Hydroxylated Polychlorinated Biphenyls Metabolites Research Articles

Targeted metabolome analysis of the dog brain exposed to PCBs suggests inhibition of oxidative phosphorylation by hydroxylated PCBs

Canis lupus familiaris (domestic dog) possess a high capacity to metabolize higher-chlorinated polychlorinated biphenyls (PCBs) to thyroid hormone (TH)-like hydroxylated PCB metabolites (OH-PCBs). As a result, the brain could be at high risk of toxicity caused by OH-PCBs. To evaluate the effect of OH-PCBs on dog brain, we analyzed OH-PCB levels in the brain and the metabolome of the frontal cortex following exposure to a mixture of PCBs (CB18, 28, 70, 77, 99, 101, 118, 138, 153, 180, 187, and 202). 4-OH-CB202 and 4-OH-CB107 were major OH-PCBs in the brain of PCB-exposed dogs. These OH-PCBs were associated with metabolites involved in urea cycle, proline-related compounds, and purine, pyrimidine, glutathione, and amino-acid metabolism in dog brain. Moreover, adenosine triphosphate levels in the PCBs exposure group were significantly lower than in the control group. These results suggest that OH-PCB exposure is associated with a disruption in TH homeostasis, generation of reactive oxygen species, and/or disruption of oxidative phosphorylation (OXPHOS) in brain cells. Among them, OXPHOS disturbance could be associated with both disruptions in cellular amino-acid metabolism and urea cycle. Therefore, an OXPHOS activity assay was performed to evaluate the disruption of OXPHOS by OH-PCBs. The results indicated that 4-OH-CB107 inhibits the function of Complexes III, IV, and V of the electron transport chain, suggesting that 4-OH-CB107 inhibit these complexes in OXPHOS. The neurotoxic effects of PCB exposure may be mediated through mitochondrial toxicity of OH-PCBs in the brain.

Accumulation of persistent organic pollutants in consumers of eel from polluted rivers compared to marketable eel

Globally, many river sediments are seriously contaminated with persistent organic pollutants (POPs) known to accumulate in aquatic food. In the Netherlands, toxicological risks of human exposure to dioxins and dioxin-like compounds led to a ban on eel fishing in the Rhine-Meuse delta. The aim of this study is to investigate differences in serum POP levels in consumers of eel from high-polluted areas and consumers of eel from low-polluted areas or aquaculture. In total 80 Dutch men were included, aged 40–70 years, with a habitual eel consumption of at least one portion (150 g) per month. Total levels of dioxins and dioxin-like compounds were measured in serum of all participants with the DR CALUX bioassay, validated with GC-MS. For a subgroup of 38 participants extensive POP measurements were performed. We revealed that consumption of eel from polluted rivers resulted in 2.5 and up to 10 times increased levels of dioxins and polychlorinated biphenyls (PCBs) respectively compared to controls. The highest PCB levels were detected for PCB 153, with a median level of 896 ng/g lipid and a maximum level of 5000 ng/g lipid in the high-exposed group. Furthermore, hydroxylated PCB metabolites (OH-PCBs: sum of 4-OH-CB107, 4-OH-CB146, 4′-OH-CB172, and 4-OH-CB187) were 8 times higher in men who consumed eel from polluted areas, and detected at levels (median 4.5 ng/g ww) reported to cause adverse health effects. Also, the majority of the perfluoroalkyl substances (PFASs) were significantly higher in consumers of eel from pullulated areas. In conclusion, this study is the first to reveal that (past) consumption of eel from polluted rivers resulted in high body burdens of dioxins, PCBs, OH-PCBs and PFASs. We confirmed the predictions made in a former risk assessment, and the high levels of dioxins and dioxin-like compounds as well as the OH-PCBs are of health concern.

A Preliminary Link between Hydroxylated Metabolites of Polychlorinated Biphenyls and Free Thyroxin in Humans.

