Mixtures Of Persistent Organic Pollutants Research Articles

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.

Obesity in relation to serum persistent organic pollutant concentrations in CHAMACOS women.

Environmental exposure to endocrine-disrupting chemicals (EDCs), including persistent organic pollutants (POPs), has been hypothesized to increase risk of obesity. Using data from the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, we examined the longitudinal relationship between serum concentrations of a POPs mixture and several obesity measures. Concentrations of 17 POPs were measured in serum collected in 2009-2011 from 468 CHAMACOS women. Anthropometry measurements and personal interviews were completed at up to three study visits between 2009 and 2014. We assessed the relationship of serum POPs concentrations with adiposity measures longitudinally using generalized estimating equation (GEE) models. We implemented Bayesian Kernel Machine Regression (BKMR) to elucidate the effects of joint exposure to the POPs mixture. In GEE models, positive associations with BMI were found for dichlorodiphenyltrichloroethane (Q4 vs Q1: adjusted-β = 3.2 kg/m2; 95%CI 1.5,4.9), β-hexachlorocyclohexane (Q4 vs Q1: adjusted-β = 3.6 kg/m2; 95%CI 2.0,5.2), and PBDE-47 (Q4 vs Q1: adjusted-β = 1.9 kg/m2; 95%CI 0.3,3.5), while PBDE-153 was inversely associated (Q4 vs Q1: adjusted-β = -2.8 kg/m2; 95%CI -4.4,-1.2). BKMR results, while largely consistent with single pollutant models, revealed the shape and direction of the exposure-response relationships, as well as interactions among pollutants within the mixture, that could not be discovered by single-pollutant models. In summary, we found significant associations of serum POPs with several adiposity measures using both conventional regressions and BKMR. Our results provide support for the chemical obesogen hypothesis, that exposure to EDCs may alter risk for later obesity.

A mixture of Persistent Organic Pollutants (POPs) and Azoxymethane (AOM) show potential synergistic effects on intestinal tumorigenesis in the A/J Min/+ mouse model

A multitude of cancer types, including breast, testicular, liver and colorectal cancer, have associations with exposure to Persistent Organic Pollutants (POPs). The present study aimed to investigate whether a mixture of POPs could affect intestinal tumorigenesis in the A/J Min/+ mouse, a model for human colorectal cancer (CRC). Pollutants were selected for their presence in Scandinavian food products and the mixture was designed based on defined human estimated daily intake levels. Mice were exposed through the diet, at control, low and high mixture concentrations, for 10 weeks. In a separate experiment, mice also received one subcutaneous injection of Azoxymethane (AOM) to explore whether this carcinogenic compound influenced the effect of the POPs. Intestinal tumorigenesis was examined by surface microscopy and histopathology. Moderate and dose-dependent increases in tumorigenesis were observed after dietary POP exposure. The AOM treatment alone stimulated the growth of colonic lesions, but did not increase the formation of new lesions. Combined AOM treatment and POP exposure demonstrated a synergistic effect on lesion formation in the colon, and to a lesser extent in the small intestine. This synergy was also evident by an increased number of malignant colonic tumors (carcinomas). In conclusion, the study shows that a mixture of POPs interacted synergistically with a known carcinogen (AOM), causing increased intestinal tumorigenesis in the A/J Min/+ mouse model.

Prenatal Exposure to a Mixture of Persistent Organic Pollutants (POPs) and Child Reading Skills at School Age

Prenatal Exposure to a Mixture of Persistent Organic Pollutants (POPs) and Child Reading Skills at School Age

A realistic mixture of persistent organic pollutants (POPs) reveals possible synergism to inhibit the transactivation activities of the rat aryl hydrocarbon receptor (rAhR) in vitro

A realistic mixture of persistent organic pollutants (POPs) reveals possible synergism to inhibit the transactivation activities of the rat aryl hydrocarbon receptor (rAhR) in vitro

Mandibular shape in farmed Arctic foxes (Vulpes lagopus) exposed to persistent organic pollutants

