Persistent Organic Pollutants Exposure Research Articles

An Overview of Methods to Address Distinct Research Questions on Environmental Mixtures

OPS 21: Methodological progress in chemicals health effects research, Room 210, Floor 2, August 26, 2019, 4:30 PM - 5:30 PM Background. Multiple methods exist to analyze environmental mixtures in health studies. To illustrate the differences among methods based on the research question each answer, we employed methods geared toward distinct research questions in a sample concerning persistent organic pollutants (POPs) as a mixture and leukocyte telomere length (LTL) as an outcome. Methods. With information on 18 POPs and LTL among 1,003 U.S. adults (NHANES, 2001– 2002), we used unsupervised methods including clustering, to identify profiles of similarly exposed participants, and Principle Component Analysis (PCA) and Exploratory Factor Analysis (EFA), to identify common exposure patterns. We also applied supervised learning techniques including penalized, weighted quantile sum (WQS), and Bayesian kernel machine (BKMR) regressions, to identify potentially toxic agents and characterize nonlinear associations, interactions, and the overall mixture effect. Results. Clustering separated participants into high, medium, and low POP exposure groups; longer log-LTL was found among those with high exposure. The first PCA component represented overall POP exposure and was positively associated with log-LTL. Two EFA factors, one representing furans and the other PCBs 126 and 118, were positively associated with log-LTL. Penalized regression methods selected three congeners in common (PCB 126, PCB 118, and furan 2,3,4,7,8-pncdf) as potentially toxic agents. WQS found a positive overall effect of the POP mixture and identified six POPs as potentially toxic agents (furans 1,2,3,4,6,7,8-hxcdf, 2,3,4,7,8-pncdf, and 1,2,3,6,7,8-hxcdf, and PCBs 99, 126, 169). BKMR found a positive linear association with furan 2,3,4,7,8-pncdf, suggestive evidence of linear associations with PCBs 126 and 169, and a positive overall effect of the mixture, but no interactions among congeners. Discussion. Using different methods, we identified patterns of POP exposure, potentially toxic agents, the absence of interaction, and estimated the overall mixture effect. These applications and results may serve as a guide for mixture method selection based on specific research questions.

Persistent Organic Pollutants and the Association with Thyroid Hormone Homeostasis in Placenta

PDS 74: Pregnancy outcomes, Exhibition Hall (PDS), Ground floor, August 26, 2019, 1:30 PM - 3:00 PM Background: Prenatal exposure to persistent organic pollutants (POPs) can interfere with thyroid hormone (TH) homeostasis, resulting in disorders in fetal and postnatal development [1]. Here we aim to develop a method for TH determination in placenta and examine the associations of THs with POPs. Methods: Liquid chromatography with quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) method was developed for the quantification of thyroxine (T4), 3,3’,5-triiodothyronine (T3), and 3,3’,5’-triiodothyronine (rT3), 3,3’-diiodo-L-thyronine (T2), 3,5-diiodo-L-thyronine (rT2), 3-iodo-L-thyronine (T1) and 3-iodothyronamine (T1AM) in placenta [2]. Fifty-eight placenta samples were collected from a Danish birth cohort study. The levels of THs and a wide variety of POPs, including polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs), organotin chemicals (OTCs), organochlorine pesticides (OCPs) were measured. The associations between placental THs and various POPs were analyzed using multiple linear regression [3]. Results: The LC-Q-TOF-MS method developed here showed high sensitivity and selectivity. T4, T3, rT3, and T2 were measured in human placenta. Five PBDEs, 35 PCBs, 14 PCDD/Fs, 3 OTCs, 25 OCPs were also quantified. Some significant associations were observed here: a) T4 was inversely associated with BDEs 99, 100, ΣPBDE, and 2378-TCDD, and positively associated with 1234678-HpCDF; b) T3 was positively associated with 2378-TCDF and 12378-PeCDF; c) rT3 was positively associated with PCB 81, 12378-PeCDF and 234678-HxCDF, and inversely associated with tributyltin (TBT), ΣOTC, and methoxychlor (MOC). Conclusion: This study shows that POP exposures were associated with TH levels in placenta, which leads to the concerns of environmental exposure on the proper development of the fetus and children. The method here allows a comprehensive evaluation of TH homeostasis in research of environmental exposures.

Folic acid supplementation reduces multigenerational sperm miRNA perturbation induced by in utero environmental contaminant exposure.

