Sources and toxicities of phenolic polychlorinated biphenyls (OH-PCBs)

Abstract

Polychlorinated biphenyls (PCBs), a group of 209 congeners that differ in the number and position of chlorines on the biphenyl ring, are anthropogenic chemicals that belong to the persistent organic pollutants (POPs). For many years, PCBs have been a topic of interest because of their biomagnification in the food chain and their environmental persistence. PCBs with fewer chlorine atoms, however, are less persistent and more susceptible to metabolic attack, giving rise to chemicals characterized by the addition of one or more hydroxyl groups to the chlorinated biphenyl skeleton, collectively known as hydroxylated PCBs (OH-PCBs). In animals and plants, this biotransformation of PCBs to OH-PCBs is primarily carried out by cytochrome P-450-dependent monooxygenases. One of the reasons for infrequent detection of lower chlorinated PCBs in serum and other biological matrices is their shorter half-lives, and their metabolic transformation, resulting in OH-PCBs or their conjugates, such as sulfates and glucuronides, or macromolecule adducts. Recent biomonitoring studies have reported the presence of OH-PCBs in human serum. The occurrence of OH-PCBs, the size of this group (there are 837 mono-hydroxyl PCBs alone), and their wide spectra of physical characteristics (pKa's and log P's ranging over 5 to 6 orders of magnitude) give rise to a multiplicity of biological effects. Among those are bioactivation to electrophilic metabolites that can form covalent adducts with DNA and other macromolecules, interference with hormonal signaling, inhibition of enzymes that regulate cellular concentrations of active hormones, and interference with the transport of hormones. This new information creates an urgent need for a new perspective on these often overlooked metabolites.

Hydroxylated and sulfated metabolites of commonly occurring airborne polychlorinated biphenyls inhibit human steroid sulfotransferases SULT1E1 and SULT2A1

“…PCBs undergo enzyme-catalyzed oxidative reactions in biological systems to form hydroxylated PCBs (OH-PCBs), and the formation, physical and chemical properties, and toxicities of these metabolites have been recently reviewed (Dhakal et al, 2017; Grimm et al, 2015b). In many cases it is either the OH-PCBs or their subsequent metabolites that are directly involved in the toxicities observed upon exposure to PCBs.…”

In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion

“…Furthermore, little is known about their further impact on cells, including their potential effects linked with tumor promotion. The rapid metabolism of abundant LC-PCB congeners may lead to formation of hydroxylated metabolites with specific toxicity profiles (Grimm et al, 2015); however, the toxicities of hydroxylated LC-PCBs are less known than those of their parent compounds, although hydroxylation significantly alters the activities of a number of PCB congeners (Dhakal et al, 2017; Machala et al, 2004), and some of them could be highly active towards ER or AR (Takeuchi et al, 2011).…”

2,3-Dichloro-3′,4′-dihydroxybiphenyl

“…Cytochrome P450 enzymes oxidize PCB congeners in two steps to dihydroxylated metabolites (Lu et al, 2013;McLean et al, 1996). PCB metabolites with ortho-or para-substituted hydroxyl groups can be further oxidized to reactive and highly toxic PCB quinones (Dhakal et al, 2018;Grimm et al, 2015). Only a few solid-state structures of dihydroxylated PCBs have been reported to date (Lehmler et al, 2001a;McKinney & Singh, 1988).…”