Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review.

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required.

Activation of aryl hydrocarbon receptor by dioxin directly shifts gut microbiota in zebrafish.

Gut microbiota is of critical importance to host health. Aryl hydrocarbon receptor (AhR) is found to be closely involved in the regulation of gut microbial dynamics. However, it is still not clear how AhR signaling shapes the gut microbiota. In the present study, adult zebrafish were acutely exposed to an AhR antagonist (CH223191), an AhR agonist (polychlorinated biphenyl 126; PCB126) or their combination for 7 d. Overall intestinal health and gut microbial community were temporally monitored (1 d, 3 d and 7 d) and inter-compared among different groups. The results showed that single exposure to PCB126 significantly disrupted the overall health of intestines (i.e., neural signaling, inflammation, epithelial barrier integrity, oxidative stress). However, CH223191 failed to inhibit but enhanced the physiological toxicities of PCB126, implying the involvement of extra mechanisms rather than AhR in the regulation of intestinal physiological activities. Dysbiosis of gut microbiota was also caused by PCB126 over time as a function of sex. It is intriguing that CH223191 successfully abolished the holistic effects of dioxin on gut microbiota, which inferred that growth of gut microbes was directly controlled by AhR activation without the involvement of host feedback modulation. When coming to detailed alterations at certain taxon, both antagonistic and synergistic interactions existed between CH223191 and dioxin, depending on fish sex, exposure duration and bacterial species. Correlation analysis found that gut inflammation was positively associated with pathogenic Legionella bacteria, but was negatively associated with epithelial barrier integrity, suggesting that integral intestinal epithelial barrier can prevent the influx of pathogenic bacteria to induce inflammatory response. Overall, this study has deciphered, for the first time, the direct regulative effects of AhR activity on gut microbiota. Future research is warranted to elucidate the specific mechanisms of AhR action on certain bacterial population.

A comprehensive review on hepatoprotective and nephroprotective activities of chrysin against various drugs and toxic agents.

Chrysin belongs to the flavonoids and has been used as traditional medicine from ancient and has been reported to exhibit a wide range of pharmacological properties. The biochemical and molecular mechanisms involved in the hepato- and nephroprotective activities of chrysin were discussed in this review. Chrysin exhibited hepatoprotective activity against 2,3,7,8-tetrachlorodibenzo-p-dioxin, carbon tetrachloride, cisplatin, d-galactosamine, doxorubicin, ethanol, lipopolysaccharide/d-galactosamine, methotrexate, ammonium chloride, paracetamol, diethylnitrosamine, streptozotocin, tert-butyl hydroperoxide, thioacetamide, 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), ischemia/reperfusion-induced hepatotoxicity and nephroprotective activity against cisplatin, doxorubicin, paracetamol, gentamicin, streptazotocin, N-nitrosodiethyl amine, 5-fluorouracil, adenine, carbon tetrachloride, copper, 2,3,7,8-tetrachlorodibenzo- p-dioxin, colistin, Nω-nitro-l-arginine-methylester and ethanol in various animal models due to its antioxidant, anti-apoptotic activities. In this review, we provide an overview of the possible mechanisms by which chrysin reduced the hepatotoxicity and nephrotoxicity of different toxicants. This will help the toxicologists, pharmacologists and chemists to develop new safer pharmaceutical products with chrysin and other toxicants.

The Role of Endocrine and Dioxin-Like Activity of Extracts of Petroleum Substances in Developmental Toxicity as Detected in a Panel of CALUX Reporter Gene Assays.