Persistent organic pollutants (POPs) can induce epigenetic changes in the paternal germline. Here, we report that folic acid (FA) supplementation mitigates sperm miRNA profiles transgenerationally following in utero paternal exposure to POPs in a rat model. Pregnant founder dams were exposed to an environmentally relevant POPs mixture (or corn oil) ± FA supplementation and subsequent F1–F4 male descendants were not exposed to POPs and were fed the FA control diet. Sperm miRNA profiles of intergenerational (F1, F2) and transgenerational (F3, F4) lineages were investigated using miRNA deep sequencing. Across the F1–F4 generations, sperm miRNA profiles were less perturbed with POPs+FA compared to sperm from descendants of dams treated with POPs alone. POPs exposure consistently led to alteration of three sperm miRNAs across two generations, and similarly one sperm miRNA due to POPs+FA; which was in common with one POPs intergenerationally altered sperm miRNA. The sperm miRNAs that were affected by POPs alone are known to target genes involved in mammary gland and embryonic organ development in F1, sex differentiation and reproductive system development in F2 and cognition and brain development in F3. When the POPs treatment was combined with FA supplementation, however, these same miRNA-targeted gene pathways were perturbed to a lesser extend and only in F1 sperm. These findings suggest that FA partially mitigates the effect of POPs on paternally derived miRNA in a intergenerational manner.

Maternal folic acid supplementation does not counteract the deleterious impact of prenatal exposure to environmental pollutants on lipid homeostasis in male rat descendants.

Prenatal exposure to persistent organic pollutants (POPs) has been associated with the development of metabolic syndrome-related diseases in offspring. According to epidemiological studies, father's transmission of environmental effects in addition to mother's can influence offspring health. Moreover, maternal prenatal dietary folic acid (FA) may beneficially impact offspring health. The objective is to investigate whether prenatal FA supplementation can overcome the deleterious effects of prenatal exposure to POPs on lipid homeostasis and inflammation in three generations of male rat descendants through the paternal lineage. Female Sprague-Dawley rats (F0) were exposed to a POPs mixture (or corn oil) +/- FA supplementation for 9 weeks before and during gestation. F1 and F2 males were mated with untreated females. Plasma and hepatic lipids were measured in F1, F2, and F3 males after 12-h fast. Gene expression of inflammatory cytokines was determined by qPCR in epididymal adipose tissue. In F1 males, prenatal POPs exposure increased plasma lipids at 14 weeks old and hepatic lipids at 28 weeks old and prenatal FA supplementation decreased plasma total cholesterol at 14 weeks old. Prenatal POPs exposure decreased plasma triglycerides at 14 weeks old in F2 males. No change was observed in inflammatory markers. Our results show an impact of the paternal lineage on lipid homeostasis in rats up to the F2 male generation. FA supplementation of the F0 diet, regardless of POPs exposure, lowered plasma cholesterol in F1 males but failed to attenuate the deleterious effects of prenatal POPs exposure on plasma and hepatic lipids in F1 males.

Exploring the associations of serum concentrations of PCBs, PCDDs, and PCDFs with walking speed in the U.S. general population: Beyond standard linear models

Studies have shown that persistent organic pollutants (POPs) can have various health effects. However, little is known about the effects of multiple chemicals with possible common sources of exposure on walking speed, a proxy index reflecting lower limb neuromuscular function and physical function. We simultaneously applied multiple linear and nonlinear statistical models to explore the complex exposure-response relationship between a mixture of 22 selected POPs and walking speed. A total of 14 polychlorinated biphenyls (PCBs), 3 polychlorinated dibenzo-p-dioxins (PCDDs), and 5 polychlorinated dibenzofurans (PCDFs) were measured in the serum of participants in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2002. Walking speed was measured during a physical examination. Linear regression (LR), least absolute shrinkage and selection operator (LASSO), and group LASSO were used to evaluate the linearity of mixtures, while restricted cubic spline (RCS) regression, random forest (RF), and Bayesian kernel machine regression (BKMR) models were used to evaluate the nonlinearity of mixtures. Potential confounders were adjusted in the above models. A total of 436 subjects were included in our final analysis. The results of the LR model did not identify any POP exposure that was significantly associated with walking speed. The LASSO results revealed an inverse association of one PCDD congener and two PCDF congeners with walking speed, while the group LASSO analysis identified PCDFs at the exposure level and at the group level. In the RCS analysis, two PCB congeners presented significant overall associations with walking speed. The PCB congener PCB194 showed statistically significant effects on the outcome (P = 0.01) when a permutation-based RF was used. The BKMR analysis suggested that PCBs and PCDFs (probabilities = 0.887 and 0.909, respectively) are potentially associated with walking speed. Complex statistical models, such as RCS regression, RF and BKMR models, can detect the nonlinear and nonadditive relationships between PCBs and walking speed, while LASSO and group LASSO can identify only the linear relationships between PCDFs and walking speed. Fully considering the influence of collinearity in each method during modelling can increase the comprehensiveness and reliability of conclusions in studies of multiple chemicals.

