Structure-activity relationships of potentially neurotoxic PCB congeners in the rat.

We have explored the effects of PCBs on Ca(2+)-homeostasis and inositol phosphates in an attempt to understand cellular mechanism(s) for neurotoxicity of PCBs. The selected prototypic congeners have non-dioxin-like (2,2'-dichlorobiphenyl; 2,2'-DCB; IUPAC # 4; ortho-substituted) and dioxin-like (3,3',4,4',5-pentachlorobiphenyl; 3,3',4,4',5-PeCB; IUPAC # 126; non-ortho substituted) properties. The hypothesis is that some PCBs in vitro alter Ca(2+)-homeostasis and interfere with intracellular second messengers. One of the consequences of this perturbation is protein kinase C (PKC) translocation, and these events could lead to cytotoxicity. Our results indicate that the non-dioxin like PCB (ortho-substituted one) is active in vitro and perturbed signal transduction mechanism including Ca(2+)-homeostasis and PKC translocation. The effects were seen at relatively low concentrations (5-50 microM), whereas higher concentrations (> 200 microM) were required to produce cytotoxicity. Results from SAR, in general, indicate that congeners with chlorine substitutions at ortho-position or low lateral substitutions (mostly meta-) are active in vitro where as non-ortho congeners are inactive. In summary, these results indicate that low lateral substitution (especially without para-substitution that favor coplanarity) or high lateral content in the presence of ortho-substitution (to hinder coplanarity) may be the most critical structural requirement underlying the activity of PCB congeners in vitro. Additional experiments with polychlorinated diphenyl ethers (PCDEs) and their analogs, where coplanarity is difficult regardless of degree and pattern of chlorination, provided important information supporting our hypothesis that coplanarity plays a key role in the activity of PCBs in vitro. For example, a PCB congener with 3,3',4,4'-chlorine substitutions is not active whereas a PCDE with the same chlorine substitutions is active. Similarity, 4,4'-DCB is not active whereas PCDE with 4,4'-substitutions is active. One major structural difference in PCDE when compared to the corresponding PCB is non-coplanarity. The PCBs compared here are coplanar and not active, whereas PCDEs are non-coplanar and active in vitro in neuronal preparations. Molecular mechanics calculations and conformational searches confirmed the extent of coplanarity among PCBs and PCDEs. Non-ortho PCBs are more coplanar in nature when compared to ortho-PCBs and PCDEs. These results demonstrate that the extent of coplanarity of certain chlorinated aromatic hydrocarbons can affect their potency in vitro, and ortho-substitutions on the biphenyl, which increase non-coplanarity, are characteristics of the most active PCB congeners.