Germany's first Total Diet Study - Occurrence of non-dioxin-like polychlorinated biphenyls and polybrominated diphenyl ethers in foods.

The occurrence of persistent organic pollutants like polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in food represents a public health concern. The BfR MEAL Study was initiated to generate a comprehensive data base of occurrence data for chemicals in the most consumed foods in Germany. Non-dioxin-like PCBs (NDL-PCBs) and PBDEs were analysed in 300 foods, purchased and prepared representatively for the eating behaviour of the population in Germany. Highest levels of NDL-PCBs and PBDEs were detected in spiny dogfish, cod liver, herring, and eel. High NDL-PCB and PBDE levels were observed in other oily fish, wild boar meat, sheep liver, and high-fat dairy products. The comparison of food from conventional and organic production revealed higher NDL-PCB values in the food group 'meat and meat products' if produced organically. Occurrence data of this study will improve future dietary exposure and risk assessments in Germany.

Multiomics reveals new biomarkers and mechanistic insights into the combined toxicity effects of 2,2',4,4',5,5'-hexachlorobiphenyl and atrazine exposures in MCF-7 cells.

Humans are constantly exposed to complicated chemical mixtures from the environment and food rather than being exposed to a single pollutant. The underlying mechanisms of the complicated combined toxicity of endocrine disrupting chemicals (EDCs) are still mainly unexplored. In this study, two representative EDCs, 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and atrazine (ATZ), were selected to explore their combined effects on MCF-7 cell proliferation at environmental exposure concentrations by an integrated analysis of metabolomics and transcriptomics. The results showed that 1 µM ATZ and PCB153 combined exposure significantly accelerated MCF-7 cell growth by 18.2%. More than 400 metabolites detected by UHPLC-QTOF/MS were used to observe metabolism differences induced by binary mixtures. Metabolomics analysis verified that ATZ and PCB153 exposure alone or in combination could have an additive effect on metabolism and induce significant disruption to glycolysis, purine metabolism and the TCA cycle, which provide energy demand and biosynthetic substrates for cell proliferation. Compared to PCB153 and ATZ exposure alone, a combined effect was observed in purine and pyrimidine metabolic pathways. Hexokinase 3 (HK3) and cytochrome P450 19 subfamily A1 (CYP19A1) were identified as differentially expressed genes based on transcriptomic analysis. By integrating metabolome and transcriptome analysis, the proliferation effects of ATZ and PCB153 were induced at low doses in MCF-7 cells through potential interference with the downstream transcription signaling of CYP19A1. Furthermore, molecular docking indicated that PCB153 and ATZ directly affected CYP19A1. Altogether, the regulation of pivotal metabolites and differentially expressed genes could provide helpful information to reveal the mechanism by which PCB153 and ATZ affect MCF-7 cell proliferation.

Resveratrol ameliorates ortho- polychlorinated biphenyls' induced toxicity in ovary cells.

Polychlorinated biphenyls (PCBs) can induce chronic oxidative stress, inflammation, and cell death, leading to coronary heart disease, endothelial dysfunction, neurotoxicity, cancer, obesity, type 2 diabetes, reproductive dysfunction, etc. The aim of this study was to investigate possible protective effect of resveratrol (2.5-20 µM) in ovarian cells exposed to PCBs. An emphasis was on identifying mechanisms of resveratrol action upon distinct structure of the individual PCB congener-planar dioxin-like PCB 77 and non-planar di-ortho-substituted PCB 153. Multiple toxicity endpoint analysis was performed. Cell viability/proliferation was assessed by Trypan Blue exclusion method, Neutral Red, Kenacid Blue, and MTT bioassays. The level of oxidative stress was measured by fluorescent probes, and flow cytometry was applied to evaluate the mode of cell death. Resveratrol applied alone did not affect cell proliferation and viability in doses up to 20 µM, although significant antioxidative activity was observed. Toxic effects of ortho-PCB 153 (cytotoxicity, oxidative stress, and cell death) were mitigated by resveratrol. On the contrary pre-incubation with resveratrol did not result in cell viability protection when planar PCB 77 was applied. This indicates that resveratrol efficacy may be linked to specific structure of the individual congener, suggesting nutritional modulation of environmental insults caused by ortho-PCBs. We point out the importance of resveratrol dosage considering that synergistic cytotoxic effect with both PCB congeners is observed at concentrations ≥ 10 µM.