Recent evidence suggests that the interaction of polycyclic aromatic hydrocarbons (PAHs), present in some petroleum substances (PS), with particular nuclear-hormone-receptors and/or the dioxin (aryl hydrocarbon receptor [AhR]) receptor, may play a role in the prenatal developmental toxicity (PDT) induced by these substances. To address this hypothesis, we evaluated the possible endocrine and dioxin-like activity of the dimethylsulfoxide (DMSO)-extracts of 9 PS, varying in PAH content, and 2 gas-to-liquid (GTL) products, containing no PAHs but having similar other properties as PS, using a series of Chemical Activated LUciferase gene eXpression (CALUX) assays. The results show that the extracts of PS tested in this study possess various endocrine and dioxin-like activities and these in vitro potencies are associated with the quantity and type of PAHs they contain. All tested DMSO-extracts of PS show a strong AhR agonist activity and rather weak antiprogesterone, antiandrogen, and estrogenic activities. In the assays that evaluate thyroid-related and antiestrogen activity, only minor effects of specific extracts, particularly those with a substantial amount of 4-5 ring PAHs, ie, sample No. 34, 98, and 99, were observed. None of the GTL extracts interacted with the selected receptors. Of all assays, the AhR agonist activity correlates best (R2 = 0.80) with the in vitro PDT of the substances as quantified previously in the embryonic stem cell test, suggesting an important role of the AhR in mediating this effect. Hierarchic clustering of the combined CALUX data clustered the compounds in line with their chemical characteristics, suggesting a PS class-specific effects signature in the various CALUX assays, depending on the PAH profile. To conclude, our findings indicate a high potential for endocrine and dioxin-like activity of some PS extracts which correlates with their in vitro PDT and is driven by the PAHs present in these substances.

[Molecular Mechanism Whereby Maternal Exposure to Dioxin Suppresses Sexual Maturation of the Offspring after Growing Up].

Dioxins, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are responsible for producing serious toxic effects in the next generation, such as sexual immaturity. Our laboratory found that treating pregnant rats on gestational day 15 with TCDD (1 µg/kg orally) targets pituitary luteinizing hormone (LH) to attenuate testicular steroidogenesis in fetuses. Because sex steroids during a short window ("the critical period") in the perinatal stage stimulate brain differentiation closely linked to sexual maturation, it is likely that TCDD imprints sexual immaturity on the offspring due to the lowered expression of LH during the fetal period. To address this hypothesis, we first investigated the effect of supplementation of equine chorionic gonadotropin (eCG), an LH-mimicking hormone, in fetuses exposed to TCDD. The result showed that eCG ameliorated defects in sexual behavior in adulthood as well as in steroidogenesis during the fetal stage. We also found that maternal exposure to TCDD induced the pituitary expression of histone deacetylases (HDACs) in fetuses. In agreement with this, TCDD deacetylated the histones wrapped around the LHß gene, and valproic acid, an HDAC inhibitor, blocked the reduced level of LHß caused by TCDD. These observations strongly suggest that TCDD induces the expression of HDACs to attenuate fetal LH production. Finally, such a transient reduction in steroidogenesis of the pituitary-gonadal axis causes a decrease in the expression of hypothalamic gonadotropin-releasing hormone, resulting in defects in sexual behavior in adulthood. This review increases our understanding of the developmental toxicities caused by endocrine disruptors including dioxins.

Inhibition of aryl hydrocarbon receptor signaling and induction of NRF2-mediated antioxidant activity by cinnamaldehyde in human keratinocytes.

BACKGROUND: Dioxins and other environmental pollutants are toxic and remain in biological tissues for a long time leading to various levels of oxidative stress. Although the toxicity of these agents has been linked to activation of the aryl hydrocarbon receptor (AHR), no effective treatment has been developed. OBJECTIVE: To explore novel phytochemicals that inhibit AHR activation in keratinocytes. METHODS: Keratinocytes were used in this study because the skin is one of the organs most affected by dioxin and other environmental pollutants. HaCaT cells, which are a human keratinocyte cell line, and normal human epidermal keratinocytes were stimulated with benzo[a]pyrene to induce AHR activation, and the effects of traditional Japanese Kampo herbal formulae were analyzed. Quantification of mRNA, western blotting, immunofluorescence localization of molecules, siRNA silencing, and visualization of oxidative stress were performed. RESULTS: Cinnamomum cassia extract and its major constituent cinnamaldehyde significantly inhibited the activation of AHR. Cinnamaldehyde also activated the NRF2/HO1 pathway and significantly alleviated the production of reactive oxygen species in keratinocytes. The inhibition of AHR signaling and the activation of antioxidant activity by cinnamaldehyde operated in a mutually independent manner as assessed by siRNA methods In addition, AHR signaling was effectively inhibited by traditional Kampo formulae containing C. cassia. CONCLUSION: Cinnamaldehyde has two independent biological activities; namely, an inhibitory action on AHR activation and an antioxidant effect mediated by NRF2/HO1 signaling. Through these dual functions, cinnamaldehyde may be beneficial for the treatment of disorders related to oxidative stress such as dioxin intoxication, acne, and vitiligo.