We investigated if dietary exposure to persistent organic pollutants (POPs) affect mandibular asymmetry and periodontal disease in paired male-siblings of Arctic foxes (Vulpes lagopus). During ontogeny, one group of siblings was exposed to the complexed POP mixture in naturally contaminated minke whale (Balaenoptere acutorostarta) blubber (n = 10), while another group was given wet feed based on pig (Sus scrofa) fat as a control (n = 11). The ∑POP concentrations were 802 ng/g ww in the whale-based feed compared to 24 ng/g ww in the control diet. We conducted a two-dimensional geometric morphometric (GM) analysis of mandibular shape and asymmetry in the foxes and compared the two groups. The analyses showed that directional asymmetry was higher than fluctuating asymmetry in both groups and that mandibular shape differed significantly between the exposed and control group based on discriminant function analysis (T2 = 58.52, p = 0.04, 1000 permutations). We also found a non-significantly higher incidence of periodontal disease (two-way ANOVA: p = 0.43) and greater severity of sub-canine alveolar bone deterioration similar to periodontitis (two-way ANOVA: p = 0.3) in the POP-exposed group. Based on these results, it is possible that dietary exposure to a complexed POP mixture lead to changes in jaw morphology in Arctic foxes. This study suggests that extrinsic factors, such as dietary exposure to POPs, may affect mandibular shape and health in a way that could be harmful to wild Arctic populations. Therefore, further studies using GM analysis as an alternative to traditional morphometric methods should be conducted for wild Arctic fox populations exposed to environmental contaminants.

Hepatoprotective effect of Red Sea sponge extract against the toxicity of a real-life mixture of persistent organic pollutants

ABSTRACTThe present study aims to evaluate the possible hepatoprotective effect of the Red Sea Hyrtios aff. erectus sponge extract against persistent organic pollutants (POPs). The induced hepatotoxicity effects were examined by using different POPs compounds, namely, α-hexachlorocyclohexane, β-hexachlorocyclohexane, γ-hexachlorocyclohexane, PCB 28, PCB 52, aldrin, o,p'-DDE, PCB 101, dieldrin, p,p'-DDE, o,p'-DDD, endrin, PCB 118, p,p'-DDD, p,p'-DDT, PCB 153, PCB 135, PCB 138 and PCB 180, extracted from sediments collected from Lake Mariout. The effects were assessed based on biochemical assays, where BALB/c albino mice (mean weight 28 ± 4 g) exposed to 130.6 mg/100 g b.w./d of POP mixtures were compared to control and induction groups. The POPs toxicity test was carried out on the BALB/c albino mice for one week. The POPs treated group had a significant increase in the levels of transaminases, ALT and AST. There was also a significant increase in serum bilirubin in response to POPs mixture toxicity. In contrast, the protective group revealed a non-significant increase in both aminotransferases and bilirubin level. The results indicate that POPs could act through free radical-induced oxidative stress. Furthermore, the hepatoprotective effect of sponge extract against POPs mixture is due to the presence of polyphenolic compounds in sponge. The present study revealed that polyphenolic compounds play a vital role in diminishing the hepatotoxicity, as confirmed by a decrease in liver toxicity.

A human exposure based mixture of persistent organic pollutants affects the stress response in female mice and their offspring

Persistent organic pollutants (POPs) are found in the food chain of both humans and animals and exert a wide spectrum of potentially adverse effects. The present experiment aimed to investigate whether a defined mixture of 29 POPs, based on the dietary intake of Scandinavians, could affect the stress response in female mice exposed through ingestion, and in their offspring. Female mice 129:C57BL/6F0 hybrids were exposed from weaning, throughout pregnancy, and up until necropsy, to either 5000 × or 100 000 × the estimated daily intake for Scandinavians. The offspring were fed a reference diet containing no POPs. Both the mothers and their offspring were tested for basal and stress responsive corticosterone levels, and in an open field test to measure locomotor activity and anxiety-like behaviours. We found mothers to have elevated basal corticosterone levels, as well as a prolonged stress response following POP exposure. In the offspring, there was no effect of POPs on the stress response in females, but the exposed males had an over-sensitised stress response. There was no effect on behaviour in either the mothers or the offspring. In conclusion, we found a human relevant POP mixture can lead to subtle dysregulation of the hypothalamus-pituitary-adrenal axis in mice. As HPA axis dysregulation is commonly associated with neurological disorders, further studies should explore the relevance of this outcome for humans.