Exposure to several polychlorinated biphenyls (PCBs) is associated with chronic kidney disease among general adults: Korean National Environmental Health Survey (KoNEHS) 2015-2017.

We investigated the association between major persistent organic pollutants (POPs) exposure and chronic kidney disease (CKD) among general adult population of Korea. For this purpose, a subset of the adult population (n = 1276) participated in Korean National Environmental Health Survey (KoNEHS) Cycle 3 (2015-2017) were analyzed for twenty-four POPs in serum, including organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs), and were derived for estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (uACR). Multivariable linear regression was conducted to assess the association between POPs exposure and CKD-related parameters including eGFR and uACR. As sensitivity analyses, principal component analysis was conducted. Moreover, the U.S. National Health and Nutrition Examination Survey (NHANES) 1999-2004 data were chosen to compare with the observations of the Korean adults. Approximately 7.7% of the Korean adult population possessed CKD based on either eGFR (<60 ml/min/1.73 m2) or uACR (≥30 mg/g) criteria. Among the POPs that were detected in ≥70% of the subjects, PCB153 (ß = -1.61, 95% CI: -2.55, -0.67, P = 0.001) and PCB180 (ß = -1.47, 95% CI: -2.53, -0.40, P = 0.007) exhibited significant associations with decreased eGFR, especially in females. In male participants, hexachlorobenzene (HCB) was associated with eGFR (ß = -0.79, 95% CI: -1.53, -0.04, P = 0.040). Sex-dependent associations with eGFR were also shown in the PCA model. Moreover, the sex-dependent associations of PCBs were similarly observed in the adult populations of the US NHANES. However, POPs exposure was not associated with uACR, regardless of association model or population. The observed associations of PCBs are supported by several experimental studies reported elsewhere. To our knowledge, it is the first report that suggests significant associations of PCBs and HCB with eGFR among general population, and further validations in other populations are warranted.

Large chromosomal deletions and impaired homologous recombination repairing in HEK293T cells exposed to polychlorinated biphenyl 153.

BACKGROUND: Polychlorinated biphenyls (PCBs) are persistent pollutants with carcinogenesis and mutagenesis effects which have been closely associated with PCBs-induced DNA damage. However, the detailed DNA damage events and corresponding pathway alterations under PCBs poisoning is still not well understood. METHODS: Whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) were used to explore genome wide variations and related pathway changes in HEK293T cells that challenged by 15 µM PCB153 for 96 h in vitro. Double strand breaks (DSBs) were measured by 53BP1 foci detection, altered pathways were confirmed by quantitative real-time PCR (qPCR). RESULTS: The results indicated that abundant copy number variations (CNVs), including four duplications and 30 deletions, occurred in PCB153-exposed HEK293T cells. Multiple large fragment deletions (>1 Mb) involving up to 245 Mb regions on many chromosomes. Missense mutations were found in six tumor susceptibility genes, two of which are key members participating in homologous recombination (HR) repair response, BRCA1 and BRCA2. RNA-seq data showed that PCB153 poisoning apparently suppressedHR repairing genes. Besides, 15 µM PCB153 exposure significantly increased 53BP1 foci formation and effectively reduced BRCA1, RAD51B and RAD51C expression, indicating an elevated DSBs and impaired HR repairing. CONCLUSION: This study firstly reported multiple large chromosomal deletions and impaired HR repairing in PCB153-exposed HEK293T cells, which provided a new insight into the understanding of early response and the mechanism underlying PCB153 genotoxicity. The chromosomal instabilities might be related to the impaired HR repairing that induced by PCB153; however, further investigations, especially on actual toxic effects of human body, are needed to confirm such speculation.