Is hepatic oxidative stress a main driver of dietary selenium toxicity in white sturgeon (Acipenser transmontanus)?

Most species of sturgeon have experienced significant population declines and poor recruitment over the past decades, leading many, including white sturgeon (Acipenser transmontanus), to be listed as endangered. Reasons for these declines are not yet fully understood but benthic lifestyle, longevity, and delayed sexual maturation likely render sturgeon particularly susceptible to factors such as habitat alteration and contaminant exposures. One contaminant of particular concern to white sturgeon is selenium (Se), especially in its more bioavailable form selenomethionine (SeMet), as it is known to efficiently bioaccumulate in prey items of this species. Studies have shown white sturgeon to be among the most sensitive species of fish to dietary SeMet as well as other pollutants such as metals, dioxin-like chemicals and endocrine disrupters. One of the primary hypothesized mechanisms of toxicity of SeMet in fish is oxidative stress; however, little is know about the specific mode by which SeMet affects the health of white sturgeon. Therefore, the aim of this study was to characterize oxidative stress and associated antioxidant responses as a molecular event of toxicity, and to link it with the pathological effects observed previously. Specifically, three-year-old white sturgeon were exposed for 72 days via their diet to 1.4, 5.6, 22.4 or 104.4µg Se per g feed (dm). Doses were chosen to range over a necessary Se intake level, current environmentally relevant intakes and an intake representing predicted increases of Se release. Lipid hydroperoxides, which are end products of lipid oxidation, were quantified as a marker of oxidative stress. Changes in gene expression of glutathione peroxidase (GPx), superoxide dismutase, catalase, glutathione S-transferase, apoptosis inducing factor and caspase 3 were quantified as markers of the response to oxidative stress. Concentrations of lipid hydroperoxides were highly variable within dose groups and no dose response was observed. GPx expression was significantly increased in the low dose group indicating an induced antioxidant response. Expression of other genes were not significantly induced or suppressed. Overall, there was very little evidence of oxidative stress, and therefore, in contrast to previous reports on other species of teleost fishes, oxidative stress is not believed to be a main driver of toxicity in white sturgeon exposed to SeMet.

Plant lignan secoisolariciresinol suppresses pericardial edema caused by dioxin-like compounds in developing zebrafish: Implications for suppression of morphological abnormalities.

Dioxins and dioxin-like compounds (DLCs) enter the body mainly through diet and cause various toxicological effects through activation of the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor. Some plant extracts and phytochemicals are reported to suppress this transformation. However, most of these reports have been from in vitro experiments and few reports have been from in vivo experiments. In addition, there has been no report of foodstuffs that effectively prevent AhR-associated morphological abnormalities such as deformities caused by dioxins and DLCs in vivo. In this study, we show that secoisolariciresinol (SECO), a natural lignan-type polyphenolic phytochemical found mainly in flaxseed, has a rescuing effect, actually suppressing morphological abnormalities (pericardial edema) in zebrafish embryos exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB126), a dioxin-like PCB congener. Importantly, the rescuing effect of SECO was still evident when it was applied 16 h after the beginning of exposure to PCB126. This study suggests that SECO may be useful as a natural suppressive agent for morphological abnormalities caused by dioxins and DLCs.

Prenatal methylmercury exposure and language delay at three years of age in the Norwegian Mother and Child Cohort Study.