Background: Polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (HO-PCBs) interfere with thyroid hormone action both in vitro and in vivo. However, epidemiologic studies on the link between PCB exposure and thyroid function have yielded discordant results, while very few data are available for HO-PCBs. Objectives: Our study aimed at investigating the relationship between clinically available markers of thyroid metabolism and serum levels of both PCBs and HO-PCBs. Subjects and Methods: In a group of 180 subjects, thyroid-stimulating hormone (TSH) and free thyroxin (fT4), 29 PCBs (expressed both in lipid weight and in wet weight) and 18 HO-PCBs were measured in serum. Results: In regression models, adjusted for gender, age, current smoking behavior, BMI and total lipid levels, serum levels of 3HO-PCB118 and 3HO-PCB180, and PCB95lw, PCB99lw and PCB149lw were independent, significant predictors of fT4. A stepwise, multiple regression with gender, age, current smoking behavior, BMI and total lipid levels and all five previously identified significant compounds retained age, BMI, PCB95lw, PCB99lw and 3HO-PCB180 as significant predictors of fT4. TSH levels were not predicted by serum levels of any of the PCBs or HO-PCBs. Conclusions: Our study indicates that in vivo, circulating fT4 levels can be linked to serum levels of several PCBs and hydroxylated PCB metabolites.

Effects of thiol antioxidants on the atropselective oxidation of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) by rat liver microsomes.

Chiral polychlorinated biphenyl (PCB) congeners, such as PCB 136, are atropselectively metabolized to various hydroxylated PCB metabolites (HO-PCBs). The present study investigates the effect of two thiol antioxidants, glutathione and N-acetyl-cysteine (NAC), on profiles and chiral signatures of PCB 136 and its HO-PCB metabolites in rat liver microsomal incubations. Liver microsomes prepared from rats pretreated with phenobarbital were incubated with PCB 136 (5 μM) in the presence of the respective antioxidant (0-10 mM), and levels and chiral signatures of PCB 136 and its HO-PCB metabolites were determined. Three metabolites, 5-136 (2,2',3,3',6,6'-hexachlorobiphenyl-5-ol), 4-136 (2,2',3,3',6,6'-hexachlorobiphenyl-4-ol), and 4,5-136 (2,2',3,3',6,6'-hexachlorobiphenyl-4,5-diol), were detected in all incubations, with 5-136 being the major metabolite. Compared to microsomal incubations without antioxidant, levels of 4,5-136 increased with increasing antioxidant concentration, whereas levels of PCB 136 and both mono-HO-PCBs were not affected by the presence of either antioxidant. PCB 136, 4-136, and 5-136 displayed significant atropisomeric enrichment; however, the direction and extent of the atropisomeric enrichment was not altered in the presence of an antioxidant. Because 4,5-136 can either be conjugated to a sulfate or glucuronide metabolite that is readily excreted or further oxidized a potentially toxic PCB 136 quinone, the effect of both thiol antioxidants on 4,5-136 formation suggests that disruptions of glutathione homeostasis may alter the balance between both metabolic pathways and, thus, PCB 136 toxicity in vivo.

Hydroxylated PCB Metabolites, Maternal Smoking and Pregnancy Outcomes

Hydroxylated PCB Metabolites, Maternal Smoking and Pregnancy OutcomesAbstract Number:2681 Gu Yiwei, Katrina Kezios, Liu Xinhua, Cirillo Piera, Tarrant Darcy, Myrto Petreas, June-Soo Park, Barbara Cohn, and Pam Factor-Litvak* Gu Yiwei Mailman School of Public Health Columbia University, United States, E-mail Address: [email protected] Search for more papers by this author , Katrina Kezios Mailman School of Public Health Columbia University, United States, E-mail Address: [email protected] Search for more papers by this author , Liu Xinhua Mailman School of Public Health Columbia University, United States, E-mail Address: [email protected] Search for more papers by this author , Cirillo Piera Child Health and Development Studies, United States, E-mail Address: [email protected] Search for more papers by this author , Tarrant Darcy Department of Toxic Substances Control, California Environmental Protection Agency, United States, E-mail Address: [email protected] Search for more papers by this author , Myrto Petreas Department of Toxic Substances Control California Environmental Protection Agency, United States, E-mail Address: [email protected] Search for more papers by this author , June-Soo Park Department of Toxic Substances Control California Environmental Agency, United States, E-mail Address: [email protected] Search for more papers by this author , Barbara Cohn Child Health and Development Studies, United States, E-mail Address: [email protected] Search for more papers by this author , and Pam Factor-Litvak* Mailman School of Public Health Columbia University, United States, E-mail Address: [email protected] Search for more papers by this author AbstractIntroduction Previous research suggests that prenatal exposure to chlorinated compounds, such as polychlorinated biphenyls (PCBs) may be associated with adverse birth outcomes. However, there are no data relating the hydroxylated metabolites (OH-PCBs) to birth outcomes.Methods In a sample of 442 births from the Child Health and Development Studies we measured 11 PCBs and five hydroxylated metabolites: 4-OH-PCB107, 3’-OH-PCB138, 4-OH-PCB146, 3-OH-PCB153, and 4-OH-PCB187 in blood collected from the mother in the immediate post-partum period. Birth weight and length of gestation were taken from the medical records. To examine the associations between maternal exposure to OH-PCBs and length of gestation and birth weight, we used linear models.Results. In adjusted analyses we found inverse associations between 4-OH-PCB107 and birth weight. The association was restricted to newborns of mothers who smoked during pregnancy. Among smokers and after additional control for PCB118, the primary parent compound of 4-OH-PCB107, newborns of women with concentrations of 4-OH-PCB107 >= 75th percentile had birth weights approximately 300 grams (95% confidence interval (CI) -533, -83) lighter than those <= 25th percentile. Each unit increase in PCB118 was associated with an increase in birth weight of 472 grams (95% CI 111, 833). Concentrations of PCB118 were similar in smoking and nonsmoking mothers. However smokers had twice the concentration of 4-OH-PCB107 compared to nonsmokers. No other OH-PCB was associated with birth weight and none were associated with length of gestation.Conclusions . It is likely that maternal prenatal smoking either increases the metabolism of PCB118 to 4-OH-PCB107 and/or decreases the clearance of 4-OH-PCB107 resulting in increased fetal exposure to 4-OH-PCB107. Maternal prenatal 4-OH-PCB 107 levels appear to contribute to lower birth weight among smokers.