Ceramide/protein phosphatase 2A axis is engaged in gap junction impairment elicited by PCB153 in liver stem-like progenitor cells.

The widespread environmental pollutant 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) is a non-dioxin-like toxicant. It is a potential carcinogen compound able to induce gap junction (GJ) intercellular communication impairment, probably the first non-genomic event leading to tumor promotion. Although PCBs have been known for many years, the molecular mode of PCB153 action is still unclear. Recent studies from our research group have shown that the toxicant elicits a transient modulation of connexin (Cx) 43-formed GJs in hepatic stem-like WB-F344 cells involving sphingosine 1-phosphate (S1P) path. Taking into account that other strictly related bioactive sphingolipids, such as ceramide (Cer), may have different effects from S1P, here we aim to clarify the signaling paths engaged by PCB153 in the control of GJs, focusing primarily on the role of Cer. Accordingly, we have achieved a combined biomolecular and electrophysiological analysis of GJs in cultured WB-F344 cells treated with PCB153 at different time points. We have found that the toxicant elicited a time-dependent regulation of GJs formed by different Cx isoforms, through a transient modulation of Cer/Cer kinase (CerK) axis and, in turn, of protein phosphatase 2A (PP2A). Our new findings demonstrate the existence of a specific molecular mechanism downstream to Cer, which distinctly affects the voltage-dependent and -independent GJs in liver stem-like cells, and open new opportunities for the identification of additional potential targets of these environmental toxicants.

Role of low-latitude forests in modulating forest filter effect on a continental scale: Long-term simulation on PCB-153 in Chinese forests.

Forests are important compartments influencing the environmental fate of persistent organic pollutants (POPs). To illustrate the effect of forests on the regional cycle of POPs, a level IV fugacity fate and transport model coupled with a detailed dynamic-forest module was applied to simulate the long-term variations of PCB-153 in China, where forest coverage accounts for approximately one fifth of land area. In the scenarios with forests, atmospheric outflow from China was 69% of that in the scenario without forests due to the enhanced storage in soil, degradation, and leaching. Previous studies regarded high-latitude areas, such as the polar region and boreal forests, as environments capable of reducing mobility of PCB-153, and they act as sinks of POPs. This modeling result suggests that tropical and subtropical forests may also play a similar role despite high temperatures favoring volatilization. Unlike boreal forest, the low-latitude forests may reduce the overall lifetime of PCB-153 in China due to enhanced degradation in warmer and moist soils of the tropical and subtropical area. Given that approximately half of the global forests are located in tropical and subtropical regions, they can be important environments influencing the global geochemical cycle and distribution of POPs, hence deserving more scientific attention by modeling and empirical studies.

Pilot study on long-term simulation of PCB-153 human body burden in the Tibetan Plateau.

The historical body burden of 2,2',4,4',5,5'-Hexachlorobiphenyl (PCB-153) in the Tibet Autonomous Region (TAR) population was simulated on the basis of localized exposure factors and dietary data, which present a preliminary attempt to quantify the influence of high lipid dietary patterns, grain transported from inland China, and atmospheric transport on human exposure to polychlorinated biphenyls (PCBs). Herdsman with large animal-based food consumption exhibited the highest body burden that was comparable with that in inland China. The body burden of other residents was within the range of low-to-moderate level. High-lipid diet of urban residents caused their body burden being 1.5--2.5 times higher than that of rural residents. The consumption of grain transported from higher polluted areas can also result in 50%-115% increase in the body burden of Tibetan rural residents compared with when local produced grain is consumed, suggesting that the influence of grain logistic can be as important as dietary patterns. The exposure risk for rural residents associated with grain logistic should not be ignored even if they consumed less high-lipid food. By splitting the inventory, over 80% of the PCB-153 pollution in the TAR was identified to be induced by atmospheric transport from foreign countries. However, the grain logistic contributed approximately half of the overall human body burden of Tibetan residents recently if assuming that the grain shortage was supplied by adjacent Sichuan Province. The combined influence of high-lipid diet, atmospheric transport and food logistic highlights the difficulties of risk control in remote regions that accumulate POPs, such as TAR.

