Identification of 4-Hydroxyheptachlorostyrene in Polar Bear Plasma and Its Binding Affinity to Transthyretin:  A Metabolite of Octachlorostyrene?

Abstract

A new compound, 4-hydroxyheptachlorostyrene (4-OHHpCS), was identified as a major component in the chlorinated phenolic compound fraction of polar bear plasma. The structure was hypothesized to be 4-OH-HpCS based on mass spectral interpretation, the assumption that it was a metabolite of octachlorostyrene, and the similarity of the structure to hydroxylated polychlorinated biphenyls (OH-PCBs) identified in plasma. High-resolution, electron impact (EI) ionization mass spectrometry of the methylated compound indicated a molecular formula of C 9 H 3 OCl 7 and major fragment ions of [M -15] + , [M -35] + , and [M -43] + , which was a mass spectral pattern identical to a synthesized and methylated 4-OH-HpCS standard. The identity was further confirmed by matching gas chromatography (GC) retention times on three different GC columns of differing polarity. Levels of 4-OH-HpCS ranged from 2.89 to 22.9 ng/g wet weight in polar bear plasma (N ) 30) and constituted between 3.8 and 24.8% of the total quantified level of chlorinated phenolic compounds. The mean ratio of 4-OHHpCS to CB153 concentrations in polar bear plasma samples was 0.712 (( 0.580 SD), which suggests selective retention of the 4-OH-HpCS in plasma. The presumed mechanism of retention involves 4-OH-HpCS binding to transthyretin (TTR). The presence of TTR was confirmed for the first time in polar bear plasma by binding of 125 Ithyroxine (T 4 ), the natural ligand of TTR, to separated plasma proteins. The binding affinity of 4-OH-HpCS to human TTR was tested and found to be 1.1 relative to T 4 . This suggests that 4-OH-HpCS has the potential to disrupt T 4 and retinol transport, by analogy to OH-PCBs with similar structure. Metabolism of octachlorostyrene (OCS) is the most likely source of 4-OH-HpCS. OCS was shown to be present at low concentrations in polar bear tissues as well as in plasma of ringed seal, the principal prey species of polar bears. The ratio of 4-OH-HpCS to OCS and 4-OHHpCS to CB153 concentrations were 150-and 44-fold higher in polar bear plasma than in ringed seal plasma. This study indicates that the phenolic metabolites of relatively minor contaminants possess the capacity to bind to circulating proteins, and their significance as potential endocrine-disrupting agents may be underestimated.

Concentrations of chlorinated and brominated contaminants and their metabolites in serum of harbour seals and harbour porpoises

“…Since HO-PCBs were not detected in liver of fish species caught in the North Sea in 2008 (Covaci, unpublished data), concentrations found in harbour seal serum are most probably the result of intrinsic metabolic breakdown of PCBs into HO-PCBs in the marine mammals. ΣHO-PCBs/ΣPCBs ratios smaller than 1 were also found for bottlenose dolphins (Tursiops truncatus) from the Indian River Lagoon (Florida, USA) and Charleston (Montie et al, 2008), for ringed seals from Québec, Canada (Sandau et al, 2000) and for bowhead whales (Balaena mysticetus) from Alaska (Hoekstra et al, 2003). In contrary, ratios greater than 1 were detected in blood of polar bears (Ursus maritimus) from Canada (Sandau et al, 2000) and Greenland (Sandala et al, 2004;Gebbink et al, 2008) as a result of a high capacity to form HO-PCBs (Table 3).…”

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

“…To our knowledge, there are only three recent publications on cord blood analysis of halogenated phenolic compounds (HPCs) (Guvenius et al, 2003;Sandau et al, 2000;Soechitram et al, 2004). Only Guvenius et al and Soechitram et al reported the HPCs' data from maternal-cord blood pairs.…”

SULFONATION OF ENVIRONMENTAL CHEMICALS AND THEIR METABOLITES IN THE POLAR BEAR (Ursus maritimus)

“…Polychlorinated biphenylols (OH-PCBs), major biotransformation products of PCBs (James, 2001), have been shown to be present in relatively high concentrations in polar bears (Sandau and Norstrom, 1998;Sandau et al, 2000). The abundance of these hydroxylated metabolites may be due to cytochrome P450 induction (Letcher et al, 1996), inefficient phase II detoxication, and inhibition of their own biotransformation.…”

“…On the other hand, the presence of PCP and, particularly, high amounts of TCPM in these Arctic carnivores may indicate poor sulfonation of these substrates. The polychlorobiphenylols 4Ј-OH-PCB159 and 4Ј-OH-PCB165 are of interest since, though they have not been detected in polar bears, they are structurally similar to 4Ј-OH-PCB172, one of the major OH-PCBs found in polar bear plasma (Sandau et al, 2000). It is thus possible that these compounds are sulfonated with similar efficiencies.…”