Microsomal Oxidation of 2,2′,3,3′,6,6′-Hexachlorobiphenyl (PCB 136) Results in Species-Dependent Chiral Signatures of the Hydroxylated Metabolites

Chiral polychlorinated biphenyls (PCBs) display variable atropisomeric enrichment in wildlife and animal models, especially at higher trophic levels. These differences in PCBs’ chiral signatures are, at least in part, due to species-dependent oxidation of PCBs to hydroxylated PCB metabolites (OH-PCBs). Here, we investigate the hypothesis that the cytochrome P450 (P450) enzyme-mediated oxidation of chiral PCBs results in species-dependent differences in the chiral signatures of OH-PCBs (i.e., the direction and extent of OH-PCBs’ atropisomeric enrichment). To investigate this hypothesis, we incubated PCB 136, a representative chiral PCB, with pooled human liver microsomes (HLMs) or liver microsomes from male guinea pig, hamster, monkey, mouse, and rabbit or female dog and determined average profiles and chiral signatures of the OH-PCBs. 2,2′,3,3′,6,6′-Hexachlorobiphenyl-4-ol (4–136) was the major metabolite in incubations with HLMs and monkey and rabbit microsomes. 2,2′,3,3′,6,6′-Hexachlorobiphenyl-5-ol (5–136) was the major metabolite formed by microsomes from all other species. Both 4–136 and 5–136 were formed atropselectively in all microsomal incubations; however, the direction and extent of the atropisomeric enrichment of both OH-PCB metabolites showed considerable differences across microsomal preparations obtained from different species. These differences in OH-PCBs’ atropisomeric enrichment may not only be toxicologically relevant but may also be useful to study sources and transport of OH-PCBs in the environment.

Sulfated Metabolites of Polychlorinated Biphenyls Are High-Affinity Ligands for the Thyroid Hormone Transport Protein Transthyretin

Background: The displacement of l-thyroxine (T4) from binding sites on transthyretin (TTR) is considered a significant contributing mechanism in polychlorinated biphenyl (PCB)-induced thyroid disruption. Previous research has discovered hydroxylated PCB metabolites (OH-PCBs) as high-affinity ligands for TTR, but the binding potential of conjugated PCB metabolites such as PCB sulfates has not been explored.Objectives: We evaluated the binding of five lower-chlorinated PCB sulfates to human TTR and compared their binding characteristics to those determined for their OH-PCB precursors and for T4.Methods: We used fluorescence probe displacement studies and molecular docking simulations to characterize the binding of PCB sulfates to TTR. The stability of PCB sulfates and the reversibility of these interactions were characterized by HPLC analysis of PCB sulfates after their binding to TTR. The ability of OH-PCBs to serve as substrates for human cytosolic sulfotransferase 1A1 (hSULT1A1) was assessed by OH-PCB–dependent formation of adenosine-3´,5´-diphosphate, an end product of the sulfation reaction.Results: All five PCB sulfates were able to bind to the high-affinity binding site of TTR with equilibrium dissociation constants (Kd values) in the low nanomolar range (4.8–16.8 nM), similar to that observed for T4 (4.7 nM). Docking simulations provided corroborating evidence for these binding interactions and indicated multiple high-affinity modes of binding. All OH-PCB precursors for these sulfates were found to be substrates for hSULT1A1.Conclusions: Our findings show that PCB sulfates are high-affinity ligands for human TTR and therefore indicate, for the first time, a potential relevance for these metabolites in PCB-induced thyroid disruption.