Resistance to Cyp3a induction by polychlorinated biphenyls, including non-dioxin-like PCB153, in gills of killifish (Fundulus heteroclitus) from New Bedford Harbor.

Previous reports suggested that non-dioxin-like (NDL) PCB153 effects on cytochrome P450 3A (Cyp3a) expression in Atlantic killifish (Fundulus heteroclitus) gills differed between F0 generation fish from a PCB site (New Bedford Harbor; NBH) and a reference site (Scorton Creek; SC). Here, we examined effects of PCB153, dioxin-like (DL) PCB126, or a mixture of both, on Cyp3a56 mRNA in killifish generations removed from the wild, without environmental PCB exposures. PCB126 effects in liver and gills differed between populations, as expected. Gill Cyp3a56 was not affected by either congener in NBH F2 generation fish, but was induced by PCB153 in SC F1 fish, with females showing a greater response. PCB153 did not affect Cyp3a56 in liver of either population. Results suggest a heritable resistance to NDL-PCBs in killifish from NBH, in addition to that reported for DL PCBs. Induction of Cyp3a56 in gills may be a biomarker of exposure to NDL PCBs in fish populations that are not resistant to PCBs.

PCB153 reduces apoptosis in primary cultures of murine pituitary cells through the activation of NF-κB mediated by PI3K/Akt.

Polychlorinated biphenyls (PCBs) are persistent pollutants involved in human tumorigenesis. PCB153 is a ubiquitous non-dioxin-like PCB with proliferative and anti-apoptotic effects. To explore the impact of PCB153 in the survival of pituitary cells, we exposed murine pituitary primary cells to PCB153 10 µM for 24 h. Apoptosis was assessed by RT-qPCR, Western-blot, immunoprecipitation, caspase activity, and immunofluorescence. We found that PCB153 decreased pituitary apoptosis through both the extrinsic and intrinsic pathways. PCB153 reduced the level of the pro-apoptotic protein p38-MAPK. Otherwise, PCB153 activated PI3K/Akt and Erk1/2 pathways and enhanced the expression and nuclear translocation of NF-κB. Cotreatments with specific inhibitors revealed that only PI3K/Akt changed the caspase-3 expression and NF-κB activation induced by PCB153. Also, PCB153 decreased the expression of the pro-apoptotic and pro-senescent cyclins p53 and p21. In summary, exposure to PCB153 leads to a downregulation of apoptosis in the pituitary driven by a PI3K/Akt-mediated activation of NF-κB.

Gut microbiota health closely associates with PCB153-derived risk of host diseases.

Although the production and use of PCB153 have been banned globally, PCB153 pollution remains because of its persistence and long half-life in the environment. There is ongoing evidence that exposure to PCB153 may influence gut microbiota health and increase the risk of host health. It is needed to illuminate whether there are associations between gut microbiota dysregulation and PCB153-induced host diseases. Importantly, it is urgently needed to find specific strains as biomarkers to monitor PCB153 pollution and associated disorders. The work aims to investigate the change of gut microbiota composition, structure and diversity and various host physiological indexes, to ravel the chain causality of PCB153, gut microbiota health and host health, and to find potential gut microbiota markers for PCB153 pollution. Here, adult female mice were administrated with PCB153. Obtained results indicated that PCB153 led to gut microbiota health deterioration. PCB153 exposure also induced obesity, hepatic lipid accumulation, abdominal adipose tissue depots and dyslipidemia in mice. Furthermore, specific gut microbiota significantly correlated with the host health indexes. This work provides support for the relationship between gut microbiota aberrance derived from PCB153 and risk of host health, and offers some indications of possible indicative functions of gut microbiota on PCB153 pollution.