Prenatal methylmercury (MeHg) exposure and its possible neurodevelopmental effects in susceptible children are of concern. Studies of MeHg exposure and negative health outcomes have shown conflicting results and it has been suggested that co-exposure to other contaminants and/or nutrients in fish may confound the effect of MeHg. Our objective was to examine the association between prenatal exposure to MeHg and language and communication development at three years, adjusting for intake of fish, n-3 long chain polyunsaturated fatty acids (n-3 LCPUFAs) and co-exposure to dioxins and dioxin like polychlorinated biphenyls (dl-PCBs). We used data from the Norwegian Mother and Child Cohort Study (MoBa) collected between 2002 and 2008. The study sample consisted of 46,750 mother-child pairs. MeHg exposure was calculated from reported fish intake during pregnancy by a FFQ in mid-pregnancy. Children's language and communication skills were measured by maternal report on the Dale and Bishop grammar rating and the Ages and Stages communication scale (ASQ). We estimated odds ratios (OR) and 95% confidence intervals (CI) using logistic regressions. Median MeHg exposure was 1.3µg/day, corresponding to 0.14µg/kgbw/week. An exposure level above the 90th percentile (>2.6µg/day, >0.29µg/kgbw/week) was defined as the high MeHg exposure. Results indicated an association between high MeHg exposure and unintelligible speech with an adjusted OR 2.22 (1.31, 3.72). High MeHg exposure was also associated with weaker communication skills adjusted OR 1.33 (1.03, 1.70). Additional adjustment for fish intake strengthened the associations, while adjusting for PCBs and n-3 LCPUFA from diet or from supplements had minor impact. In conclusion, significant associations were found between prenatal MeHg exposure above the 90th percentile and delayed language and communication skills in a generally low exposed population.

The non-genomic effects of endocrine-disrupting chemicals on mammalian sperm.

Exposure to toxicants present in the environment, especially the so-called endocrine-disrupting chemicals (EDCs), has been associated with decreased sperm quality and increased anomalies in male reproductive organs over the past decades. Both human and animal populations are continuously exposed to ubiquitous synthetic and natural-occurring EDCs through diet, dermal contact and/or inhalation, therefore potentially compromising male reproductive health. Although the effects of EDC are likely induced via multiple genomic-based pathways, their non-genomic effects may also be relevant. Furthermore, spermatozoa are transcriptionally inactive cells that can come in direct contact with EDCs in reproductive fluids and secretions and are therefore a good model to address non-genomic effects. This review thus focuses on the non-genomic effects of several important EDCs relevant to mammalian exposure. Notably, EDCs were found to interfere with pre-existing pathways inducing a panoply of deleterious effects to sperm function that included altered intracellular Ca(2) (+) oscillations, induction of oxidative stress, mitochondrial dysfunction, increased DNA damage and decreased sperm motility and viability, among others, potentially jeopardizing male fertility. Although many studies have used non-environmentally relevant concentrations of only one compound for mechanistic studies, it is important to remember that mammals are not exposed to one, but rather to a multitude of environmental EDCs, and synergistic effects may occur. Furthermore, some effects have been detected with single compounds at environmentally relevant concentrations.

The value of information for managing contaminated sediments.

Effective management of contaminated sediments is important for long-term human and environmental health, but site-management decisions are often made under high uncertainty and without the help of structured decision support tools. Potential trade-offs between remedial costs, environmental effects, human health risks, and societal benefits, as well as fundamental differences in stakeholder priorities, complicate decision making. Formal decision-analytic tools such as multicriteria decision analysis (MCDA) move beyond ad hoc decision support to quantitatively and holistically rank management alternatives and add transparency and replicability to the evaluation process. However, even the best decisions made under uncertainty may be found suboptimal in hindsight, once additional scientific, social, economic, or other details become known. Value of information (VoI) analysis extends MCDA by systematically evaluating the impact of uncertainty on a decision. VoI prioritizes future research in terms of expected decision relevance by helping decision makers estimate the likelihood that additional information will improve decision confidence or change their selection of a management plan. In this study, VoI analysis evaluates uncertainty, estimates decision confidence, and prioritizes research to inform selection of a sediment capping strategy for the dibenzo-p-dioxin and -furan contaminated Grenland fjord system in southern Norway. The VoI model extends stochastic MCDA to model decisions with and without simulated new information and compares decision confidence across scenarios with different degrees of remaining uncertainty. Results highlight opportunities for decision makers to benefit from additional information by anticipating the improved decision confidence (or lack thereof) expected from reducing uncertainties for each criterion or combination of criteria. This case study demonstrates the usefulness of VoI analysis for environmental decisions by predicting when decisions can be made confidently, for prioritizing areas of research to pursue to improve decision confidence, and for differentiating between decision-relevant and decision-irrelevant differences in evaluation perspectives, all of which help guide meaningful deliberation toward effective consensus solutions.