Nonlegacy PCBs: Pigment Manufacturing By-Products Get a Second Look

Polychlorinated biphenyls (PCBs) were commercially manufactured in the United States from about 1930 until 1979, when their production was banned under the Toxic Substances Control Act (TSCA) because of concerns about their extreme environmental persistence, ability to bioaccumulate, and adverse human health effects. PCBs were used in numerous industrial and consumer applications, most notably as insulation fluids in electrical transformers and generators but also in products including fluorescent lamp ballasts, caulk, and carbonless copy paper. These now-discontinued manufactured chemicals have received a great deal of attention in terms of research and environmental remediation. But other, lesser-known PCBs continue to be generated and released into the environment, not from intentionally created commercial products but as unintentional by-products of manufacturing processes including, according to recent studies, those used to make certain pigments used in dyes, inks, and paints. PCBs do not occur naturally, and once in the environment they can last for decades. Until recently, PCBs that were being detected in the environment were thought to come entirely from “legacy” sources. Yet developments in analytical technology have given researchers a better understanding of PCB sources, of the patterns of individual PCBs (or congeners) that are being detected environmentally, and the fate of PCBs in the environment—how they move between soil, sediment, water, and air. These advances have also enabled the detection of individual congeners at very low levels and the identification of many new and ongoing sources of PCBs beyond those resulting from historical commercial mixtures. Unintentionally produced PCBs were known to be present in inks and dyes when the U.S. Environmental Protection Agency (EPA) announced the final rule barring commercial PCB production in 1979. A rule allowing exemptions for PCBs in controlled manufacturing processes and as unintentional contaminants was promulgated under TSCA a few years later. This rule allowed for PCB concentrations of up to 50 ppm in certain products as a result of manufacturing processes.1 Recently, manufacturing by-product PCBs have been identified in wastewater, sediments, and air in numerous locations. They have also been positively identified in testing of new products colored with such pigments, so it is clear these PCBs are not occurring as a result of legacy commercial mixtures. What is emerging is an increasingly complex picture of the prevalence of nonlegacy PCBs alongside the persisting environmental presence of legacy PCBs, and a concurrent and likewise complex picture of how PCBs can affect human health at very low levels of exposure.

In Vitro Toxicity Profiling of Ultrapure Non–Dioxin-like Polychlorinated Biphenyl Congeners and Their Relative Toxic Contribution to PCB Mixtures in Humans

The toxic equivalency concept used for the risk assessment of polychlorinated biphenyls (PCBs) is based on the aryl hydrocarbon receptor (AhR)-mediated toxicity of coplanar dioxin-like (DL) PCBs. Most PCBs in the environment, however, are non-dioxin-like (NDL) PCBs that cannot adopt a coplanar structure required for AhR activation. For NDL-PCBs, no generally accepted risk concept is available because their toxicity is insufficiently characterized. Here, we systematically determined in vitro toxicity profiles for 24 PCBs regarding 10 different mechanisms of action. Prior to testing, NDL-PCB standards were purified to remove traces of DL compounds. All NDL-PCBs antagonized androgen receptor activation and inhibited gap junctional intercellular communication (GJIC). Lower chlorinated NDL-PCBs were weak estrogen receptor (ER) agonists, whereas higher chlorinated NDL-PCBs were weak ER antagonists. Several NDL-PCBs inhibited estradiol-sulfotransferase activity and bound to transthyretin (TTR) but with much weaker potencies than reported for hydroxylated PCB metabolites. AhR-mediated expression of uridine-glucuronyl transferase isozyme UGT1A6 was induced by DL-PCBs only. Hierarchical cluster analysis of the toxicity profiles yielded three separate clusters of NDL-PCBs and a fourth cluster of reference DL-PCBs. Due to small differences in relative potency among congeners, the highly abundant indicator PCBs 28, 52, 101, 118, 138, 153, and 180 also contributed most to the antiandrogenic, (anti)estrogenic, antithyroidal, tumor-promoting, and neurotoxic potencies calculated for PCB mixtures reported in human samples, whereas the most potent AhR-activating DL-PCB-126 contributed at maximum 0.2% to any of these calculated potencies. PCB-168 is recommended as an additional indicator congener, given its relatively high abundance and antiandrogenic, TTR-binding, and GJIC-inhibiting potencies.