Bisphenol A and polychlorinated biphenyls enhance the cancer stem cell properties of human ovarian cancer cells by activating the WNT signaling pathway.

Cancer stem cells (CSCs) are a very small subpopulation that have stem-cell qualities, such as exhibiting self-renewal, immortality, and pluripotency, and the capability to differentiate into different tumor cell subtypes. CSCs contribute to tumor onset, expansion, metastasis, resistance and recurrence. Meanwhile, organic pollutants, including nonpersistent pollutants, such as bisphenol A (BPA), and persistent pollutants, such as polychlorinated biphenyls (PCBs), are toxic chemicals that can be readily ingested via dietary exposure and other exposure routes and can accumulate through the food chain. Many organic pollutants increase the risk of ovarian cancer depending on their estrogenic effects. Nonetheless, most previous studies have focused on the toxic effects of these pollutants on the proliferation, metastasis and development of ovarian cancer cells. However, little research has investigated the adverse effect of these pollutants on ovarian cancer stem cells. The current study found that BPA, PCB126 and PCB153 greatly enhanced the formation of cancer stem-like cell spheres of OVCAR-3 cells (human ovarian cancer cells) under low-dose exposure. In parallel, the CD44highCD24low cell subpopulation was increased in treated cells relative to untreated cells. Elevated expression of cancer stem cell markers, including ALDH1A1, CD133, SOX2, NANOG and OCT4, was demonstrated in treated cells compared to untreated cells. In summary, these data demonstrate that the oncogenic effects of pollutants can be evaluated according to changes in caner stem cell properties.

Developmental Exposure to PCB153 (2,2',4,4',5,5'-Hexachlorobiphenyl) Alters Circadian Rhythms and the Expression of Clock and Metabolic Genes.

Polychlorinated biphenyls (PCBs) are highly persistent and ubiquitously distributed environmental pollutants. Based on their chemical structure, PCBs are classified into non-ortho-substituted and ortho-substituted congeners. Non-ortho-substituted PCBs are structurally similar to dioxin and their toxic effects and mode of action are well-established. In contrast, very little is known about the effects of ortho-substituted PCBs, particularly, during early development. The objective of this study is to investigate the effects of exposure to an environmentally prominent ortho-substituted PCB (2,2',4,4',5,5'-hexachlorobiphenyl; PCB153) on zebrafish embryos. We exposed zebrafish embryos to 3 different concentrations of PCB153 starting from 4 to 120 hours post-fertilization (hpf). We quantified gross morphological changes, behavioral phenotypes, gene expression changes, and circadian behavior in the larvae. There were no developmental defects during the exposure period, but starting at 7 dpf, we observed spinal deformity in the 10 µM PCB153 treated group. A total of 633, 2227, and 3378 differentially expressed genes were observed in 0.1 µM (0.036 µg/ml), 1 µM (0.36 µg/ml), and 10 µM (3.6 µg/ml) PCB153-treated embryos, respectively. Of these, 301 genes were common to all treatment groups. KEGG pathway analysis revealed enrichment of genes related to circadian rhythm, FoxO signaling, and insulin resistance pathways. Behavioral analysis revealed that PCB153 exposure significantly alters circadian behavior. Disruption of circadian rhythms has been associated with the development of metabolic and neurological diseases. Thus, understanding the mechanisms of action of environmental chemicals in disrupting metabolism and other physiological processes is essential.

A Bayesian framework for estimating parameters of a generic toxicokinetic model for the bioaccumulation of organic chemicals by benthic invertebrates: Proof of concept with PCB153 and two freshwater species.