Decreased macrophage phagocytic function due to xenobiotic exposures in vitro, difference in sensitivity between various macrophage models

Both autoimmune disease prevalence and exposure to immunotoxic chemicals have increased the last decades. As a first screening of immunotoxic chemicals possibly affecting development of autoimmunity through attenuated macrophage function, we demonstrate a promising model measuring macrophage function in isolated peritoneal macrophages (PCM) from Wistar rats and C57Bl/6 mice. Immunotoxic effects of bisphenol A (BPA) and a selection of perfluoroalkyl acids (PFAAs) were analysed in vitro assessing phagocytic function of macrophages from different sources. Phagocytosis was reduced in PCM of C57Bl/6 mice and Wistar rats after BPA and perfluoroundecanoic acid (PFUnDA) exposure, but not in macrophages derived from human and rat monocyte derived macrophages (MDM). On the other hand, in vitro exposure to mixtures of persistent organic pollutants (POPs) showed similar reductions in rat PCM and rat and human MDM phagocytosis. Reduced phagocytosis was partly due to cytotoxicity. PCM isolated from non-obese diabetic (NOD) mice, interleukin 1α/β knockout (IL-1KO) mice and new-born rats were less sensitive to the xenobiotics than PCM from adult wild type rodents. Finally, in vivo studies with NOD mice verified that POP exposure also decreased the number of pancreatic macrophages in pancreatic islets, reflecting early signs of autoimmunity development, similarly as previously described for BPA.

Receptor activities of persistent pollutant serum mixtures and breast cancer risk.

Studies on associations between persistent organic pollutants (POPs) and breast cancer risk are inconclusive. The majority of studies have evaluated the effect of single compounds, without considering multiple exposures to and interactions between different POPs. The present study aimed at evaluating breast cancer risk related to combined effects of serum POP mixtures on cellular receptor functions. Data on breast cancer cases (n = 77) and controls (n = 84) were collected among Greenlandic Inuit women. Serum mixtures of lipophilic POPs (lipPOPs), perfluoroalkyl acids (PFAAs) and dioxin-like POPs were extracted. The effect of the mixture extracts on the estrogen receptor (ER), androgen receptor (AR) and aryl hydrocarbon receptor (AhR) was determined using cell culture reporter gene assays. The serum mixtures were analyzed alone and upon co-exposure with natural receptor ligands to determine agonistic and antagonistic/competitive activity. We found that the frequency of lipPOP mixtures eliciting no, decreasing, or agonizing xenoandrogenic effect differed by breast cancer status. Using lipPOP mixtures with no effect on AR as reference, the mixtures with decreasing effects reduced breast cancer risk (OR: 0.30 (0.12; 0.76)). The AhR-toxic equivalent of serum mixtures was significantly lower in cases than in controls, and a reduced breast cancer risk was found when comparing the third tertile to the first (OR: 0.34 (0.14; 0.83)). We found no association between the xenoestrogenic activities of lipPOPs or PFAAs and breast cancer risk. Serum lipPOP mixtures are hormone disruptive and may influence breast cancer risk, whereas PFAAs seem to influence breast cancer risk through other pathways.