Associations between persistent organic pollutants and risk of breast cancer metastasis

BackgroundBreast cancer (BC) is a major public health concern with over 2 million new cases diagnosed and over 600,000 deaths in 2018 in women worldwide. When distant metastases are present at diagnosis, the 5-year survival rate is only 26%. Recent studies have suggested that persistent organic pollutants (POPs) that accumulate in adipose tissue (AT) can influence tumor phenotype and stimulate cellular processes important for metastasis such as invasion. We, therefore, tested the hypothesis that POP exposure is associated with BC metastasis. MethodsWe conducted an exploratory case-control study in which the concentrations of 49 POPs were measured in both AT and serum samples from BC patients, with or without lymph node metastasis, who underwent partial or total mastectomies, lymph node biopsies and sampling of the adipocytic tumor microenvironment. Adjusted, unconditional logistic models were used to study the associations between the POP concentrations and the risk of metastasis and other hallmarks of cancer aggressiveness. Results2.3.7.8-TCDD concentrations in AT are positively associated with the risk of metastasis in 43 patients who have BMIs equal or higher than 25 kg/m2 (odds ratio: 4.48 (1.32–20.71)). Furthermore, the concentrations of 2.3.7.8-TCDD and two coplanar PCBs (77&169) in AT also were positively associated with the risk of lymph node metastasis and the tumor size. ConclusionOur study suggests that 2.3.7.8-TCDD and some PCBs contribute to the development of tumor metastasis and other hallmarks of cancer aggressiveness. While these results should be considered with caution, this is the first study to identify such potential risk factors. Larger longitudinal studies are necessary to confirm our results.Clinical Trial Protocol Record: 2013-A00663-42.

Joint Analysis of Metabolite Markers of Fish Intake and Persistent Organic Pollutants in Relation to Type 2 Diabetes Risk in Swedish Adults

There is conflicting evidence regarding the association between fish intake and type 2 diabetes (T2D) incidence, possibly owing to measurement errors in self-reported intake and coexposure to persistent organic pollutants (POPs) present in fish. The aim of this study was to identify plasma metabolites associated with fish intake and to assess their association with T2D risk, independently of POPs, in Swedish adults. In a case-control study nested in the Swedish Västerbotten Intervention Programme, fasting plasma samples from 421 matched T2D case-control pairs of men and women aged 30-60 y at baseline and 10-y follow-up samples from a subset of 149 pairs were analyzed using untargeted metabolomics. Moreover, 16 plasma POPs were analyzed for the 149 pairs who had repeated samples available. Fish-related plasma metabolites were identified using multivariate modelling and partial correlation analysis. Reproducibility of metabolites and metabolite patterns, derived via principal component analysis (PCA), was assessed by intraclass correlation. A unique component of metabolites unrelated to POPs was dissected by integrating metabolites and POPs using 2-way orthogonal partial least squares regression. ORs of T2D were estimated using conditional logistic regression. We identified 31 metabolites associated with fish intake that had poor to good reproducibility. A PCA-derived metabolite pattern strongly correlated with fish intake (ρ=0.37, P<0.001) but showed no association with T2D risk. Integrating fish-related metabolites and POPs led to a unique metabolite component independent of POPs, which tended to be inversely associated with T2D risk (OR: 0.75; 95% CI: 0.54, 1.02, P=0.07). This component mainly consisted of metabolites reflecting fatty fish intake. Our results suggest that fatty fish intake may be beneficial for T2D prevention, after removing the counteractive effects of coexposure to POPs in Swedish adults. Integrating metabolite markers and POP exposures appears a promising approach to advance the understanding of associations between fish intake and T2D incidence.

Associations between Exposure to Persistent Organic Pollutants and Thyroid Function in a Case-Control Study of East China.

Animal studies have indicated that persistent organic pollutants (POPs) affect thyroid hormone homeostasis, while epidemiological studies involving human have not shown consistent results. In this study, we investigated the associations between POP exposure and thyroid function among adult population of East China. One hundred eighty-six participants diagnosed with thyroid disease and 186 participants without thyroid disease from Shandong, China were enrolled in the case-control study during 2016 to 2017. We found that POP exposure was significantly and positively associated with the risk of thyroid disease. The association of thyroid disease with a sum of 17 POPs followed a nonmonotonic dose response, with an adjusted odds ratio of 2.09 (95% confidence intervals: 1.13-3.87, p = 0.019) for the second quartile. Among 186 participants in the control group, concentrations of POPs showed negative associations with triiodothyronine (T3), free T3 (FT3), thyroxine (T4), and free T4 (FT4) in males and positive associations with T4 and FT4 in females. Taken together, these findings suggest that POP exposure can disrupt thyroid hormone homeostasis and increase the risk of thyroid disease.

Persistent organic pollutants (POPs) increase rage signaling to promote downstream cardiovascular remodeling.