Toxicokinetic (TK) models are relevant and widely used to predict chemical concentrations in biological organisms. The importance of dietary uptake for aquatic invertebrates has been increasingly assessed in recent years. However, the model parameters are estimated on limited specific laboratory data sets that are bounded by several uncertainties. The aim of this study was to implement a Bayesian framework for simultaneously estimating the parameters of a generic TK model for benthic invertebrate species from all data collected. We illustrate our approach on the bioaccumulation of PCB153 by two species with different life traits and therefore exposure routes: Chironomus riparius larvae exposed to spiked sediment for 7 days and Gammarus fossarum exposed to spiked sediment and/or leaves for 7 days and then transferred to a clean media for 7 more days. The TK models assuming first-order kinetics were fitted to the data using Bayesian inference. The median model predictions and their 95% credibility intervals showed that the model fit the data well. From a methodological point of view, this paper illustrates that simultaneously estimating all model parameters from all available data by Bayesian inference, while considering the correlation between parameters and different types of data, is a real added value for TK modeling. Moreover, we demonstrated the ability of a generic TK model considering uptake and elimination routes as modules to add according to the availability of the data measured. From an ecotoxicological point of view, we show differences in PCB153 bioaccumulation between chironomids and gammarids, explained by the different life traits of these two organisms.

Association between polychlorinated biphenyl 153 exposure and serum testosterone levels: analysis of the National Health and Nutrition Examination Survey.

BACKGROUND: To examine the effects of environmental polychlorinated biphenyls (PCBs) 153 exposure, an industrial plasticizer, on serum testosterone levels. METHODS: Using data collected from the 1999-2000 and 2001-2002 National Health and Nutrition Examination Survey (NHANES), we analyzed serum total testosterone and PCB153 levels, demographic data and comorbidities for men aged 18 years and older. Univariate and multivariate linear regression analysis was used to evaluate the association between total testosterone and serum PCB153. RESULTS: Five hundred and fifty-seven men met inclusion criteria. Median age was 45.7 [33.4-60.4] years old while median serum total testosterone and PCB153 levels were 479 [352.5-607] ng/dL and 0.20 [0.11-0.39] ng/g, respectively. Increasing age, higher body mass index (BMI), higher levels of serum PCB153, lower levels of activity and a history of diabetes mellitus and coronary heart disease were associated with decreasing serum testosterone levels on univariate linear regression. On multivariate linear regression, increasing age (estimate -6.29 ng/dL per year of life, P<0.001) and BMI (estimate -7.08 ng/dL per unit BMI, P<0.001) were associated with declining serum testosterone levels. While serum PCB153 levels were found to be negatively correlated with serum testosterone levels on univariate analysis (estimate -179.67, P<0.001), this association was not significant on the multivariable model (estimate -12.83, P=0.673). CONCLUSIONS: In this population-based analysis, we report an association between a decrease in serum testosterone with increasing serum levels of PCB153. Identifying environmental factors for etiology of low testosterone and mechanisms for causation will be important to aid in strategies to increase testosterone naturally in men.

Analysis of glycerophospholipid metabolism after exposure to PCB153 in PC12 cells through targeted lipidomics by UHPLC-MS/MS.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that have neurotoxicity, reproductive toxicity, hepatotoxicity and immunotoxicity in both animals and humans. Few studies have focused on the changes to endogenous glycerophospholipid metabolism caused by PCB153. To evaluate the relationships between exposure to PCB153 and specific endogenous glycerophospholipid metabolism, an ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was implemented in this study. Twenty-two endogenous glycerophospholipids in PC12 cells were analyzed after exposure to PCB153 at dosages of 0.05 µg mL-1, 0.5 µg mL-1 or 20 µg mL-1 for 120 h. PC(14:0/14:0), PE(16:0/18:1), PE(16:0/18:2), PS(18:0/18:1) and PI(16:0/18:1) were identified as potential biomarkers under the rules of t-test (P) value < 0.05 and variable importance at projection (VIP) value > 1. It was also found that the alterations at 0.05 µg mL-1 and 20 µg mL-1 PCB153 were similar at 120 h, while 0.5 µg mL-1 PCB153 presented an opposite trend. Additionally, significant upregulation of PC, PE and PS with the same fatty acid chains of 18:0/18:2 was found after exposure to 0.05 µg mL-1 and 20 µg mL-1 PCB153 at 120 h. This study revealed that PCB153 exposure modulated 22 endogenous glycerophospholipids in PC12 cells and provided the basis for the further study of PCB153 on the effects of glycerophospholipids on PC12 cells.