Persistent Endocrine-Disrupting Chemicals and Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most prominent chronic liver disease in Western countries, affecting approximately 25% of the population worldwide. Sex-specific differences in the development of NAFLD are apparent. While obesity and insulin resistance are major contributors to the increasing prevalence of NAFLD, a growing body of literature suggests that exposure to persistent endocrine-disrupting chemicals (pEDCs) may also play a role. This review summarizes recent (2011 and later) scientific literature investigating exposures to pEDCs, specifically persistent organic pollutants (POPs), and NAFLD, with a focus on sex-specific associations. The overwhelming majority of studies were conducted in single-sex animal models and provide biological evidence that exposures to 2,3,7,8-tetrachlorodibenzo-p-dioxin polychlorinated biphenyls, and other POPs or POP mixtures are negatively associated with liver health. There were four cross-sectional epidemiological studies in humans that reported associations for several POPs, including polychlorinated biphenyls and perfluorinated chemicals, with elevated liver enzymes. Only one of these studies, using a sample of gastric bypass surgery patients, examined sex-specific associations of POPs and liver enzymes, finding adverse associations among women only. The noticeable lack of studies investigating how differences (i.e., biochemical, physiological, and behavioral) between men and women may influence associations of pEDCs and NAFLD represents a large research gap in environmental health. Sexual dimorphism in metabolic processes throughout the body, including the liver, is established but often overlooked in the designs and analyses of studies. Other factors identified in this review that may also act to modulate associations of environmental chemicals and NAFLD are reproductive status and dietary nutrient intakes, which also remain understudied in the literature. Despite knowledge of sexual dimorphism in the actions of pEDCs, as well as in metabolic processes related to NAFLD development, few experimental or epidemiological studies have investigated sex-dependent associations. Future studies, especially those in humans, should be designed to address this research need. Consideration of other factors, such as reproductive status, dietary intakes, and mixtures of chemicals with varying endocrine-disrupting capabilities, should be explored.

The design of an environmentally relevant mixture of persistent organic pollutants for use in in vivo and in vitro studies

ABSTRACTAmongst the substances listed as persistent organic pollutants (POP) under the Stockholm Convention on Persistent Organic Pollutants (SCPOP) are chlorinated, brominated, and fluorinated compounds. Most experimental studies investigating effects of POP employ single compounds. Studies focusing on effects of POP mixtures are limited, and often conducted using extracts from collected specimens. Confounding effects of unmeasured substances in such extracts may bias the estimates of presumed causal relationships being examined. The aim of this investigation was to design a model of an environmentally relevant mixture of POP for use in experimental studies, containing 29 different chlorinated, brominated, and perfluorinated compounds. POP listed under the SCPOP and reported to occur at the highest levels in Scandinavian food, blood, or breast milk prior to 2012 were selected, and two different mixtures representing varying exposure scenarios constructed. The in vivo mixture contained POP concentrations based upon human estimated daily intakes (EDIs), whereas the in vitro mixture was based upon levels in human blood. In addition to total in vitro mixture, 6 submixtures containing the same concentration of chlorinated + brominated, chlorinated + perfluorinated, brominated + perfluorinated, or chlorinated, brominated or perfluorinated compounds only were constructed. Using submixtures enables investigating the effect of adding or removing one or more chemical groups. Concentrations of compounds included in feed and in vitro mixtures were verified by chemical analysis. It is suggested that this method may be utilized to construct realistic mixtures of environmental contaminants for toxicity studies based upon the relative levels of POP to which individuals are exposed.

Protective role of antioxidants capacity of Hyrtios aff. Erectus sponge extract against mixture of persistent organic pollutants (POPs)-induced hepatic toxicity in mice liver: biomarkers and ultrastructural study.