Exposure to environmental contaminants and consumption of a high, saturated fatty diet has been demonstrated to promote precursors for metabolic syndrome (hyperglycemia, hyperinsulinemia, and hypertriglyceridemia). The purpose of this study was to determine if exposure to the most prevalent environmental persistent organic pollutants (POPs) would act as causative agents to promote metabolic syndrome independent of dietary intake. We hypothesized that POPs will activate the advanced glycated end‐product (AGE)‐and receptor for AGE (RAGE) signaling cascade to promote downstream signaling modulators of cardiovascular remodeling and oxidative stress in the heart. At 5‐weeks of age nondiabetic (WT) and diabetic (ob/ob) mice were exposed POPs mixtures by oral gavage twice a week for 6‐weeks. At the end of 6‐weeks, animals were sacrificed and the hearts were taken for biochemical analysis. Increased activation of the AGE‐RAGE signaling cascade via POPs exposure resulted in elevated levels of fibroblast differentiation (α‐smooth muscle actin) and RAGE expression indicated maladaptive cardiac remodeling. Conversely, the observed decreased superoxide dismutase‐1 and ‐2 (SOD‐1 and SOD‐2) expression may exacerbate the adverse changes occurring as a result of POPs treatment to reduce innate cardioprotective mechanisms. In comparison, ventricular collagen levels were decreased in mice exposed to POPs. In conclusion, exposure to organic environmental pollutants may intensify oxidative and inflammatory stressors to overwhelm protective mechanisms allowing for adverse cardiac remodeling.

Maternal exposures to persistent organic pollutants are associated with DNA methylation of thyroid hormone-related genes in placenta differently by infant sex

Exposure to persistent organic pollutants (POPs) during pregnancy is associated with a disruption in thyroid hormone balance. The placenta serves as an important environment for fetal development and also regulates thyroid hormone supply to the fetus. However, epigenetic changes of thyroid regulating genes in placenta have rarely been studied. This study was conducted to evaluate the association between several POP concentrations in maternal serum and DNA methylation of thyroid hormone-related genes in the placenta. The placenta samples were collected from 106 Korean mother at delivery, and the promoter methylation of the placental genes was measured by a bisulfite pyrosequencing. The deiodinase type 3 (DIO3), monocarboxylate transporter 8 (MCT8), and transthyretin (TTR) genes were selected as the target genes as they play an important role in the regulation of fetal thyroid balance. Because people are exposed to multiple chemicals at the same time, a multiple-POP model using principal component analysis (PCA) was applied to evaluate the association between the multiple POPs exposure and the epigenetic change in placenta. In addition, a single-POP model which includes one chemical each in the statistical model for association was conducted.Based on the single-POP models, serum concentrations of p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) and brominated diphenyl ether-47 (BDE-47) were significantly associated with an increase in placental DIO3 methylation, but only among female infants. Among male infants, a positive association between serum p,p′-DDT and MCT8 methylation level was found. According to the multiple-POP models, serum DDTs were positively associated with DIO3 methylation in the placenta of female infants, while a positive association with MCT8 methylation was observed in those of the male infants. Our observation showed that in utero exposure to DDTs may influence the DNA methylation of DIO3 and MCT8 genes in the placenta, in a sexually dimorphic manner. These alterations in placental epigenetic regulation may in part explain the thyroid hormone disruption observed among the newborns or infants followed by in utero exposure to POPs.

1816-P: Sex-Specific Metabolic Imbalance and Hypothalamic Inflammation Triggered by Low-Grade Benzene Exposure

Current studies have shown that insulin resistance, T2D have been associated with long- term exposure to air and traffic pollution. Benzene is a highly volatile liquid, which is a constituent of crude petroleum. Given its ubiquitous utilization in industry as well as consumer products, it is classified as a common airborne pollutant. We hypothesized that benzene, at levels below carcinogenic contributes to insulin resistance and inflammatory responses linking persistent organic pollutants exposure to T2D mellitus. For this purpose, C57BL/6 mice in inhalation chambers were exposed to benzene concentration of 50 ppm for 6h/day for 4 weeks. We found that under these conditions, exposure to benzene did not significantly influence mice body weight, neither had it trigger any toxic responses in these animals. Despite normal fasting glucose and insulin levels, benzene-exposed male mice displayed significantly impaired glucose tolerance. Consequently, we detected an increase in hepatic genes associated with gluconeogenesis, G6Pase and Pck1, and the expression of SREBP-1c and SREBP-2, genes associated with lipid synthesis was significantly elevated in livers from benzene exposed male mice as compared to control mice. Female mice were completely resistant to the negative metabolic consequences of chronic benzene exposure. Further sex differences were apparent in neuroinflammatory responses, with greater male vulnerability observed in the hypothalamus of benzene- exposed animals. Benzene exposure promoted hypothalamic gliosis and robust neuronal activation in the arcuate, paraventricular, ventromedial and dorsomedial hypothalamic nucleus. These findings demonstrate male vulnerability to air pollution, and provide evidence that exposure to benzene induces metabolic imbalance and severe neuroinflammatory responses in a sex-specific manner. Persistent ambient benzene exposure may be a heretofore unrecognized contributor to metabolic diseases with male bias. Disclosure L.K. Debarba: None. A. Mulka: None. A.A. Awada: None. O. Didyuk: None. U. Klueh: Research Support; Self; The Leona M. and Harry B. Helmsley Charitable Trust. Other Relationship; Self; Cell and Molecular Tissue Engineering, LLC. M. Sadagurski: None. Funding The Leona M. and Harry B. Helmsley Charitable Trust

