Increased (3H) Phorbol Ester Binding in Rat Cerebellar Granule Cells by Polychlorinated Biphenyl Mixtures and Congeners: Structure-Activity Relationships

doi:10.1006/taap.1995.1018

Toxicology and Applied Pharmacology

Volume 130, Issue 1, January 1995, Pages 140-148

https://doi.org/10.1006/taap.1995.1018 Get rights and content

Abstract

Our previous reports indicate that polychlorinated biphenyl (PCB) congeners in vitro perturbed cellular Ca²⁺ homeostasis and protein kinase C (PKC) translocation. We have now studied the structure-activity relationship (SAR) of 3 PCB mixtures, 24 PCB congeners, and 1 dibenzofuran for their effects on PKC translocation by measuring [³H]phorbol ester ([³H]PDBu) binding in cerebellar granule cells (7 days in culture). All the PCB mixtures studied increased [³H]PDBu binding significantly and in a concentration-dependent manner. However, Aroclor 1016 and Aroclor 1254 were more potent than Aroclor 1260. Of the 24 congeners studied, di-ortho congeners such as 2,2′,5,5′tetrachlorobiphenyl (-TeCB), 2,2′,4,6,6′-pentachlorobiphenyl (-PeCB), 2,2′,4,6-TeCB, and 2,2′-dichlorobiphenyl (-DCB) were the most potent (E50 = 28-43 μM) while non-ortho congeners such as 3,3′,4,4′-TeCB and 3,3′,4,4′,5-PeCB were not effective. The potential contaminant of PCB mixtures, 1,2,3,7,8-pentachlorodibenzofuran had no significant effect on [³H]PDBu binding. The SAR among these congeners revealed: (i) congeners with ortho-chlorine substitution such as 2,2′-DCB (E50 = 43 ± 3 μM) or ortho-lateral (meta, para) chlorine substitution such as 2,2′,5,5′-TeCB (E50 = 28 ± 3 μM) and 2,2′,4,6-TeCB (E50 = 41 ± 6 μM) were most potent; (ii) congeners with only para-substitution such as 4,4′-DCB or high lateral content in the absence of ortho-substitution such as 3,3′,4,4′,5,5′-HCB were not effective; and (iii) increased chlorination was not clearly related to the effectiveness of these congeners, although hexa- and heptachlorination was less effective than di- and tetrachlorination. Low lateral substitution, especially without para-substitution, or lateral content in the presence of ortho-substitution, may be the most important structural requirement for the in vitro activity of these PCB congeners in neuronal preparations.

References (0)

Cited by (88)

