Brominated flame retardants in placental tissues: associations with infant sex and thyroid hormone endpoints.

BACKGROUND: Brominated flame retardants (BFRs) are endocrine disruptors that bioaccumulate in the placenta, but it remains unclear if they disrupt tissue thyroid hormone (TH) metabolism. Our primary goal was to investigate associations between placental BFRs, TH levels, Type 3 deiodinase (DIO3) activity and TH sulfotransferase (SULT) activities. METHODS: Placenta samples collected from 95 women who delivered term (>37 weeks) infants in Durham, NC, USA (enrolled 2010-2011) were analyzed for polybrominated diphenyl ethers (PBDEs), 2,4,6-tribromophenol (2,4,6-TBP), THs (T4, T3 and rT3), and DIO3 and TH SULT activities. RESULTS: PBDEs and 2,4,6-TBP were detected in all placenta samples. PBDEs were higher in placental tissues from male infants compared to female infants, with 2,4,6-TBP and BDE-209 levels approximately twice as high. Among male infants, placental BDE-99 and BDE-209 were negatively associated with rT3 placental levels. For female infants, placental BDE-99 and 2,4,6-TBP were positively associated with T3 concentrations. DIO3 activity was also significantly higher in placental tissues from male infants compared to females, while 3,3'-T2 SULT activity was significantly higher in placental tissues from females compared to males. Among males, several PBDE congeners were positively correlated with T3 SULT, while BDE-99 was negatively associated with T3 SULT among females. Associations generally remained after adjustment for potential confounding by maternal age and gestational age at delivery. CONCLUSIONS: These results suggest BFRs accumulate in the placenta and potentially alter TH function in a sex-specific manner, a possible mechanism to explain the sex-dependent impacts of environmental exposure on children's growth and development. More research is needed to elucidate the effects of BFRs on placenta function during pregnancy, as well as the biological consequences of exposure and thyroid disruption.

The role of T56 in controlling the flexibility of the distal histidine in dehaloperoxidase-hemoglobin from Amphitrite ornata.

The activation of dehaloperoxidase-hemoglobin (DHP) to form a ferryl intermediate requires the distal histidine, H55, to act as an acid base catalyst. The lack of ancillary amino acids in the distal pocket to assist in this process makes H55 even more important to the formation of active intermediates than in conventional peroxidases. Therefore, one can infer that the precise conformation H55 may greatly affect the enzymatic activity. Using site-direct mutagenesis at position T56, immediately adjacent to H55, we have confirmed that subtle changes in the conformation of H55 affect the catalytic efficiency of DHP. Mutating T56 to a smaller amino acid appears to permit H55 to rotate with relatively low barriers between conformations in the distal pocket, which may lead to an increase in catalytic activity. On the other hand, larger amino acids in the neighboring site appear to restrict the rotation of H55 due to the steric hindrance. In the case of T56V, which is an isosteric mutation, H55 appears less mobile, but forced to be closer to the heme iron than in wild type. Both proximity to the heme iron and flexibility of motion in some of the mutants can result in an increased catalytic rate, but can also lead to protein inactivation due to ligation of H55 to the heme iron, which is known as hemichrome formation. A balance of enzymatic rate and protein stability with respect to hemichrome formation appears to be optimum in wild type DHP (WT-DHP).

Biotransformation of 2,4,6-tris(2,4,6-tribromophenoxy)-1,3,5-triazine (TTBP-TAZ) can contribute to high levels of 2,4,6-tribromophenol (2,4,6-TBP) in humans.

2,4,6-Tribromophenol (2,4,6-TBP) is a brominated flame retardant that accumulates in human tissues and is a potential toxicant. Previous studies found 2,4,6-TBP levels in human tissues were significantly higher than those of brominated flame retardants measured in the same samples. In contrast, the levels of 2,4,6-TBP in the environment and foodstuff are not elevated, suggesting a low potential for direct intake through environmental exposure or diet. Here, we hypothesized that high levels of 2,4,6-TBP in human tissues are partially from the indirect exposure sources, such as biotransformation of highly brominated substances. We conducted in vitro assays utilizing human and rat liver microsomes to compare the biotransformation rates of four highly brominated flame retardants, which could potentially transform to 2,4,6-TBP, including decabromodiphenyl ethane (DBDPE), 2,4,6-tris-(2,4,6-tribromophenoxy)-1,3,5-triazine (TTBP-TAZ), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), and tetrabromobisphenol A (TBBPA). Our results show that TTBP-TAZ rapidly metabolizes in both human and rat liver microsomes with a half-life of 1.1 and 2.2 h, respectively, suggesting that TTBP-TAZ is a potential precursor of 2,4,6-TBP. In contrast, 2,4,6-TBP was not formed as a result of biotransformation of TBBPA, BTBPE, and DBDPE in both human and rat liver microsomes. We applied suspect and target screening to explore the metabolic pathways of TTBP-TAZ and identified 2,4,6-TBP as a major metabolite of TTBP-TAZ accounting for 87% of all formed metabolites. These in vitro results were further tested by an in vivo experiment in which 2,4,6-TBP was detected in the rat blood and liver at concentrations of 270 ± 110 and 50 ± 14 µg/g lipid weight, respectively, after being exposed to 250 mg/kg body weight/day of TTBP-TAZ for a week. The hepatic mRNA expression demonstrated that TTBP-TAZ significantly activates the aryl hydrocarbon receptor (AhR) and promotes fatty degeneration (18 and 28-fold change compared to control, respectively) in rats.

Occurrence of halogenated flame retardants in commercial seafood species available in European markets.

PBDEs (congeners 28, 47, 99, 100, 153, 154, 183, 209), HBCD (α, ß, γ), emerging brominated flame retardants (PBEB, HBB and DBDPE), dechloranes (Dec 602, 603, 604, syn- and anti-DP), TBBPA, 2,4,6-TBP and MeO-PBDEs (8 congeners) were analysed in commercial seafood samples from European countries. Levels were similar to literature and above the environmental quality standards (EQS) limit of the Directive 2013/39/EU for PBDEs. Contaminants were found in 90.5% of the seafood samples at n. d.-356 ng/g lw (n. d.-41.1 ng/g ww). DBDPE was not detected and 2,4,6-TBP was detected only in mussels, but at levels comparable to those of PBDEs. Mussel and seabream were the most contaminated species and the Mediterranean Sea (FAO Fishing Area 37) was the most contaminated location. The risk assessment revealed that there was no health risk related to the exposure to brominated flame retardants via seafood consumption. However, a refined risk assessment for BDE-99 is of interest in the future. Moreover, the cooking process concentrated PBDEs and HBB.