Hydroxylated Polychlorinated Biphenyls Selectively Bind Transthyretin in Blood and Inhibit Amyloidogenesis: Rationalizing Rodent PCB Toxicity

Purkey, Hans E.; Palaninathan, S.K.; Kent, Kathleen C.; Smith, Craig; Safe, Stephen; Sacchettini, James C.; Kelly, Jeffery W.

doi:10.1016/j.chembiol.2004.10.009

Cited by 135 publications

(134 citation statements)

References 72 publications

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“…However, the percentage of OH-PCBs in cord blood was higher than in maternal blood (mean = 56 ± 19%). OH-PCBs bind with high affinity and selectivity to transthretin (TTR) in plasma [42]. OH-PCBs inhibit thyroxine transport and accumulate in fetuses by competitive binding to TTR in rats [43].…”

Section: Discussionmentioning

confidence: 99%

Perinatal Exposure to Brominated Flame Retardants and Polychlorinated Biphenyls in Japan

et al. 2008

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Abstract. 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.

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Section: Discussionmentioning

confidence: 99%

Perinatal Exposure to Brominated Flame Retardants and Polychlorinated Biphenyls in Japan

et al. 2008

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“…The lower chlorinated OHPCBs have also been shown to interact with cytosolic sulfotransferases (SULTs) that are active in metabolism of steroid hormones [16] and thyroid hormones [17]. Moreover, OHPCBs [18, 19] as well as the products of sulfation of OHPCBs [20] have been shown to bind with high affinity to the thyroid hormone transport protein transthyretin. These interactions of OHPCBs with sulfotransferases involved in the metabolism of steroid hormones and with thyroid hormone carriers may contribute to the endocrine disruption observed with some PCBs [16,17].…”

Section: Introductionmentioning

confidence: 99%

Binding interactions of hydroxylated polychlorinated biphenyls (OHPCBs) with human hydroxysteroid sulfotransferase hSULT2A1

Ekuase

Lehmler

Robertson

et al. 2014

Chemico-Biological Interactions

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Polychlorinated biphenyls (PCBs) are persistent environmental contaminants, and exposure to PCBs and their hydroxylated metabolites (OHPCBs) has been associated with various adverse health effects. The mammalian cytosolic sulfotransferases (SULTs) catalyze the sulfation of OHPCBs, and the interaction of OHPCBs with both the SULT1 and SULT2 families of these enzymes has received attention both with respect to metabolic disposition of these molecules and the potential mechanisms for their roles in endocrine disruption. We have previously shown that OHPCBs interact with human hydroxysteroid sulfotransferase hSULT2A1, an enzyme that catalyzes the sulfation of dehydroepiandrosterone (DHEA), other alcohol-containing steroids, bile acids, and many xenobiotics. The objective of our current studies is to investigate the mechanism of inhibition of hSULT2A1 by OHPCBs by combining inhibition kinetics with determination of equilibrium binding constants and molecular modeling of potential interactions. Examination of the effects of fifteen OHPCBs on the sulfation of DHEA catalyzed by hSULT2A1 showed predominantly noncompetitive inhibition patterns. This was observed for OHPCBs that were substrates for sulfation reactions catalyzed by the enzyme as well as those that solely inhibited the sulfation of DHEA. Equilibrium binding experiments and molecular modeling studies indicated that the OHPCBs bind at the binding site for DHEA on the enzyme, and that the observed noncompetitive patterns of inhibition are consistent with binding in more than one orientation to more than one enzyme complex. These results have implications for the roles of SULTs in the toxicology of OHPCBs, while also providing molecular probes of the complexity of substrate/inhibitor interactions with hSULT2A1.

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“…The investigation of this mechanism of action is restrained by interspecies differences, as TTR is the principal transport protein in rodents and TBG in humans. It is unlikely that enough T4 could be displaced from TTR to be toxic in adult humans (117). However, TTR is the major TH transport protein in the human brain, presumably playing an essential role in the determination of FT4 levels in the extracellular compartment, which is independent of the T4 homeostasis in the body.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Environmental chemicals and thyroid function

Boas¹,

Feldt‐Rasmussen

Skakkebæk³

et al. 2006

eur j endocrinol

451

288

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There is growing evidence that environmental chemicals can disrupt endocrine systems. Most evidence originates from studies on reproductive organs. However, there is also suspicion that thyroid homeostasis may be disrupted. Several groups of chemicals have potential for thyroid disruption. There is substantial evidence that polychlorinated biphenyls, dioxins and furans cause hypothyroidism in exposed animals and that environmentally occurring doses affect human thyroid homeostasis. Similarly, flame retardants reduce peripheral thyroid hormone (TH) levels in rodents, but human studies are scarce. Studies also indicate thyroid-disruptive properties of phthalates, but the effect of certain phthalates seems to be stimulative on TH production, contrary to most other groups of chemicals. Thyroid disruption may be caused by a variety of mechanisms, as different chemicals interfere with the hypothalamic -pituitary -thyroid axis at different levels. Mechanisms of action may involve the sodium-iodide symporter, thyroid peroxidase enzyme, receptors for THs or TSH, transport proteins or cellular uptake mechanisms. The peripheral metabolism of the THs can be affected through effects on iodothyronine deiodinases or hepatic enzymes. Even small changes in thyroid homeostasis may adversely affect human health, and especially fetal neurological development may be vulnerable. It is therefore urgent to clarify whether the animal data showing effects of chemicals on thyroid function can be extended to humans. European Journal of Endocrinology 154 599-611

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Hydroxylated Polychlorinated Biphenyls Selectively Bind Transthyretin in Blood and Inhibit Amyloidogenesis: Rationalizing Rodent PCB Toxicity

Cited by 135 publications

References 72 publications

Perinatal Exposure to Brominated Flame Retardants and Polychlorinated Biphenyls in Japan

Perinatal Exposure to Brominated Flame Retardants and Polychlorinated Biphenyls in Japan

Binding interactions of hydroxylated polychlorinated biphenyls (OHPCBs) with human hydroxysteroid sulfotransferase hSULT2A1

Environmental chemicals and thyroid function

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