Post-Vietnam military herbicide exposures in UC-123 Agent Orange spray aircraft.

BACKGROUND: During the Vietnam War, approximately 20 million gallons of herbicides, including ~10.5 million gallons of dioxin-contaminated Agent Orange, were sprayed by about 34 UC-123 aircraft that were subsequently returned to the United States, without decontamination or testing, to three Air Force reserve units for transport operations (~1971-1982). In 1996, observed dioxin contamination led to withdrawal of these UC-123s from public auction and to their smelting in 2009. Current Air Force and Department of Veterans Affairs policies stipulate that "dried residues" of chemical herbicides and dioxin had not lead to meaningful exposures to flight crew and maintenance personnel, who are thus ineligible for Agent Orange-related benefits or medical examinations and treatment. Sparse monitoring data are available for analysis. METHODS: Three complementary approaches for modeling potential exposures to dioxin in the post-Vietnam war aircraft were employed: (1) using 1994 and 2009 Air Force surface wipe data to model personnel exposures and to estimate dioxin body burden for dermal-oral exposure for dried residues using modified generic US Environmental Protection Agency intake algorithms; (2) comparing 1979 Air Force 2,4- dichlorophenoxyacetic acid and 2,4-5-trichlorophenoxyacetic acid air samples to saturated vapor pressure concentrations to estimate potential dioxin exposure through inhalation, ingestion and skin contact with contaminated air and dust; and (3) applying emission models for semivolatile organic compounds from contaminated surfaces to estimate airborne contamination. RESULTS: Model (1): Body-burden estimates for dermal-oral exposure were 0.92 and 5.4pg/kg body-weight-day for flight crew and maintainers. The surface wipe concentrations were nearly two orders of magnitude greater than the US Army guidance level. Model (2): measured airborne concentrations were at least five times greater than saturated vapor pressure, yielding dioxin estimates that ranged from 13.2-27.0pg/m(3), thus supporting the likelihood of dioxin dust adsorption. Model (3): Theoretical models yielded consistent estimates to Model 2, 11-49pg/m(3), where the range reflects differences in experimental value of dioxin vapor pressure and surface area used. Model (3) results also support airborne contamination and dioxin dust adsorption. CONCLUSIONS: Inhalation, ingestion and skin absorption in aircrew and maintainers were likely to have occurred during post-Vietnam use of the aircraft based on the use of three complementary models. Measured and modeled values for dioxin exceeded several available guidelines. Deposition-aerosolization-redeposition homeostasis of semivolatile organic compound contaminants, particularly dioxin, is likely to have continually existed within the aircraft. Current Air Force and Department of Veterans Affairs policies are not consistent with the available industrial hygiene measurements or with the widely accepted models for semivolatile organic compounds.

A sensitivity analysis using alternative toxic equivalency factors to estimate U.S. dietary exposures to dioxin-like compounds.

EPA recommends sensitivity analyses when applying the toxic equivalency factor (TEF) method to evaluate exposures to dioxin-like compounds (DLCs). Applying the World Health Organization's (WHO) 2005 TEF values and estimating average U.S. daily dietary intakes of 25 DLCs from eight food categories, we estimate a toxic equivalency (TEQ) intake of 23 pg/day. Among DLCs, PCB 126 (26%) and 1,2,3,7,8-PeCDD (23%) dominate TEQ intakes. Among food categories, milk (14%), other dairy (28%), beef (25%), and seafood (18%) most influenced TEQ intakes. We develop two approaches to estimate alternative TEF values. Based on WHO's assumption regarding TEF uncertainty, Approach1 estimates upper and lower TEFs for each DLC by multiplying and dividing, respectively, its individual TEF by ± half a log. Based on compiled empirical ranges of relative potency estimates, Approach2 uses percentile values for individual TEFs. Total TEQ intake estimates using the lower and upper TEFs based on Approach1 were 8 and 68 pg TEQ/day, respectively. The 25th and 75th percentile TEFs from Approach2 yielded 12 and 28 pg TEQ/day, respectively. The influential DLCs and food categories remained consistent across alternative TEFs, except at the 90th percentile using Approach2. We highlight the need for developing underlying TEF probability distributions.