Changes in serum concentrations of polychlorinated biphenyls (PCBs), hydroxylated PCB metabolites and pentachlorophenol during pregnancy

We studied pregnancy-related changes in serum concentrations of five polychlorinated biphenyls (PCBs, CB 118, CB 138, CB 153, CB 156, CB 180), three hydroxylated PCB metabolites (4-OH-CB107, 4-OH-CB146, 4-OH-CB187), and pentachlorophenol (PCP). Median serum lipid content increased 2-fold between early (weeks 9–13) and late pregnancy (weeks 35–36) ( N = 10), whereas median PCB levels in serum lipids decreased 20–46%, suggesting a dilution of PCB concentrations in serum lipids. Nevertheless, strong positive intra-individual correlations (Spearman’s r = 0.61–0.99) were seen for PCBs during the whole study period. Thus, if samples have been collected within the same relative narrow time window during pregnancy, PCB results from one single sampling occasion can be used in assessment of relative differences in body burdens during the whole pregnancy period. Concentrations of OH-PCBs in blood serum tended to decline as pregnancy progressed, although among some women the concentrations increased at the end of pregnancy. Positive intra-individual correlations ( r = 0.66–0.99) between OH-PCB concentrations were observed during the first and second trimester, whereas correlations with third trimester concentrations were more diverging ( r = −0.70–0.85). No decline in PCP concentrations was observed during pregnancy and no significant correlations were found between concentrations at different sampling periods. Our results suggest that for both OH-PCBs and PCP, sampling has to be more specifically timed depending on the time period during pregnancy that is of interest. The differences in patterns of intra- and inter-individual variability of the studied compounds may be due to a combination of factors, including lipid solubility, persistence of the compounds, distribution in blood, metabolic formation, and pregnancy-related changes in body composition and physiological processes.

Thyroid hormone levels of pregnant inuit women and their infants exposed to environmental contaminants.

BackgroundAn increasing number of studies have shown that several ubiquitous environmental contaminants possess thyroid hormone–disrupting capacities. Prenatal exposure to some of them, such as polychlorinated biphenyls (PCBs), has also been associated with adverse neurodevelopmental effects in infants.ObjectivesIn this study we examined the relationship between exposure to potential thyroid hormone–disrupting toxicants and thyroid hormone status in pregnant Inuit women from Nunavik and their infants within the first year of life.MethodsWe measured thyroid hormone parameters [thyroid stimulating hormone (TSH), free thyroxine (fT4), total triiodothyronine (T3), thyroxine-binding globulin (TBG)] and concentrations of several contaminants [PCB-153, hydroxylated metabolites of PCBs (HO-PCBs), pentachlorophenol (PCP) and hexachlorobenzene (HCB)] in maternal plasma at delivery (n = 120), in umbilical cord plasma (n = 95), and in infant plasma at 7 months postpartum (n = 130).ResultsIn pregnant women, we found a positive association between HO-PCBs and T3 concentrations (β = 0.57, p = 0.02). In umbilical cord blood, PCB-153 concentrations were negatively associated with TBG levels (β = −0.26, p = 0.01). In a subsample analysis, a negative relationship was also found between maternal PCP levels and cord fT4 concentrations in neonates (β = −0.59, p = 0.02). No association was observed between contaminants and thyroid hormones at 7 months of age.ConclusionOverall, there is little evidence that the environmental contaminants analyzed in this study affect thyroid hormone status in Inuit mothers and their infants. The possibility that PCP may decrease thyroxine levels in neonates requires further investigation.