Selected persistent organic pollutants associated with the risk of primary ovarian insufficiency in women

Although some persistent organic pollutants (POPs) may not be currently in production, many of these chemicals still exist ubiquitously in the environment and continue to represent significant environmental health concern. One of the important concerns of POPs exposure may lead to the adverse reproductive consequences including primary ovarian insufficiency (POI), but the limited evidence has been reported so far. Our case-control study was performed to explore the association between serum levels of selected POPs and risk for POI in a Chinese female population, including 157 cases and 217 healthy controls. Serum concentrations of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs) and serum levels of reproductive hormones [follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol] were measured. The medians of dioxin-like PCBs (DL-PCBs) and p,p′-dichlorodiphenyltrichloroethane (p,p′-DDT) were significantly higher in case sera than in controls. Higher concentrations of DL-PCBs and p,p’-DDT were significantly associated with elevated risk of POI. A dose-response relationship was observed between the sum of DL-PCBs (Σ6 DL-PCBs) and the risk of POI (p for trend = 0.003), with odds ratios for the second and third tertiles, compared with the first, of 1.31- (95% CIs: 0.67–2.57) and 3.15-fold (95% CIs: 1.63–6.10), respectively. Similar results were observed for the sum of p,p′-DDT and its metabolites (Σ2 p,p′-DDTs). In control women, FSH levels were negatively associated with PCBs exposure, while LH had a positive association with OCPs. In patients with POI, exposure to PCBs was correlated with higher levels of LH, whereas exposure to OCPs was associated with lower levels of AMH. To the best of our knowledge, this study for the first provided evidence that exposure to PCBs and DDT could be the potential risk factors for POI in women.

SAT-179 Low Grade Benzene Exposure Induces Metabolic Dysbalance and Hypothalamic Inflammation in Mice

Type 2-diabetes mellitus (T2D) has become a global pandemic resulting in a reduced quality of life due to comorbidity and premature mortality. The World Health Organization estimates the current global prevalence at 8.4%, which represents a fourfold increase over the last four decades. In this same interval, the US prevalence has increased by 160%, such that it affects 1 in 11 Americans with a disproportionate impact on minorities. The choice of lifestyle, diet, lack of physical activity and the growing aging population is often used to explain the rise of the diabetes pandemic. However, it is now increasingly accepted that insulin resistance, T2D prevalence and mortality have been associated with long- term exposure to air and traffic pollution. Benzene is a highly volatile liquid, which is a constituent of crude petroleum. Given its ubiquitous utilization in industry as well as consumer products, it is classified as a common airborne pollutant. As such, any exposure to petroleum or its products can result in significant occupational benzene exposure. While it is well accepted that excessive benzene exposure is carcinogenic in animals and humans, little is known regarding the effect of non-carcinogenic benzene level exposure and its metabolic effects. Notably, benzene exposure from motor vehicle exhaust is higher in inner city populations, which suggests a causative role in the pathogenesis of T2D. We hypothesized that benzene, at levels below carcinogenic contributes to insulin resistance and inflammatory responses linking persistent organic pollutants (POP) exposure to type 2 diabetes mellitus. For this purpose, C57BL/6 mice in inhalation chambers were exposed to benzene concentration of 50 ppm for 6h/day for 4 weeks. We found that under these conditions, exposure to benzene did not significantly change male mice body weight, neither had it trigger any toxic responses in these animals. However, despite normal fasting glucose and insulin levels, glucose tolerance test (GTT) of benzene exposed male mice displayed significantly impaired IP glucose tolerance. Consequently, we detected an increase in hepatic genes associated with gluconeogenesis, G6Pase and Pck1, and the expression of SREBP-1c and SREBP-2, genes associated with lipid synthesis was significantly elevated in livers from benzene exposed mice as compared to control mice. Additionally, we detected significant neuroinflammatory response in the hypothalamus of benzene exposed mice. Benzene exposure promoted a significant increase on microglia and astrocytes numbers in the arcuate, ventromedial and dorsomedial hypothalamic nucleus. We conclude that exposure to benzene induces hyperglycemia and that hypothalamic inflammatory responses may be a sensitive indicator of inhaled benzene toxicity.