Intestinal exposure to PCB 153 induces inflammation via the ATM/NEMO pathway.

BACKGROUND: Polychlorinated biphenyls (PCBs) are persistent organic pollutants that adversely affect human health. PCBs bio-accumulate in organisms important for human consumption. PCBs accumulation in the body leads to activation of the transcription factor NF-κB, a major driver of inflammation. Despite dietary exposure being one of the main routes of exposure to PCBs, the gut has been widely ignored when studying the effects of PCBs. OBJECTIVES: We investigated the effects of PCB 153 on the intestine and addressed whether PCB 153 affected intestinal permeability or inflammation and the mechanism by which this occurred. METHODS: Mice were orally exposed to PCB 153 and gut permeability was assessed. Intestinal epithelial cells (IECs) were collected and evaluated for evidence of genotoxicity and inflammation. A human IEC line (SW480) was used to examine the direct effects of PCB 153 on epithelial function. NF-кB activation was measured using a reporter assay, DNA damage was assessed, and cytokine expression was ascertained with real-time PCR. RESULTS: Mice orally exposed to PCB 153 had an increase in intestinal permeability and inflammatory cytokine expression in their IECs; inhibition of NF-кB ameliorated both these effects. This inflammation was associated with genotoxic damage and NF-кB activation. Exposure of SW480 cells to PCB 153 led to similar effects as seen in vivo. We found that activation of the ATM/NEMO pathway by genotoxic stress was upstream of NF-kB activation. CONCLUSIONS: These results demonstrate that oral exposure to PCB 153 is genotoxic to IECs and induces downstream inflammation and barrier dysfunction in the intestinal epithelium.

PCB95 and PCB153 change dopamine levels and turn-over in PC12 cells.

Polychlorinated biphenyls (PCB) exposure at low chronic levels is a significant public health concern. Animal and epidemiological studies indicate that low PCB body burden may cause neurotoxicity and be a risk factor for neurodegenerative diseases. In the current study, we measured the ability of two non-dioxin like PCBs, 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and 2,2'3,5',6-pentachlorobiphenyl (PCB95), to alter dopamine (DA) levels and metabolism using the dopaminergic PC12 cell line. Our hypothesis is that treatment of PC12 cells with non-toxic concentrations of PCB153 or PCB95 for 12 and 24 h will have different effects due to different congener structures. Levels of DA and of 3,4-dihydroxyphenylacetaldehyde (DOPAL), 3, 4-dihyroxylphenylethanol (DOPET), and 3,4-dihyroxylphenylacetic acid (DOPAC) metabolite, gene expression of the dopamine synthesis enzyme tyrosine hydroxylase (TH) and the vesicular monoamine transporter (VMAT2), and gene expression of the anti-oxidant enzymes Cu/Zn and Mn superoxide oxidase (Cu/ZnSOD, MnSOD), glutathione peroxidase (GPx) and catalase were determined. PCB153 decreased intracellular and extracellular levels of DA after 12 h exposure and this was consistent with an increase in DA metabolites. After 24 h, the level of DA in medium increased compared to the control. In contrast, PCB95 exposure increased the intracellular DA level and decreased DA in medium consistent with a down-regulation of VMAT2 expression at 12 h. After 24 h exposure, PCB95 increased DA levels in media. Expression of TH mRNA increased slightly following 12 h but not at 24 h exposure. MnSOD mRNA increased up to 6-7 fold and Cu/ZnSOD increased less than two-fold after treatment with both congeners. Catalase expression was up-regulated following 24 h exposure to PCB153 and PCB95, but GPx expression was down-regulated after 12 h exposure to PCB95 only. These results suggest that PCB153 and PCB95 are neurotoxic and affect DA turnover with structure-dependent differences between these two congeners.