Chiral Polychlorinated Biphenyls Are Biotransformed Enantioselectively by Mammalian Cytochrome P-450 Isozymes to Form Hydroxylated Metabolites

In vitro incubations of purified rat cytochrome P-450 (CYP) 2B1 and human CYP 2B6 were performed to determine if CYP isozymes biotransform polychlorinated biphenyls (PCBs) enantioselectively. Enantioselective metabolism of chiral PCBs 45, 84, 91, 95, 132, and 136 and production of hydroxylated PCB metabolites (OH-PCBs) were observed, while no changes in PCB 183 atropisomer composition were observed for either isozyme. Enantiomer fractions (EFs) of parent PCBs, individually incubated as racemates at 25 ng/mL initial concentration, with rat CYP 2B1 ranged from 0.353 to 0.822. Enantioselectivity was also observed for PCBs 45 (EF = 0.437) and 132 (EF = 0.537) incubated at that concentration with human CYP 2B6. Both atropisomers of chiral PCBs appeared to be biotransformed simultaneously by rat CYP 2B1, except for (+)-PCB 132, but at different rates. Hydroxylated PCBs were identified using gas chromatography-high resolution mass spectrometry for all chiral PCBs enantioselectively transformed by CYPs. These metabolites did not correspond to any commercially available authentic standards, supporting the hypothesis that many unidentified OH-PCBs detected in wildlife may have arisen from in vivo biotransformation of chiral PCBs. A rough estimate suggested that more than half of the total congener metabolized by rat CYP 2B1 was converted to OH-PCBs. Similar concentration decreases were observed for congeners incubated with human CYP 2B6, but less OH-PCBs were formed. Formation of OH-PCBs via an enantioselective OH insertion mechanism was suggested, and may be a source of the unidentified OH-PCBs currently found in the environment.

Perinatal Exposure to Brominated Flame Retardants and Polychlorinated Biphenyls in Japan

Brominated flame retardants (BFRs) are used to prevent combustion in consumer products. Examples of BFRs are polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A (TBBPA), and tribromophenol (TBP). These compounds are reported to have adverse effects on human health and endocrine disrupting effects. The purpose of this study was to identify the Japanese perinatal exposure to PBDEs, hydroxylated PBDE metabolites (OH-PBDEs), TBBPA, and TBP compared with polychlorinated biphenyls (PCBs) and hydroxylated PCB metabolites (OH-PCBs). We investigated the concentrations of these compounds in maternal blood, maternal milk, cord blood, and umbilical cords from 16 Japanese mother-infant pairs by HRGC/HRMS. PBDEs were detected in all samples of maternal blood (mean+/-SD; median=25+/-23 pg/g; 18 pg/g wet weight), maternal milk (140+/-220 pg/g; 59 pg/g wet weight), cord blood (4.8+/-6.5 pg/g; 1.6 pg/g wet weight), and umbilical cords (3.1+/-3.1 pg/g; 2.1 pg/g wet weight). The mothers were divided into two groups, a high-concentration group and a low-concentration group. The percentage of BDE-47 showed the greatest difference between the two groups. 6-OH-BDE-47, TBBPA, and TBP were detected in all umbilical cord samples (mean+/-SD; median=8.4+/-8.1 pg/g; 8.0 pg/g, 16+/-5.5 pg/g; 15 pg/g, and 33+/-8.2 pg/g; 32 pg/g wet weight respectively), but not in all maternal blood or cord blood samples. These results indicate that OH-PBDEs, TBBPA, and TBP, in addition to PBDEs, PCBs, and OH-PCBs, pass through the blood-placenta barrier and are retained in the umbilical cord.

Placental transfer of polychlorinated biphenyls, their hydroxylated metabolites and pentachlorophenol in pregnant women from eastern Slovakia

