Polychlorinated biphenyls as hormonally active structural analogues.

Abstract

Among the environmental chemicals that may be able to disrupt the endocrine systems of animals and humans, the polychlorinated biphenyls (PCBs) are a chemical class of considerable concern. One possible mechanism by which PCBs may interfere with endocrine function is their ability to mimic natural hormones. These actions reflect a close relationship between the physicochemical properties encoded in the PCB molecular structure and the responses they evoke in biological systems. These physicochemical properties determine the molecular reactivities of PCBs and are responsible for their recognition at biological acceptors and receptors, as well as for triggering molecular mechanisms that lead to tissue response. "Coplanarity" of PCB phenyl rings and "laterality" of chlorine atoms are important structural features determining specific binding behavior with proteins and certain toxic responses in biological systems. We compare qualitative structure-activity relationships for PCBs with the limited information on the related non-coplanar chlorinated diphenyl ethers, providing further insights into the nature of the molecular recognition processes and support for the structural relationship of PCBs to thyroid hormones. Steroidlike activity requires conformational restriction and possibly hydroxylation. We offer some simple molecular recognition models to account for the importance of these different structural features in the structure-activity relationships that permit one to express PCB reactivities in terms of dioxin, thyroxine, and estradiol equivalents. The available data support the involvement of PCBs as mimics of thyroid and other steroidal hormones. The potential for reproductive and developmental toxicity associated with human exposure to PCBs is of particular concern.(ABSTRACT TRUNCATED AT 250 WORDS)Imagesp290-aFigure 2.Figure 3.Figure 4.Figure 5.Figure 6.

Effects of in ovo exposure to 3,3′,4,4′-tetrachlorobiphenyl (PCB 77) on heart development in tree swallow (Tachycineta bicolor)

“…Avian species are variable in their sensitivity to PCB congeners, but it has been well established that coplanar dioxin-like congeners such as PCBs 77, 81, and 126 induce toxicity at higher rates than non-dioxin-like congeners [4][5][6][7][8]. Recent contaminant analysis has shown that concentrations of PCBs 77, 81, and 126 account for approximately 86, 9, and 3% respectively, of the total PCB toxic equivalents (TEQs) in tree swallow eggs collected along the Upper Hudson River in 2004 [9].…”

Polychlorinated biphenyls induce arachidonic acid release in human platelets in a tamoxifen sensitive manner via activation of group IVA cytosolic phospholipase A2-α

“…Many of the biological effects observed for PCBs are due to their ability to mimic hormones such as thyroid and steroid hormones [31][32][33]. Planar PCBs congeners, i.e.…”

“…nonortho-substituted biphenyls, are high-affinity ligands for the aromatic-hydrocarbon (Ah) receptor while the non-planar PCB congeners, i.e. ortho-substituted biphenyls, display no or weak affinity for the Ah-receptor [31]. Some of the toxicity observed for PCBs involves reproductive toxicity [31], immunotoxicity [34], neurotoxicity [35] as well as induction of hepatic xenobiotic-metabolizing enzymes [36].…”

“…ortho-substituted biphenyls, display no or weak affinity for the Ah-receptor [31]. Some of the toxicity observed for PCBs involves reproductive toxicity [31], immunotoxicity [34], neurotoxicity [35] as well as induction of hepatic xenobiotic-metabolizing enzymes [36]. PCB exposure is also associated with a modest decrease in maternal and umbilical cord serum arachidonic acid concentrations [37].…”

Interrenal Stress Responsiveness of Tilapia (Oreochromis mossambicus) Is Impaired by Dietary Exposure to PCB 126

“…Studies investigating the mechanisms of action underlying the effects of PCBs on endocrine tissues revealed that PCBs can interfere with steroido genesis and steroid receptors (McKinney and Waller, 1994) and with the mixed-function oxygenase systems involved in steroid metabolism (Goksoyr and Forlin, 1992), and are able to bind to the Ah receptor (Nebert, 1989). PCBs may interfere with corticosteroidogenesis and corticosteroid action in a similar manner as de scribed for gonadosteroidogenesis (Barron et al, 1995) and thyroid hormone synthesis (McKinney and Waller, 1994;Murk et al, 1994). Little information is available, however, on PCB effects on adrenal function, in particu lar during stress.…”