PBDE) and 2,2′,4,4′,5,5′-hexabromobiphenyl (PBB153) were measured in the adipose tissue surrounding the tumor. BC aggressiveness was defined using tumor size and metastasis (distant or lymph nodes). Two complementary models were used to evaluate the impact of the mixture of pollutants: the BKMR (Bayesian Kernel machine regression) and WQS (weighted quantile sum regression) models. The WQS estimates the weight (positive or negative) of a certain chemical based on its quantile and the BKMR model applies a kernel-based approach to estimate posterior inclusion probabilities. The sub-group of patients with a body mass index (BMI) > 22 kg/ m2 was also analyzed. ResultsNinety-one patients were included. Of these, 38 patients presented a metastasis, and the mean tumor size was 25.4 mm. The mean BMI was 24.5 kg/m2 (+/- 4.1). No statistical association was found in the general population. However, in patients with a BMI > 22 kg/ m2, our mixture was positively associated with tumor size (OR: 9.73 95 %CI: 1.30–18.15) and metastasis (OR = 3.98 95 %CI = 1.09–17.53) using the WQS model. Moreover, using the BKMR model on chemical families, dioxin like chemicals and PCDD were associated with a higher risk of metastasis. DiscussionThese novel findings identified a mixture associated with breast cancer aggressiveness in patients with a BMI > 22 kg/ m2.

Principal Component Pursuit for Pattern Identification in Environmental Mixtures.

Environmental health researchers often aim to identify sources or behaviors that give rise to potentially harmful environmental exposures. We adapted principal component pursuit (PCP)-a robust and well-established technique for dimensionality reduction in computer vision and signal processing-to identify patterns in environmental mixtures. PCP decomposes the exposure mixture into a low-rank matrix containing consistent patterns of exposure across pollutants and a sparse matrix isolating unique or extreme exposure events. We adapted PCP to accommodate nonnegative data, missing data, and values below a given limit of detection (LOD). We simulated data to represent environmental mixtures of two sizes with increasing proportions and three noise structures. We applied PCP-LOD to evaluate its performance in comparison with principal component analysis (PCA). We next applied principal component pursuit with limit of detection (PCP-LOD) to an exposure mixture of 21 persistent organic pollutants (POPs) measured in 1,000 U.S. adults from the 2001-2002 National Health and Nutrition Examination Survey (NHANES). We applied singular value decomposition to the estimated low-rank matrix to characterize the patterns. PCP-LOD recovered the true number of patterns through cross-validation for all simulations; based on an a priori specified criterion, PCA recovered the true number of patterns in 32% of simulations. PCP-LOD achieved lower relative predictive error than PCA for all simulated data sets with up to 50% of the data . When 75% of values were , PCP-LOD outperformed PCA only when noise was low. In the POP mixture, PCP-LOD identified a rank-three underlying structure and separated 6% of values as extreme events. One pattern represented comprehensive exposure to all POPs. The other patterns grouped chemicals based on known structure and toxicity. PCP-LOD serves as a useful tool to express multidimensional exposures as consistent patterns that, if found to be related to adverse health, are amenable to targeted public health messaging. https://doi.org/10.1289/EHP10479.

Exposure of zebrafish to an environmental mixture of persistent organic pollutants triggers an increase in anxiety-like syndrome but does not affect boldness in unexposed offspring.

Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants (POPs) that are present as complex mixtures in all environmental compartments, including aquatic ecosystems. However, little is known about the effects of such complex mixtures on teleost behaviour. In this study, zebrafish (Danio rerio) were chronically exposed to an environmentally relevant mixture (MIX) containing 22 PCB and 7 PBDE congeners through diet from 5days post fertilization onwards. MIX-exposed F0 fish produced offspring (F1 and F2 generations) that were fed using plain food and grown until adulthood. In each generation, five behavioural traits (i.e. boldness, activity, sociality, exploration and anxiety) were evaluated by the mean of different experimental set-ups. Two distinct behavioural syndromes were identified: boldness, positively correlated to activity and exploration; and anxiety, associated with low sociality. F0 fish did not display any behavioural disruption resulting from POP exposure whereas F1 MIX fish were bolder than fish from other generations but did not differ significantly from F1 controls. F2 MIX fish displayed a higher anxiety syndrome than F2 controls. This is of particular importance since such behavioural changes in offspring generations may have persistent ecological consequences, may affect fitness and hence cause detrimental effects on wild fish populations exposed to POP mixtures.

Exposure to environmental contaminants and folic acid supplementation intergenerationally impact fetal skeleton development through the paternal lineage in a rat model.

Persistent organic pollutants (POPs) are ubiquitous in the environment, which is of concern since they are broadly toxic for wildlife and human health. It is generally accepted that maternal prenatal folic acid supplementation (FA) may beneficially impact offspring development, but it has been recently shown that the father's exposures also influence the health of his offspring. Bone is an endocrine organ essential for whole-body homeostasis and is susceptible to toxicants. Herein, we tested the hypotheses that prenatal paternal exposure to POPs induces developmental bone disorders in fetuses across multiple generations and that FA supplementation attenuates these disorders. We used a four-generation rat model, in which F0 founder females were divided into four treatment groups. F0 females were gavaged with corn oil or an environmentally-relevant POPs mixture and fed either a control diet (2 mg FA/kg), or FA supplemented diet (6 mg FA/kg) before mating and until parturition (four treatments in total). After the birth of the F1 litters, all F0 females and subsequent generations received the FA control diet. Staining with alcian blue and alizarin red S of male and female fetal skeletons was performed at Gestational Day 19.5. Paternal direct and ancestral exposure to POPs delayed bone ossification and decreased the length of long limb bones in fetuses. Maternal FA supplementation did not counteract the POPs-associated delayed fetal ossification and reduced long bone length. In conclusion, prenatal paternal POPs exposure causes developmental bone abnormalities over multiple generations, which were not corrected by maternal FA supplementation.