The aim of the present study was to understand the placental transfer of polychlorinated biphenyls (PCBs), specific hydroxylated PCB metabolites (OH-PCBs), and pentachlorophenol (PCP) in blood serum, in a birth cohort from eastern Slovakia. During the period 2002–2004, cord blood specimens were collected in parallel with maternal specimens from women delivering in the two eastern Slovak districts of Michalovce and Svidnik/Stropkov. A total of 92 pairs of mother-cord specimens at delivery were selected for this study. 4-OH-CB107, 3-OH-CB153, 4-OH-CB146, 3′-OH-CB138, 4-OH-CB187, and 4′-OH-CB172 were quantified. The median concentrations of Σ 17PCBs, Σ 6OH-PCBs, and PCP in cord serum were 0.92, 0.33, and 0.69 ng/g wet wt., respectively and highly correlated with the corresponding maternal serum levels (correlations were R 2 = 0.61, 0.78, and 0.82, respectively). The median cord to mother ratios of the Σ 17PCBs, Σ 6OH-PCBs, and PCP were 0.18, 0.75, and 1.10, respectively. The median ratio of the Σ 6OH-PCBs to the Σ 17 PCBs in the cord serum was 0.38 from wet weight based concentrations, which was about four times higher than the ratio of these compounds in maternal serum (0.09). PCP was more abundant than any PCB or OH-PCB congener measured in cord serum. The higher cord to maternal ratios of OH-PCB metabolites as compared with the parent compounds suggests either a higher placental transfer rate or greater metabolism in the fetus as compared with the maternal compartment. These findings are consistent with their preferential binding to TTR that can cross the placenta. The cord to maternal ratio varies by congener (e.g., 4-OH-CB107 = 0.58, 4-OH-CB146 = 0.74, 3′-OH-CB138 = 1.01).

Thyroid hormone status of newborns in relation to in utero exposure to PCBs and hydroxylated PCB metabolites

The associations between in utero exposure to polychlorinated biphenyls (PCBs) or hydroxylated PCB metabolites (OH-PCBs), and free thyroxin (fT4) or thyroid-stimulating hormone (TSH) status in the newborn were investigated as a pilot study of a large-scale epidemiologic study on in utero PCB or OH-PCB exposure and thyroid function of the newborns. Umbilical cord tissue was used as the media for the biological monitoring of PCBs/OH-PCBs exposure in utero. For the measurement of fT4 and TSH, a heel-prick blood sample spotted on filter paper, which is called Guthrie card, is collected from each neonate at day 4–6 postpartum for this study when the mass screening sampling was performed. We showed that the concentration of total OH-PCBs and one of the OH-PCB congeners (OH-PCB 187) was related significantly to higher fT4 level of newborns. On the other hand, the concentration of total PCBs and PCB congeners (PCB 118, 138, 153, and 180) showed no relationship with fT4 and TSH level of the newborns. The results obtained in this pilot study indicated the possibility that in utero OH-PCBs exposure affects thyroid hormone status of newborns.

Effect of an environmentally relevant metabolized organochlorine mixture on porcine cumulus–oocyte complexes

Organochlorine compounds and their metabolites bioaccumulate and have been detected in follicular and genital tract fluids of humans and animals. This study was designed to investigate the effect of a metabolised organochlorine mixture, extracted from plasma of sows treated with an environmentally relevant organochlorine mixture in the course of a previous study, on porcine cumulus–oocyte complexes (COCs) in vitro. The major component of the metabolised mixture is 2,2-bis( p-chlorophenyl)-1,1-dichloroethylene ( p, p′ -DDE) at 15.1 mg/l, which accounts for 40.7% of the total extract. Polychlorinated biphenyls (PCBs) account for 30.8% of the extract and hydroxylated PCB metabolites (OH-PCBs) for 11.8%. Exposure of COCs to the metabolised mixture induced a decrease of apoptotic cumulus cells at low concentrations and an increase at higher concentrations following a U-shaped curve ( p = 0.0106), with the intermediate treatment (3.6 μg/l OH-PCBs) significantly reducing apoptosis compared to the extraction control ( p = 0.05). However, the metabolised mixture did not affect cumulus expansion, oocyte maturation, penetration, development to blastocyst, or the number of cells per blastocyst. This study also indicates that organochlorine metabolites similar in concentrations to levels found in Arctic populations can affect growing cumulus–oocyte complexes without inducing an overt toxicological response.