Examining the relationships between blubber steroid hormones and persistent organic pollutants in common bottlenose dolphins

Odontocete cetaceans bioaccumulate high concentrations of endocrine disrupting persistent organic pollutants (POPs), including dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyltrichloroethylene (DDE), and dichlorodiphenyldichloroethane (DDD) – collectively DDTs – but few studies have explored DDTs-mediated endocrine disruption in cetaceans. Herein, we use remotely collected blubber biopsies from common bottlenose dolphins (Tursiops truncatus) inhabiting a site with high localized DDTs contamination to study the relationships between DDTs exposure and steroid hormone homeostasis in cetaceans. We quantified blubber steroid hormone concentrations by liquid chromatography-tandem mass spectrometry and blubber POP concentrations by gas chromatography-mass spectrometry. We detected six steroid hormones in blubber, including progesterone (P4), 17-hydroxyprogesterone (17OHP4), androstenedione (AE), testosterone (T), cortisol (F), and cortisone (E). Sampled dolphins (n = 62) exhibited exposure to DDT, DDE, DDD, chlordanes (CHLDs), mirex, dieldrin, hexachlorobenzene, polychlorinated biphenyls (PCBs), and brominated diphenyl ethers (BDEs). Using principal components analysis (PCA), we determined that blubber DDTs primarily loaded to the first principal component (PC1) explaining 81.6% of the total variance in POP exposure, while the remaining POPs primarily loaded to the PC2 (10.4% of variance). PC1 scores were negatively correlated with blubber T in males and blubber F in females, suggesting that exposure to DDTs impacted androgen and corticosteroid homeostasis. These conclusions were further supported by observed negative correlations between T and o,p’-DDE, o,p’-DDD, and p,p’-DDD in males sampled in the fall, and between F and the six individual DDTs and ∑6DDTs in females. Overall, these results suggest that POP-mediated endocrine disruption may have occurred in this stock of dolphins, which could negatively impact their health and fitness. However, this study relied on uncontrolled incidental exposures, making it impossible to establish a causal relationship between DDTs exposure and endocrine effects. Importantly, this study demonstrates that remotely collected blubber biopsies are a useful matrix for studying endocrine disruption in marine mammals.

Transcriptomic analysis of Anabas testudineus and its defensive mechanisms in response to persistent organic pollutants exposure

The freshwater climbing perch (Anabas testudineus) can tolerate water environments contaminated with persistent organic pollutants (POPs). The mechanisms underlying this tolerance are unknown. We used de novo transcriptomic analysis to investigate the defensive mechanisms of A. testudineus against POPs based on its genetic features and biological responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure. Our results revealed a specific expansion of cytochrome P450 (CYP) 3A subfamily, which may be involved in the elimination of certain POPs. In xenobiotic responses, the aryl-hydrocarbon receptor (AhR) pathway represents a critical signaling mechanism, and we characterized four AhR and two AhR nuclear translocator homologs and one AhR repressor (AhRR) gene in A. testudineus. TCDD-induced AhRR and CYP1A mRNA upregulation suggests that negative-feedback regulation of AhR signaling through AhRR helps avoid excessive xenobiotic responses. Furthermore, liver and gill transcriptomic profiles were markedly altered after TCDD exposure, with some of the altered genes being related to common defensive responses reported in other species. Based on the newly identified TCDD-altered genes, several A. testudineus-specific responses are proposed, such as enhanced fatty acid β-oxidation. The genetic features of CYP3A subfamily and AhR pathway and the TCDD-induced defensive biological processes elucidated here enhance our understanding of A. testudineus defensive responses against POPs.

Persistent Organic Pollutant-Mediated Insulin Resistance.

Persistent organic pollutants (POPs) such as organochlorine (OC) pesticides, polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) have become wide-spread environmental contaminants as a consequence of their extensive use, long-range transport, and persistence. Because POPs are highly resistant to metabolic degradation, humans bioaccumulate these lipophilic and hydrophobic pollutants in fatty tissues for many years. Previous studies have demonstrated that POPs including PCBs are involved in the development of diabetes mellitus (DM) type 2 and insulin resistance. Numerous epidemiological studies suggest an association between POP burden and DM type 2/metabolic syndrome. In addition, several experimental studies have provided additional evidence supporting the association between POP exposure and DM type 2 or insulin resistance. Epidemiological and experimental studies have provided compelling evidence indicating that exposure to POPs increases the risk of developing insulin resistance and metabolic disorders. However, the detailed molecular mechanism underlying POP-induced insulin resistance is yet to be elucidated. In this article, we review literature that has reported on the association between POP burden and insulin resistance and the mechanism underlying POP-induced insulin resistance, and discuss implications for public health.

