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

Abstract

The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.

Identifying sex differences arising from polychlorinated biphenyl exposures in toxicant-associated liver disease

“…In addition to acting as metabolism-disrupting chemicals, PCBs are also established endocrine-disrupting chemicals through their interactions with endocrine receptors (Luthe et al, 2008). Most low molecular weight PCBs that are not heavily chlorinated are known to activate estrogen receptors (ERα and ERβ) and antagonize AR (Pencikova et al, 2018). Higher molecular PCB congeners that are more heavily chlorinated are considered antiestrogenic and this is relevant to sex-specific effects (Zhang et al, 2014).…”

Polychlorinated Biphenyls (PCBs): Risk Factors for Autism Spectrum Disorder?

“…The reasons for the discrepant findings of the association between hydroxylated PCB exposure and cognitive performance are not known but could be linked to the diverse effects of PCB metabolites on dendritic architecture (see Section 3) and/or endocrine disruption. Hydroxylated PCBs have a differential ability to agonize or antagonize steroid hormone pathways [95], and in vitro evidence indicates that estrogenic effects of hydroxylated PCBs can be greater than that of their parent compound [96]. Maternal serum levels of hydroxylated PCBs have also been associated with free thyroxin levels in neonates [97], suggesting disruption of thyroid hormone signaling may influence the effects of hydroxylated PCB on cognition.…”

“…For example, the estrogenic chemical bisphenol A has been linked to abnormal lower urinary tract function [236,239]. Several PCBs have been identified to have estrogenic activity [96], but whether they alter urinary function is unknown. Of particular relevance to the question of whether developmental PCB exposures alter bladder function, developmental exposure to TCDD has been documented to disrupt lower urinary tract function [237,238].…”

Cell membrane‐related toxic responses and disruption of intercellular communication in PCB mechanisms of toxicity: A review

“…Non‐ ortho ‐substituted PCBs 80 and 126 had no effect on GJIC. Lower‐chlorinated PCB (dichloro‐ and trichloro‐) congeners also express potencies in disruption of GJIC at micromolar concentrations (Pěnčíková et al, 2018). Hemming, Warngard and Ahlborg (1991) suggested that GJIC inhibition increases with the number of chlorinated ortho positions.…”