ヒト血液中ＰＣＢｓ水酸化代謝物に関する研究―母体血及びさい帯血中の濃度レベルと母子間移行―

HO-PCBsはPCBsの代謝物であり, 甲状腺ホルモンの撹乱を引き起こすことが疑われている。胎児・乳幼児期の中枢神経の発達に甲状腺ホルモンはきわめて重要であることが指摘され, HO-PCBsが脳機能の発達に悪影響を及ぼすことが懸念される。本研究では, PCBs及びHO-PCBsの胎児・乳幼児期での母子間移行と曝露評価を行なうことを目的に, 妊婦より提供された母体血及び臍帯血のHO-PCBs, PCBsの濃度レベルを明らかにした。HO-PCBsの6種の異性体が全て母体血及び臍帯血から検出された。このうち4-HO-CB107, 4-HO-CB146, 4-HO-CB187の3異性体が母体血及び臍帯血中の主要異性体であり, 4-HO-CB187≫4-HO-CB146>4-HO-CB107の濃度順位で検出された。母体血及び臍帯血中に含まれる総HO-PCBs濃度は, それぞれ16～92pg/g湿重 (中央値42pg/g湿重) , 8.7～87pg/g湿重 (中央値24pg/g湿重) であり, 総濃度に占める主要3異性体の割合は合計で母体血79%, 臍帯血72%であった。臍帯血中のPCBsの濃度レベルは, 母体血に比べ約1/5のレベルに減少していたが, HO-PCBsは母体血 [に対し近い濃度レベルで臍帯血中に存在していた。胎児は母体に近い濃度レベルで胎児期にHO-PCBsより曝露されていることが考えられ, 脳の発育段階である胎児期での曝露は, 脳の機能発達において何らかの影響を与える可能性が考えられる。

Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells.

Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The 'dioxin-like' PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the 'non-dioxin-like' compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 muM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.

Fetal exposure to PCBs and their hydroxylated metabolites in a Dutch cohort.

Polychlorinated biphenyls (PCBs) are still the most abundant pollutants in wildlife and humans. Hydroxylated PCB metabolites (OH-PCBs) are known to be formed in humans and wildlife. Studies in animals show that these metabolites cause endocrine-related toxicity. The health effects in humans have not yet been evaluated, especially the effect on the fetus and newborn. The aim of this study is to measure the levels of PCBs and OH-PCBs in maternal and cord blood samples in a population with background levels of PCBs. We analyzed 51 maternal and corresponding cord blood samples in the northern part of the Netherlands. The PCB concentrations in maternal plasma ranged from 2 to 293 ng/g lipid, and OH-PCB concentrations from nondetectable (ND) to 0.62 ng/g fresh weight. In cord plasma, PCB concentrations were 1–277 ng/g lipid, and OH-PCB concentrations, ND to 0.47 ng/g fresh weight. The cord versus maternal blood calculated ratio was 1.28 ± 0.56 for PCBs and 2.11 ± 1.33 for OH-PCBs, expressed per gram of lipid. When expressed per gram fresh weight, the ratios are 0.32 ± 0.15 and 0.53 ± 0.23 for PCBs and OH-PCBs, respectively. A significant correlation between the respective maternal and cord levels for both PCBs and OH-PCBs was found. Our results indicate that OH-PCBs and PCBs are transferred across the placenta to the fetus in concentrations resulting in levels of approximately 50 and 30%, respectively, of those in maternal plasma. More research in humans is needed to evaluate potential negative effects of these endocrine disruptors on the fetus.

Analysis of HO-PCBs and PCP in blood plasma from individuals with high PCB exposure living on the Chukotka Peninsula in the Russian Arctic.

A trace analytical method is presented for the analysis of hydroxylated polychlorinated biphenyl metabolites (HO-PCBs) and pentachlorophenol (PCP) in human plasma. The described methodology is a modification of a previously validated method used for PCB and organochlorine pesticide analysis. The modified method enables the combined analysis of phenolic and neutral halogenated compounds. A tandem Florisil column is used for separating the HO-PCBs and PCP from the neutral fraction, instead of the more common chemical partitioning. In the same step the neutral fraction is purified for GC analysis. The extraction of the HO-PCBs and PCP was found to be highly dependent on sufficient acidification of the sample and the polarity of the extracting solvent. Analysis of plasma samples gave recovery rates for (13)C(6)-PCP and (13)C(12)-4-HO-CB 187 of 64 and 72%, respectively. The limit of detection ranged between 2-20 pg g(-1) plasma for the HO-PCBs and 5 pg g(-1) plasma for PCP. No matrix interferences were observed in the chromatograms. In plasma samples (n = 15) from the native Chukchi people in Uelen (Russian Arctic), a population with high PCB exposure, the median ratio of sum HO-PCBs to sum PCBs was as high as 0.4 and the sum HO-PCBs and PCBs were significantly correlated (r(2) > 0.7, p < 0.01). The median sum HO-PCBs (10 congeners) was 5920 pg g(-1) plasma with 4-HO-CB 107 as the dominating congener (median: 1670 pg g(-1) plasma). The median PCP level was measured at 642 pg g(-1) plasma.