Dioxin sensitivity-related two critical amino acids of arylhydrocarbon receptor may not correlate with the taxonomy or phylogeny in avian species.

There are two arylhydrocarbon receptor (AhR) isoforms in birds, AhR1 and AhR2. The varying sensitivity of AhR is reported to be related to two critical amino acids at positions 325 and 381 in the AhR1 ligand-binding domain. In this study, seven avian species whose in vivo dioxin sensitivity was known, and 13 species with no data regarding their in vivo dioxin sensitivity were examined. The two critical amino acids in the ligand-binding domain were investigated in avian species, and the results were compared with the taxonomy or phylogenetic trees for the bird AhR proteins. We found that the two critical amino acids did not correlate with the taxonomy or phylogeny of these proteins, suggesting that dioxin sensitivity was independent of taxonomy.

Risk trade-offs in fish consumption: a public health perspective.

Fish consumption advisories instruct vulnerable consumers to avoid high mercury fish and to limit total fish intake to reduce neurotoxic risk. Consumption data from the U.S. suggest that nontarget consumers also respond to such advice. These consumers reduce exposure to mercury and other toxicants at the cost of reduction in cardioprotective fatty acids. We present a probabilistic model to assess these risk trade-offs. We use NHANES consumption data to simulate exposure to contaminants and nutrients in fish, employ dose-response relationships to convert exposure to health end points, and monetize them using benefit transfer. Our results suggest that newborns gained on average 0.033 IQ points from their mothers' compliance with the prominent FDA/EPA advisory. The welfare gain for a birth cohort is estimated at $386 million. This gain could be fully offset by increments in cardiovascular risk if 0.6% of consumers aged 40 and older reduced fish intake by one monthly meal until they reached the age of 60 or if 0.1% of them permanently reduced fish intake.

Fish liver and seagull eggs, vitamin D-rich foods with a shadow: results from the Norwegian Fish and Game Study.

SCOPE: Fish liver, fish liver oil, oily fish and seagull eggs have been major sources of vitamin D for the coastal population of Norway. They also provide dioxin and polychlorinated dioxin-like compounds (dl-compounds), which may interfere with vitamin D homeostasis. We investigated whether serum 25-hydroxyvitamin D (25(OH)D) might be compromised by concomitant intake of dl-compounds. METHODS AND RESULTS: We studied 182 adults participating in the Norwegian Fish and Game Study. Participants who consumed fish liver and/or seagull eggs had higher dl-compound intake and blood concentrations than non-consumers (p < 0.001). Vitamin D intake was higher (p < 0.001), whereas serum 25(OH)D was lower (p = 0.029) in consumers than in non-consumers. Among non-consumers, vitamin D intake was associated with serum 25(OH)D (ß=1.06; 95% CI: 0.48, 1.63). This association was weaker among consumers (ß = 0.52; 95% CI: -0.05, 1.08), but strengthened when adjusted for retinol intake (ß = 0.66; 95% CI: 0.12, 1.21). The association between vitamin D intake and serum 25(OH)D did not seem to be compromised by intake of dl-compounds. CONCLUSION: To secure adequate vitamin D status while keeping the intake of dioxins and dl-polychlorinated biphenyls low, a healthy diet should include both supplemental vitamin D and oily fish. Despite high nutrient content, dietary fish liver and seagull eggs should be restricted, due to dl-compounds and possible vitamin A-D antagonism.

Harmaline and harmalol inhibit the carcinogen-activating enzyme CYP1A1 via transcriptional and posttranslational mechanisms.

Dioxins are known to cause several human cancers through activation of the aryl hydrocarbon receptor (AhR). Harmaline and harmalol are dihydro-ß-carboline compounds present in several medicinal plants such as Peganum harmala. We have previously demonstrated the ability of P. harmala extract to inhibit TCDD-mediated induction of Cyp1a1 in murine hepatoma Hepa 1c1c7 cells. Therefore, the aim of this study is to examine the effect of harmaline and its main metabolite, harmalol, on dioxin-mediated induction of CYP1A1 in human hepatoma HepG2 cells. Our results showed that harmaline and harmalol at concentrations of (0.5-12.5µM) significantly inhibited the dioxin-induced CYP1A1 at mRNA, protein and activity levels in a concentration-dependent manner. The role of AhR was determined by the inhibition of the TCDD-mediated induction of AhR-dependent luciferase activity and the AhR/ARNT/XRE formation by both harmaline and harmalol. In addition, harmaline significantly displaced [(3)H]TCDD in the competitive ligand binding assay. At posttranslational level, both harmaline and harmalol decreased the protein stability of CYP1A1, suggesting that posttranslational modifications are involved. Moreover, the posttranslational modifications of harmaline and harmalol involve ubiquitin-proteasomal pathway and direct inhibitory effects of both compounds on CYP1A1 enzyme. These data suggest that harmaline and harmalol are promising agents for preventing dioxin-mediated effects.

