The human AHR: identification of single nucleotide polymorphisms from six ethnic populations.

BACKGROUND: The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related dioxin-like chemicals are mediated through binding-dependent activation of the cytosolic aryl hydrocarbon receptor (AHR). The human AHR is a low-affinity receptor relative to most rodents, but some reports suggest that there may be individuals with polymorphic high-affinity receptors, thereby possibly increasing the sensitivity to dioxins in such people. METHODS: Although no polymorphisms have been reported in the ligand binding region of the AHR in the over 100 reported sequences, we sequenced 108 additional human AHR genes in an effort to further identify single single nucleotide polymorphisms (SNPs) within the open reading frames of the AHR locus. The DNA was sequenced from six ethnic populations that included Japanese, Chinese, European/Caucasian, African-American, South East Asian, and Hispanic. RESULTS: Six exonic SNPs were identified; four had been described as previously reported and two seem to be novel. Four of the SNPs identified lead to amino acid changes in the AHR protein and two of the SNPs lead to synonymous substitutions. An additional four SNPs have been reported elsewhere that were not identified in the current analysis. With these new sequences, more than 200 human AHR gene sequences have been analyzed for SNPs. CONCLUSION: The results indicate a very limited presence of polymorphisms in the core ligand binding region of the human AHR. Other regions, such as the transactivation domain, seem to be slightly more polymorphic in the human population and the impact on functionality should be further examined.

Disposition of BDE 47 in developing mice.

Despite its minor contribution to global polybrominated diphenyl ether (PBDE) production and usage, 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) is the dominant congener found in most biotic samples in North America. The majority of public health concern has focused on potential hazardous effects resulting from exposure of infants and young children to BDE 47 because of previous studies reporting adverse developmental effects in rodent studies, in combination with human exposure estimates suggesting that nursing infants and young children have the highest exposure to BDE 47. This study was designed with two objectives: (1) to investigate the disposition of BDE 47 in infantile mice reported to be susceptible to BDE 47 and (2) to investigate the disposition and excretion of BDE 47 at various developmental stages in an attempt to further identify the mechanism responsible for rapid urinary excretion. The disposition of (14)C-BDE 47 was monitored in C57BL/6 mice following a single oral dose of BDE 47 (1 mg/kg) at different stages of development. The results show that the toxicokinetics of BDE 47 are different in developing mice than in adult mice; whereas disposition patterns are similar, concentrations of BDE 47 are higher in pups because they have a reduced capacity to excrete BDE 47. These differences lead to higher concentrations of BDE 47 at target tissues during critical windows of development.

Toxicokinetics of polybrominated diphenyl ether congeners 47, 99, 100, and 153 in mice.

The congener profiles of polybrominated diphenyl ethers (PBDEs) in human and wildlife samples are dominated by brominated diphenyl ether (BDE) congeners 47, 99, 100, 153, and 154, all of which are components of the commercial pentaBDE mixtures commonly used in a variety of flammable consumer products. Very little information is available on the toxicokinetics of these congeners and no studies are available directly comparing these BDE congeners in mice. Therefore, the objective of this study was to compare the distribution, metabolism, and excretion of BDEs 47, 99, 100 and 153. Female C57BL/6 mice were administered a single dose of BDE (1 mg/kg: 2.1, 1.9, 1.9, and 1.8 mumol/kg, respectively) intravenously. Excretion was monitored daily, and terminal tissue disposition was examined 5 days following exposure. All BDE congeners in this study distribute with similar patterns into lipophilic tissues; however, tissue concentrations 5 days following exposure were much higher for BDE-153 than for 100, 99, and 47, respectively. Excretion rates were inversely related to tissue concentrations as BDE-47 was the most rapidly excreted congener, followed by BDE-99, -100, and -153. Differences in tissue concentrations were largely driven by congener-specific urinary elimination rates which were associated with protein binding in the urine. While the overall rate of metabolism appeared to be low, analysis of metabolites in daily feces samples revealed that BDE-99 was the most rapidly metabolized congener in this study. The results of this study demonstrate that congener substitution plays a role in the distribution, metabolism, and excretion of PBDEs in mice and it is therefore important to consider the differential toxicokinetic parameters associated with each congener when assessing the risk to human health from these PBDE congeners.

Brominated flame retardants: cause for concern?

Brominated flame retardants (BFRs) have routinely been added to consumer products for several decades in a successful effort to reduce fire-related injury and property damage. Recently, concern for this emerging class of chemicals has risen because of the occurrence of several classes of BFRs in the environment and in human biota. The widespread production and use of BFRs; strong evidence of increasing contamination of the environment, wildlife, and people; and limited knowledge of potential effects heighten the importance of identifying emerging issues associated with the use of BFRs. In this article, we briefly review scientific issues associated with the use of tetrabromobisphenol A, hexabromocyclododecane, and three commercial mixtures of polybrominated diphenyl ethers and discuss data gaps. Overall, the toxicology database is very limited; the current literature is incomplete and often conflicting. Available data, however, raise concern over the use of certain classes of brominated flame retardants.

Health effects of polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs).