Monitoring of environmental persistent organic pollutants in hair samples collected from wild terrestrial mammals of Primorsky Krai, Russia.

Persistent organic pollutants (POPs) constitute a wide range of chemicals. Their release into the environment has raised great concern due to their potentially harmful impact in humans and wildlife species. The aim of this current study was to detect selected POPs in hair samples of wild terrestrial mammals from Primorsky Krai, Russia, so as to assess potential environmental exposure. The tested wild species were leopard cat, musk deer, wolf, amur hedgehog, and raccoon dog. The targeted organochlorines were hexachlorobenzene (HCB) and DDTs (opDDE, ppDDE, and opDDD), polychlorinated biphenyl (PCB) congeners (28, 52, 101, 118, 138, 153, and 180), and polycyclic aromatic hydrocarbons (PAHs) (acenaphylene (ACEN), fluorene (FLU), anthracene (ANTH) phenathrene (PHEN), and pyrene (PYR)). The detection of POPs was conducted in hair samples by a one-step hair extraction method, by using a headspace solid-phase microextraction technique (HS-SPME) and analyzed then by GC-MS. The majority of the wild animal hair samples were found positive in all tested pollutants. More specifically, the percentage of positive hair samples for HCB was 93.3% and for DDTs, PCBs, and PAHs, 20.0 to 100.0%, 6.7 to 100.0%, and 75.0 to 100.0%, respectively. DDT, PCB, and PAH detection ranged from 1.26 to 52.06pgmg-1, 0.73 to 31.34pgmg-1, and 2.59 to 35.00pgmg-1, respectively. The highest mean concentration levels of all tested pollutants were found for musk deer (PCBs 12.41pgmg-1, DDTs 21.87pgmg-1, PAHs 22.12pgmg-1) compared to the other wild species. To the best of our knowledge, this is the first study that provides results regarding contamination in different terrestrial mammals by POP exposure. The use of hair as a matrix is proven to be an effective tool for nondestructive biological monitoring of POP contamination in terrestrial ecosystems.

Epigenetic and Neurological Impairments Associated with Early Life Exposure to Persistent Organic Pollutants.

The incidence of neurodevelopmental and neurodegenerative diseases worldwide has dramatically increased over the last decades. Although the aetiology remains uncertain, evidence is now growing that exposure to persistent organic pollutants during sensitive neurodevelopmental periods such as early life may be a strong risk factor, predisposing the individual to disease development later in life. Epidemiological studies have associated environmentally persistent organic pollutant exposure to brain disorders including neuropathies, cognitive, motor, and sensory impairments; neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD); and neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). In many ways, this expands the classical “Developmental Origins of Health and Disease” paradigm to include exposure to pollutants. This model has been refined over the years to give the current “three-hit” model that considers the individual's genetic factors as a first “hit.” It has an immediate interaction with the early-life exposome (including persistent organic pollutants) that can be considered to be a second “hit.” Together, these first two “hits” produce a quiescent or latent phenotype, most probably encoded in the epigenome, which has become susceptible to a third environmental “hit” in later life. It is only after the third “hit” that the increased risk of disease symptoms is crystallised. However, if the individual is exposed to a different environment in later life, they would be expected to remain healthy. In this review, we examine the effect of exposure to persistent organic pollutants and particulate matters in early life and the relationship to subsequent neurodevelopmental and neurodegenerative disorders. The roles of those environmental factors which may affect epigenetic DNA methylation and therefore influence normal neurodevelopment are then evaluated.

Study on the Association of some Single Nucleotide Polymorphisms of CYP19A1 Gene with Breast Cancer in Vietnamese Women