The current study investigates the hepatoprotective effect of Hyrtios aff. Erectus sponge extract against POPs intoxication on endogenous antioxidant enzymes and lipid peroxidation in mice liver tissue. In the present study, the mice BALB/C were assigned into four groups: group I: received saline subcutaneously for 7days and served as negative control; group II: received subcutaneously for 7days, 130.6mg/100g/b. w/day POPs mixture(mixture of PCB 28, PCB 52,, PCB 101, PCB 118, PCB 153, PCB 138 and PCB 180, alpha-Hexachlorocyclohexane, beta-Hexachloro-cyclohexane, gamma-hexachlorocyclohexane, Aldrin, O,P'-DDE, Dieldrin, P,p DDE, O,P DDD, Endrin, P,p DDD and P,pDDT were extracted from sediments collected from Lake Mariout), and served as induced group; group III: pretreated with Hyrtios aff. Erectus sponge extract for 7days, as a protection dose and then treated with POPs as group II and served as protective group; and group IV: received i.p Hyrtios aff. Erectus sponge extract of dose 0.7mg/100g b.wt/day for 7days and served as positive control. After 7days (experimental period), mice were scarified and the liver was harvested for biochemical estimation. Significant reduction in lipid peroxidation (p<0.002) was noticed compared to POPs-protected group. The antioxidant biomarkers levels were significantly increase as the hepatic GSH and GST increased by 69.9 and 89.9%, respectively. Such increase was accompanied by a decrease in tyrosine kinase activity by 59.82%, additionally remarkable histopathological changes in liver tissue indicate the protective effect of Hyrtios aff. Erectus sponge extract. The results of this study revealed that the Hyrtios aff. Erectus sponge extract has the potential to diminish the destructive effect of POPs intoxication through enhancement of the endogenous antioxidant status. The hepatoprotective activity of Hyrtios aff. Erectus sponge extract is mediated, by the antioxidant effect of its active constituents. The active constituents of Hyrtios aff. Erectus sponge extract were identified by LC-MS/MS.

Maternal exposure to a mixture of persistent organic pollutants (POPs) affects testis histology, epididymal sperm count and induces sperm DNA fragmentation in mice

Persistent organic pollutants (POPs) are widespread throughout the environment and some are suspected to induce reproductive toxicity. As animals and humans are exposed to complex mixtures of POPs, it is reasonable to assess how such mixtures could interact with the reproductive system. Our aim is to investigate how maternal exposure to a mixture of 29 different persistent organic pollutants, formulated to mimic the relative POP levels in the food basket of the Scandinavian population, could alter reproductive endpoints. Female mice were exposed via feed from weaning, during pregnancy and lactation in 3 exposure groups (control (C), low (L) and high (H)). Testicular morphometric endpoints, epididymal sperm concentration and sperm DNA integrity were assessed in adult male offspring. We found that the number of tubules, proportion of tubule compartments and epididymal sperm concentration significantly decreased in both POP exposed groups. Epididymal sperm from both POP exposed groups showed increased DNA fragmentation. It is concluded that maternal exposure to a defined POP mixture relevant to human exposure can affect testicular development, sperm production and sperm chromatin integrity.

A Mixture of Persistent Organic Pollutants and Perfluorooctanesulfonic Acid Induces Similar Behavioural Responses, but Different Gene Expression Profiles in Zebrafish Larvae.

Persistent organic pollutants (POPs) are widespread in the environment and some may be neurotoxic. As we are exposed to complex mixtures of POPs, we aimed to investigate how a POP mixture based on Scandinavian human blood data affects behaviour and neurodevelopment during early life in zebrafish. Embryos/larvae were exposed to a series of sub-lethal doses and behaviour was examined at 96 h post fertilization (hpf). In order to determine the sensitivity window to the POP mixture, exposure models of 6 to 48 and 48 to 96 hpf were used. The expression of genes related to neurological development was also assessed. Results indicate that the POP mixture increases the swimming speed of larval zebrafish following exposure between 48 to 96 hpf. This behavioural effect was associated with the perfluorinated compounds, and more specifically with perfluorooctanesulfonic acid (PFOS). The expression of genes related to the stress response, GABAergic, dopaminergic, histaminergic, serotoninergic, cholinergic systems and neuronal maintenance, were altered. However, there was little overlap in those genes that were significantly altered by the POP mixture and PFOS. Our findings show that the POP mixture and PFOS can have a similar effect on behaviour, yet alter the expression of genes relevant to neurological development differently.