This article reviews the state of the science regarding the health effects of polybrominated dibenzo-p-dioxins (PBDDs) and dibenzofurans (PBDFs). While thousands of articles have been published on the health effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related polychlorinated dibenzodioxins (PCDDs) and dibenzofurans (PCDFs), little is know about the brominated and mixed chloro/bromo homologs. Available literature suggests that brominated compounds have similar toxicity profiles to their chlorinated homologs. However, further research investigating health effects will only be useful if exposure scenarios truly exist. Current exposure data is extremely limited, posing a major data gap in assessing potential risk of these chemicals. The rapid increase in the use of brominated flame retardants has raised the level of environmental concern regarding PBDDs/PBDFs as it is likely that human, as well as wildlife, exposure to brominated dioxins and furans will increase with their use.

Levels of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in southern Mississippi catfish and estimation of potential health risks.

Fish consumption has been classified as one of the primary pathways of exposure to polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and biphenyls (PCBs). In this study, we evaluated tissue levels of the 17 laterally substituted PCDD/Fs, 12 dioxin-like PCBs, and 97 non-dioxin-like PCBs in a number of wild-caught and farm-raised catfish collected throughout southern Mississippi. Total lipid-adjusted TEQ and non-dioxin-like PCB concentrations in wild-caught catfish fillets were significantly higher than concentrations in farm-raised fillet samples. The percent contribution of PCDDs, PCDFs, and dioxin-like PCBs to mean total TEQ varied between wild-caught and farm-raised samples as well as by collection site for wild-caught catfish. The non-dioxin-like PCBs that contributed the most to total PCB concentrations also differed between wild-caught and farm-raised samples. Regardless of whether samples were farm-raised or wild-caught, estimated cancer risks associated with consumption of these catfish were less than 27.0E-06. Overall, results of this study indicate that levels of dioxin-like compounds and PCBs in Mississippi catfish are similar to those measured in more recent studies in the US and that levels of these compounds appear to be decreasing in this food source.

Possible mechanisms of thyroid hormone disruption in mice by BDE 47, a major polybrominated diphenyl ether congener.

Polybrominated diphenyl ethers (PBDEs) are a class of polyhalogenated aromatic compounds commercially used as fire retardants in consumer products. These compounds have been shown to decrease thyroid hormone concentrations in rodents after acute exposures. This study examines the ability of 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) to decrease circulating thyroid hormone concentrations and pairs this with BDE 47-induced effects on genes involved in thyroid hormone homeostasis. Female C57BL/6 mice (9 weeks old) were orally administered 3, 10, or 100 mg/kg/day of BDE 47 for 4 days. Animals were euthanized 24 h after the final dose (day 5) and liver, kidney, and serum were collected for analysis. BDE 47 caused a significant 43% decrease at 100 mg/kg/day in serum total thyroxine (T(4)) concentrations. There was no increase in hepatic T(4)-glucuronidation activity, but significant increases in hepatic Ugt1a1, Ugt1a7, and Ugt2b5 mRNA expression accompany significant decreases in T(4) concentrations at 100 mg/kg/day of BDE 47. Induction of PROD activity occurred at the lowest dose (3 mg/kg/day). Cyp2b10 mRNA expression also increased significantly at 10 and 100 mg/kg/day. These key findings show that BDE activates the nuclear receptor, CAR. Decreases in Mdr1a mRNA expression also occurred at the lowest dose administered (3 mg/kg/day BDE 47). BDE 47 exposure also decreased hepatic transthyretin and monocarboxylate transporter 8 (Mct8) mRNA expression, suggesting that while induction of UGTs may be partly responsible for T(4) decreases, other mechanisms are also involved. No effects were seen in the kidney. We conclude that changes in hepatic UGTs and transporters may be involved in decreases in circulating T(4) following BDE 47 exposure.

Assessment of polybrominated diphenyl ether exposures and health risks associated with consumption of southern Mississippi catfish.

Despite the growing public interest in polybrominated diphenyl ethers (PBDEs), there are relatively few studies in the published literature which characterize and quantify human intake of these compounds. In this study, PBDE concentrations were measured in southern Mississippi catfish to determine background levels, daily intake, and risk associated with the consumption of these chemicals from a primary food source for residents in this region of the United States. A total of 33 wild catfish samples were collected from five sites, and 28 farm-raised catfish samples were purchased, all of which were from locations in southern Mississippi. All samples were analyzed for 43 PBDEs (mono- through deca-congeners) using high-resolution gas chromatography-mass spectrometry. Both PBDE concentrations (sigmaPBDE ranged from 0.3 to 23.3 ng/g wet weight) and congener profiles varied by fish type and location; however, BDE congeners 47, 99, 100, 153, and 154 were the dominant contributors in all samples. The estimated daily intake of PBDEs associated with consumption of the catfish ranged from 0.03 to 1.80 ng/kg-day. Evaluation of the cancer risk for BDE 209 and the noncancer hazard for BDE congeners 47, 99, 153, and 209 indicated that health risks/hazards due to fish consumption in adults are substantially lower than risk levels generally considered to be at the U.S. EPA minimum concern level.