Polychlorinated biphenyls (PCBs) contamination and aryl hydrocarbon receptor (AhR) agonist activity of Omega-3 polyunsaturated fatty acid supplements: implications for daily intake of dioxins and PCBs.

Omega-3 polyunsaturated fatty acid (n-3 PUFA) rich oils derived primarily from fish are frequently consumed as supplements. Due to the tendency of persistent organic pollutants (POPs) to accumulate in exposed organisms, n-3 PUFA supplements can contain sufficient POPs to present a risk to consumers. Here we investigated PCB concentrations and aryl hydrocarbon receptor (AhR) agonist activity in 17 n-3 PUFA supplements available in Canada. PCBs ranged from <0.8 to 793 ng g(-1) oil, with salmon- and seal-derived products yielding the highest values. AhR agonist activity from a reporter gene assay ranged from 1.3 to 72.2 pg TEQ g(-1) oil, with salmon and tuna yielding the highest values. When consumed at the recommended doses and as a supplement to the average Canadian diet, seal-derived oil can contribute to exceedance of the tolerable daily intake of 20 ng PCBs kg-BW(-1)day(-1), and salmon-, tuna-, and sea herring-derived oils can contribute to exceedance of the tolerable daily intake limit of 2.3 pg TEQ kg-BW(-1)day(-1). The beneficial properties of fish and n-3 PUFA supplements, and the results of this study suggest that it is prudent to consume supplements derived from small, cold-water fatty fish. Further research will be necessary to draw firm conclusions.

Thyroid disruption: mechanism and clinical implications in human health.

Exposure to specific environmental toxins, including polychlorinated biphenyls, dioxins, phthalates, polybrominated diphenyl ethers (PBDEs), and other halogenated organochlorines, has been shown to interfere with the production, transportation, and metabolism of thyroid hormones by a variety of mechanisms. A broad range of chemicals, with structural similarity to thyroid hormone, have been shown to bind to thyroid receptors with both agonist and antagonist effects on thyroid hormone signaling. The incidence of thyroid disease in the United States, particularly for thyroid cancer and thyroid autoimmune disease, is increasing substantially. The evidence for the significant effects of background levels of thyroid-disrupting chemicals, the known pathways for thyroid disruptors, and the evidence and implications for neurodevelopmental damage due to thyroid-disrupting chemicals is reviewed.

Lipid peroxidation and oxidative status compared in workers at a bottom ash recovery plant and fly ash treatment plants.

Fly ash and ambient emissions of municipal solid waste incinerators contain polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polycyclic aromatic hydrocarbons (PAHs), other organic compounds, metals, and gases. Hazardous substances such as PCDD/Fs, mercury vapors and other silicates, and the components of bottom ash and fly ash elevate the oxidative damage. We compared oxidative damage in workers exposed to hazardous substances at a bottom ash recovery plant and 3 fly ash treatment plants in Taiwan by measuring their levels of plasma malondialdehyde (MDA) and urine 8-hydroxydeoxyguanosine (8-OH-dG). Significantly higher MDA levels were found in fly ash treatment plant workers (3.20 microM) than in bottom ash plant workers (0.58 microM). There was a significant association between MDA levels in workers and their working environment, especially in the fly ash treatment plants. Levels of 8-OH-dG varied more widely in bottom ash workers than in fly ash workers. The association between occupational exposure and 8-OH-dG levels may be affected by the life style of the workers. Because more dioxins and metals may leach from fly ash than from bottom ash, fly ash treatment plant workers should, as much as possible, avoid exposing themselves to fly ash.