Risk of POP mixtures on the Arctic food chain.

The exposure of the Arctic ecosystem to persistent organic pollutants (POPs) was assessed through a review of literature data. Concentrations of 19 chemicals or congeneric groups were estimated for the highest levels of the Arctic food chain (Arctic cod, ringed seals, and polar bears). The ecotoxicological risk for seals, bears, and bear cubs was estimated by applying the concentration addition (CA) concept. The risk of POP mixtures was very low in seals. By contrast, the risk was 2 orders of magnitude higher than the risk threshold for adult polar bears and even more (3 orders of magnitude above the threshold) for bear cubs fed with contaminated milk. Based on the temporal trends available for many of the chemicals, the temporal trend of the mixture risk for bear cubs was calculated. Relative to the 1980s, a decrease in risk from the POP mixture is evident, mainly because of international control measures. However, the composition of the mixture substantially changes, and the contribution of new POPs (particularly perfluorooctane sulfonate) increases. These results support the effectiveness of control measures, such as those promulgated in the Stockholm Convention, as well as the urgent need for their implementation for new and emerging POPs. Environ Toxicol Chem 2017;36:1181-1192. © 2017 SETAC.

The Ameliorative Role of a Marine Sponge Extract against Mixture of Persistent Organic Pollutants induced Changes in Hematological Parameters in Mice

The Ameliorative Role of a Marine Sponge Extract against Mixture of Persistent Organic Pollutants induced Changes in Hematological Parameters in Mice Persistent organic pollutants (POPs), especially polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) are highly toxic to the marine environment. Since little is known about the effect of natural life mixture of POPs on the hematological parameters in Mice, the present study investigated the effect of POPs compounds to induce toxicity in mice using hematological parameter as biomarkers .The protective role of Hyrtios aff. Erectus sponge extract isolated from red sea was also examined. A mixture of PCB 28, PCB 52, , PCB 101, PCB 118, PCB 153, PCB 138 and PCB 180,alpha-Hexachlorocyclohexane, beta-Hexachlorocyclohexane, gamma-hexachlorocyclohexane, Aldrin , O,P’-DDE, Dieldrin, P,p DDE, O,P DDD, Endrin, P,p DDD and P,pDDT were extracted from sediments collected from Lake Mariout. Mice groups were assign into four groups and hematological parameters were compared between these different groups. Total white blood cell (WBC) count, red blood cells (RBC), hemoglobin, and hematocrit were decreased significantly in the induced group. No significant increase were observed for MCV, HCH, MCHC for induction group; while a significant increase in WBC, RBC, and PLT was observed in the pretreated group. On the other hand, a little or almost no change was observed in the pre-treated group by Hyrtios aff. Erectus extract. These findings were confirmed with immunohistochemistry results which showed marked eosinophilia of hepatocyte cytoplasm. At the same time the centrilobular showed hypertrophy and midzonal cytoplasmic vacuolization of hepatocytes in contrast to the pretreated group and the extract group. The present study concluded the existence of significant associations between POPs induce toxicity and hematological different parameters, i.e. WBC, RBC, HCT and PLT. Also the present results confirmed the protective role of Hyrtios aff. Erectus extract which harbor a great diversity of bioactive compounds and minerals.

Effect of Naringenin, Quercetin, and Sesamin on Xenobiotica-Metabolizing CYP1A and CYP3A in Mice Offspring after Maternal Exposure to Persistent Organic Pollutants