The CYP19A1 gene encodes for aromatase P450, which is a key enzyme in estrogen metabolism, catalyzes the conversation of testosterone to estradiol and androstenedione to estrone. It is generally believed that polymorphisms in genes coding for key enzymes involved in these pathways could effect to the activity of enzymes, which can change the level of endogenous hormones. Therefore genetic polymorphisms in hormone-related genes could increase the breast cancer susceptibility. In this study, 60 blood samples of breast cancer women and 50 control populations were analyzed to identify the genotype frequency at SNP loci rs10046 C&gt;T and rs2236722 Trp39Arg (T&gt;C) on CYP19A1 using PCR-RFLP and PCR-CTPP respectively. The data were analyzed to determine the association between these polymorphism loci and susceptibility to breast cancer. The result showed that, the genotype frequencies at SNP rs10046 in the control as: CC (14%), CT (48%), TT (38%), in case group are CC (18.33%) , CT (58.33%) and TT (23.34%); at SNP rs2236722 in the control group: TT (94%), TC (6%), in case group TT (90%), TC (10%). The OR analyses for the gene carrying the CC and TC genotypes compared with TT genotype at both loci (OR=2.01; 95% CI=0.87–4.67 with rs10046 and OR = 1.74; 95% CI= 0.40 – 7.42 with rs2236722) indicated that these SNP loci in CYP19A1 have no effect on breast cancer susceptibility.&#x0D; Keywords&#x0D; Breast cancer, SNP, rs10046, rs2236722, CYP19A1 gene&#x0D; References&#x0D; 1. Bora M. T., Tülin Ö., Halil I. K., Sennur I., Calay Z., Oğuz Ö., Turgay I. (2010), “CYP17 (T-34C) and CYP19 (Trp39Arg) Polymorphisms and their Cooperative Effects on Breast Cancer Susceptibility”, In vivo, 24, pp.71–74.2. Chen C., Sakoda L. C., Doherty J. A., Loomis M. M., Fish S., Ray R. M. (2008), “Genetic variation in CYP19A1 and risk of breast cancer and brocystic breast conditions among women in Shanghai, China”, Cancer Epidemiology Biomarkers Prevention, 17(12), pp.3457–3466.3. Dunning A. M., Dowsett M., Healey C. S., Tee L., Luben R. N., Folkerd E., Novik K. L., Kelemen L., Ogata S., Pharoah P. D., Easton D. F., Day N. E., Ponder B. A. (2004), “Polymorphisms associated with circulating sex hormone levels in postmenopausal women”, J. Natl. Cancer Inst., 96(12), pp.936–945.4. Farzaneh F., Noghabaei G., Barouti E., Pouresmaili F., Jamshidi J., Fazeli A. (2016), “Analysis of CYP17, CYP19 and CYP1A1 gene polymorphisms in Iranian women with breast cancer”, Asian Pacific Journal of Cancer Prevention, 17, pp.23–26.5. Ghisari M., Eiberg H., Long M. (2014), “Polymorphisms in phase I and phase II genes and breast cancer risk and relations to persistent organic pollutant exposure: A case-control study in Inuit women”, Environmental Health, 13(1), pp.19.6. Henderson B. 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Prenatal exposure to persistent organic pollutants in Northern Tanzania and their distribution between breast milk, maternal blood, placenta and cord blood

Human exposure to persistent organic pollutants (POPs) begins during pregnancy and may cause adverse health effects in the fetus or later in life. The present study aimed to assess prenatal POPs exposure to Tanzanian infants and evaluate the distribution of POPs between breast milk, maternal blood, placenta and cord blood. For assessment of prenatal exposure, 48 maternal blood samples from Mount Meru Regional Referral Hospital (MMRRH), Arusha Tanzania, were analyzed for organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), brominated flame retardants (BFRs), dioxin-like (DL) activity and perfluorinated alkyl substances (PFASs). For evaluation of POPs distribution between maternal/infant compartments, breast milk, placenta and cord blood corresponding to the maternal blood were analyzed for OCPs, PCBs and BFRs. In maternal blood, p,p´- DDE was detected in 100% of the samples ranging between 29 and 1890 ng/g lipid weight (lw). PCB-153 was the only PCB detected in maternal blood, with detection rate of 29% and concentrations up to 116 ng/g lw. BDE-47 was detected in 65% of the maternal blood samples, ranging between <LOD and 83.2 ng/g lw. DL activity was measured using Dioxin Responsive CALUX® bioassay. The DL activity was above LOQ in 92% of the samples, ranging from <LOQ to 114 pg CALUX TEQ/g lw. PFASs was dominated by PFOS and PFOA, however, the concentrations were low (range ∑PFASs 0.18–3.14 ng/mL). p,p´-DDE was detected in 100% of the breast milk, placenta and cord blood samples and the concentrations were strongly correlated (r = 0.89–0.98) between all compartments. Maternal blood (MB) had significantly lower p,p´-DDE concentrations (ng/g lw) than cord blood (CB) and breast milk (BM). The median CB/MB ratio was 1.3 and median MB/BM ratio was 0.8. p,p´-DDE concentrations in breast milk and cord blood did not show significant difference and median CB/BM ratio was 1. In addition, the relative p,p`-DDE transfer from maternal blood to breast milk and to cord blood increased when p,p`-DDE concentrations in maternal blood increased. This study shows that Tanzanian infants are exposed to a wide range of POPs during fetal life, which raise concerns for potential health effects. In addition, this study found that maternal blood concentrations may lead to underestimation of prenatal exposure, while breast milk collected close to delivery may be a more suitable indicator of prenatal exposure.