Persistent organic pollutants and risk of diabetes and obesity on healthy adults: Results from a cross-sectional study in Spain.

Environmental exposure to persistent organic pollutants (POPs) has been reported to be relevant in the population of the Canary Islands (Spain), especially that of organochlorine pesticides. On the other hand, the population of this archipelago presents a high prevalence of type 2 diabetes (T2D), and it has been recently reported that environmental chemical contamination could play a role in the development of this disease. We performed a cross-sectional study in a representative sample from this archipelago to evaluate whether serum levels of selected POPs could be considered as risk factors for diabetes in this population. Serum levels of 30 POPs were determined in 429 adults (9.3% with T2D). We found that serum levels of p,p'-DDE (DDE), PCB-153 and PCB-118 were significantly higher among subjects having diabetes than in non-diabetic subjects (p=0.001, p=0.046, and p<0.0001, respectively). We observed a positive correlation between serum p,p'-DDE and glucose levels. Serum p,p'-DDE was identified as a risk factor for diabetes in univariate analysis in the whole series, and it remained as an independent risk factor for diabetes in subjects with serum glucose <126mg/dL (multivariate analysis, Exp(B)=1.283, CI 95% (1.023-1.611), p=0.031). Those normoglycemic subjects that are most exposed to p,p'-DDE (95th percentile: serum p,p'-DDE>5µg/L) seem to be those people at higher risk. Our results showed that p,p'-DDE levels were significantly higher among subjects having diabetes. These findings should be considered by public health Authorities to implement measures devoted to minimize human exposure to pollutants that could be harmful to the population.

Non-dioxin-like organic toxicant PCB153 modulates sphingolipid metabolism in liver progenitor cells: its role in Cx43-formed gap junction impairment.

The non-dioxin-like environmental toxicant 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153), member of a group of persistent organic pollutants wide-spread throughout the environment, reduces gap junction intercellular communication (GJIC), an event possibly associated with tumor promotion. Since very few studies have investigated the signaling effectors and mode(s) of action of PCB153, and it is known that the gap junction (GJ) protein Cx43 can be regulated by the bioactive sphingolipid (SL) sphingosine 1-phosphate (S1P), this in vitro study mainly addresses whether SL metabolism is affected by PCB153 in rat liver epithelial WB-F344 cells. PCB153 treatment obtained significant changes in the S1P/ceramide (Cer) ratio, known to be crucial in determining cell fate. In particular, an increase in S1P at 30 min and a decrease of the bioactive lipid at 3 h were observed, whereas Cer level increased at 1 h and 24 h. Notably, a time-dependent modulation of sphingosine kinase (SphK), the enzyme responsible for S1P synthesis, and of its regulators, ERK1/2 and protein phosphatase PP2A, supports the involvement of these signaling effectors in PCB153 toxicity. Electrophysiological analyses, furthermore, indicated that the lipophilic environmental toxicant significantly reduced GJ biophysical properties, affecting both voltage-dependent (such as those formed by Cx43 and/or Cx32) and voltage-independent channels, thereby demonstrating that PCB153 may act differently on GJs formed by distinct Cx isoforms. SphK down-regulation alone induced GJIC impairment, and, when combined with PCB153, the acute effect on GJ suppression was additive. Moreover, after enzyme-specific gene silencing, the SphK1 isoform appears to be responsible for down-regulating Cx43 expression, while being the target of PCB153 at short-term exposure. In conclusion, we provide the first evidence of novel effectors in PCB153 toxic action in rat liver stem-like cells, leading us to consider SLs as potential markers for preventing GJIC deregulation and, thus, the tumorigenic action elicited by this environmental toxicant.