The aim of the present study was to evaluate in vitro effects of dietary phytochemicals naringenin, quercetin, and sesamin on the activities of ethoxy- (EROD; CYP1A) and benzyloxy- (BROD; CYP3A) resorufin O-dealkylases after the exposure to the cocktail of persistent organic pollutants (POPs). CD-1 mice were exposed from weaning, through gestation and lactation to a defined mixture of POPs. Hepatic microsomes were prepared from their female offspring at postnatal day 42. Hepatic EROD and BROD activity were evaluated in the presence of quercetin, naringenin, and sesamin at nine concentrations from 5 to 100000 nM. EROD activity was strongly inhibited by quercetin with Ki values from 1.7 to 2.6 μM. BROD activity was inhibited by quercetin with Ki values from 64.9 to 75.3 μM and naringenin with Ki values from 39.3 to 45.8 μM. The IC50 and Ki values did not differ between the groups of mice with different levels of POPs exposure in any of the experimental sets. Sesamin did not inhibit either EROD or BROD. We concluded that the interactions of quercetin and naringenin with CYP1A and CYP3A in mice liver were not affected by the levels of POPs exposure.

Exposure to an environmentally relevant mixture of organochlorine compounds and polychlorinated biphenyls Promotes hepatic steatosis in male Ob/Ob mice.

Hepatic steatosis is recognized as an independent risk factor for the development of cardiovascular disease. While obesity and type 2 diabetes are well-established risk factors in the development of hepatic steatosis, recent studies have revealed exposure to mixtures of persistent organic pollutants (POPs), which are environmental contaminants in various fatty foods, can promote steatosis. Thus, the present study was designed to determine if exposure to a defined mixture of prevalent polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides or their metabolites promote hepatic steatosis in a genetically induced model of type 2 diabetes, the leptin-deficient ob/ob mouse. Male C57BL/6J wild type (WT) or ob/ob mice were administered an environmentally relevant mixture of PCBs and OCs for 7 weeks via oral gavage. Exposure to POPs did not significantly alter fasting serum glucose or insulin levels. However, POPs exposure significantly increased hepatic triglyceride content in ob/ob animals, while decreasing serum triglyceride levels. This POPs-mediated increase in hepatic triglyceride content did not appear to be associated with significantly increased inflammation in either the liver or adipose. Exposure to POPs significantly induced the expression of cytochrome P450 3a11 in WT animals, yet the expression of this cytochrome was significantly downregulated in ob/ob animals regardless of POPs exposure. Taken together, the present data indicate exposure to an environmentally relevant mixture of both PCBs and OC pesticides in ob/ob mice promotes hepatic steatosis while decreasing hypertriglyceridemia, which demonstrates exposure to a defined mixture of POPs alters systemic lipid metabolism in a genetically induced model of obesity and type 2 diabetes. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1399-1411, 2017.

Parental exposure to natural mixtures of persistent organic pollutants (POP) induced changes in transcription of apoptosis-related genes in offspring zebrafish embryos

ABSTRACTApoptosis is an integral element of development that may also be initiated by environmental contaminants. The aim of the present study was to assess potential changes in the regulation of apoptotic genes in zebrafish embryos following parental exposure to two natural mixtures of persistent organic pollutants (POP). The mixture from Lake Mjøsa contained exceptionally high concentrations of polybrominated diphenyl ethers (PBDE), as well as relatively high levels of polychlorinated biphenyls (PCB) and dichlorodiphenyltrichloroethane (DDT). The mixture from Lake Losna contained background concentrations of POP. Genes involved in the apoptotic machinery were screened for their expression profile at four time points during embryonic development. Thirteen and 15 genes involved in apoptosis were found to be significantly upregulated in the high-exposure and background exposure groups, respectively, compared with controls. Modulation of apoptotic genes was restricted only to the first time point, which corresponds with the blastula stage. Although there were substantial differences in POP concentrations between mixtures, genes underlying the apoptosis process showed almost similar responses to the two mixtures. In both exposure groups the main executors of apoptosis p53, casp 2, casp 6, cassp 8, and BAX displayed upregulation compared to controls, suggesting that these POP induce apoptosis via a p53-dependent mechanism. Upregulation of genes that play a critical role in apoptosis suggests that disturbance of normal apoptotic signaling during gametogenesis and embryogenesis may be one of the central mechanisms involved in adverse reproductive effects produced by POP in zebrafish.