Predicted versus observed activity of PCB mixtures toward the ryanodine receptor
2024, NeuroToxicology
Non-dioxin-like polychlorinated biphenyls (NDL PCBs) alter the activity of the ryanodine receptor (RyR), and this activity is linked to developmental neurotoxicity. Most work to date has focused on the activity of single congeners rather than relevant mixtures. The current study assessed the RyR activity of single congeners or binary, tertiary, and complex PCB mixtures. Observed mixture activity was then compared to the expected activity calculated using the concentration addition (CA) model or a RyR-specific neurotoxic equivalency scheme (rNEQ). The predictions of the CA model were consistent with the observed activity of binary mixtures at the lower portion of the concentration-response curve, supporting the additivity of RyR1 active PCBs. Findings also show that minimally active congeners can compete for the RyR1 binding site, and congeners that do not activate the RyR1 do not interfere with the activity of a full agonist. Complex PCB mixtures that mimic PCB profiles detected in indoor air, fish tissue, and the serum of mothers and children activated the RyR1 and displayed similar efficacy and potency regardless of varying congener profiles. Neither the CA model nor the rNEQ perfectly predicted the observed activity of complex mixtures, but predictions were often within one magnitude of change from the observed response. Importantly, PCB mixtures approximating profiles found in environmental samples or human serum displayed RyR1 activity at concentrations reported in published research. The work presented will aid in the development of risk assessment platforms for NDL PCBs and similar compounds toward RyR1 activation and related neurotoxicity.
Neurochemical effects of halogenated organic compounds: Possible adverse outcome pathways and structure–activity relationships
2023, Advances in Neurotoxicology
Halogenated organic compounds (HOCs) are long-lived toxic compounds and are of major concern for ecosystem and health. The use and manufacture of several HOCs is banned or phased out in most countries, but some HOCs are still being used in several countries. The levels of certain HOCs, such as polychlorinated biphenyls (PCBs), declined in the environment, but new HOCs, such as polybrominated diphenyl ethers (PBDEs), have been increasing or stable. HOCs exposure is known to cause a wide spectrum of effects including reproductive, developmental, immunologic, carcinogenic, and neurotoxic effects. It is of particular concern that neurotoxic effects have been observed in humans at low parts per billion (ppb) environmental concentrations. Epidemiological and experimental evidence shows that PCB exposure is associated with motor, sensory, and cognitive deficits in humans and animal models. Although several adverse outcome pathways (AOPs) were postulated for PCB and other HOC-induced neurotoxic effects, changes in altered intracellular signaling processes including calcium and protein kinase C (PKC) signaling, altered neurotransmitters, oxidative stress, and thyroid hormone imbalance are predominant. The current chapter focuses on (1) discussing the potential AOPs in detail with data from both in vitro and in vivo studies (2) extend structure–activity relationship (SAR) among PCBs with other structurally related chemicals such as PBDEs and polychlorinated diphenyl ethers. For more details about role of thyroid hormone imbalance, please see Chapters 3 and 6. For the role of Ryanodine receptor in intracellular signaling processes, please see Chapter 4. This book chapter is a comprehensive review discussing molecular effects of HOCs at cellular level to the adverse effects seen in whole animals including structural, physiological, sensory, and functional changes.
Unintentionally produced polychlorinated biphenyls in pigments: An updated review on their formation, emission sources, contamination status, and toxic effects
2021, Science of the Total Environment
Citation Excerpt :
Potentially toxic effects of some typical pd-PCBs and their metabolites have been demonstrated by several in vivo and in vitro studies conducted over the last three decades (Table 6). CB-11, 4-OH-CB-11, and 4′-OH-CB-35 can exhibit neurotoxicity in human and rat cell lines via different pathways such as decreasing cell dopamine content (Shain et al., 1991), inducing reactive oxygen species (ROS) production (Brown et al., 1998; Dreiem et al., 2009; Zhu et al., 2013), perturbing protein kinase C (PKC) translocation (Kodavanti et al., 1995), and promoting dendritic growth (Sethi et al., 2018). CB-11 and its hydroxylated and sulfated metabolites and CB-35 have been found as agonists/antagonists of androgen, estrogen, and thyroid hormone receptors (Flor et al., 2016; Takeuchi et al., 2017; Pencikova et al., 2018; Ren et al., 2019; Sethi et al., 2019).
The formation, emission, environmental occurrence, and potential adverse effects of unintentionally produced polychlorinated biphenyls (PCBs) in pigments are reviewed, providing a comprehensive and up-to-date picture on these pollutants. PCBs are typically formed during manufacturing of organic pigments that involve chlorinated intermediates and reaction solvents, rather than those of inorganic pigments. Concentrations and profiles of PCBs vary greatly among pigment types and producers, with total PCB levels ranging from lower than detection limits to several hundred ppm; major components can be low-chlorinated (e.g., CB-11) or high-chlorinated congeners (e.g., CB-209). Pigment-derived PCBs can be released into the environment through different steps including pigment production, application, and disposal. They can contaminate atmospheric, terrestrial, and aquatic ecosystems, and then affect organisms living there. This situation garners scientific and public attention to nonlegacy emissions of PCBs and suggests the need for appropriate monitoring, management, and abatement strategies regarding these pollutants.
Integrating data gap filling techniques: A case study predicting TEFs for neurotoxicity TEQs to facilitate the hazard assessment of polychlorinated biphenyls
2019, Regulatory Toxicology and Pharmacology
Citation Excerpt :
The correlation coefficient between the individual experiments with the alternative NEF values derived in this work and NEF values derived by Simon et al. (2007) were very similar, with an exception to Kodavanti PEB (Kodavanti et al., 1996b), Pessah/Holland RyR1 (Pessah et al., 2006; Holland et al., 2017), Stenberg Dop (Stenberg et al., 2011) and Stenberg DAT (Stenberg et al., 2011) which correlated better with the alternative NEF values. The correlation coefficients derived by Simon et al. (2007) and NEF values from this work are: (0.50, 0.66) for protein kinase C translocation effect (Kodavanti et al., 1995), (0.73, 0.76) for reduction in dopamine content effect (Shain et al., 1991), (0.72, 0.69) and (0.82, 0.84) for microsomal and mitochondrial Ca+2-sequestration effect, respectively (Kodavanti et al., 1996a), (0.40, 0.70) for enhanced RyR1 activity (Pessah et al., 2006), inhibition of dopamine uptake (0.52, 0.85 - Stenberg Dop (Stenberg et al., 2011); 0.57, 0.69 – Stenberg DAT (Stenberg et al., 2011); 0.58, 0.49 – Wigestrand DAT (Wigestrand et al., 2013)). Overall, we derived alternative NEF values for 87 congeners that were used to develop QSAR models (Table 2).
The application of toxic equivalency factors (TEFs) or toxic units to estimate toxic potencies for mixtures of chemicals which contribute to a biological effect through a common mechanism is one approach for filling data gaps. Toxic Equivalents (TEQ) have been used to express the toxicity of dioxin-like compounds (i.e., dioxins, furans, and dioxin-like polychlorinated biphenyls (PCBs)) in terms of the most toxic form of dioxin: 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD). This study sought to integrate two data gap filling techniques, quantitative structure–activity relationships (QSARs) and TEFs, to predict neurotoxicity TEQs for PCBs. Simon et al. (2007) previously derived neurotoxic equivalent (NEQ) values for a dataset of 87 PCB congeners, of which 83 congeners had experimental data. These data were taken from a set of four different studies measuring different effects related to neurotoxicity, each of which tested overlapping subsets of the 83 PCB congeners. The goals of the current study were to: (i) evaluate an alternative neurotoxic equivalent factor (NEF) derivations from an expanded dataset, relative to those derived by Simon et al. and (ii) develop QSAR models to provide NEF estimates for the large number of untested PCB congeners. The models used multiple linear regression, support vector regression, k-nearest neighbor and random forest algorithms within a 5-fold cross validation scheme and position-specific chlorine substitution patterns on the biphenyl scaffold as descriptors. Alternative NEF values were derived but the resulting QSAR models had relatively low predictivity (RMSE ∼0.24). This was mostly driven by the large uncertainties in the underlying data and NEF values. The derived NEFs and the QSAR predicted NEFs to fill data gaps should be applied with caution.
Cell Signaling and Neurotoxicity
2018, Comprehensive Toxicology: Third Edition
Neuroendocrine actions of organohalogens: Thyroid hormones, arginine vasopressin, and neuroplasticity
2010, Frontiers in Neuroendocrinology
Citation Excerpt :
Based on the structure–activity relationships (SAR), Chauhan et al. [27] proposed two binding modes, one for lateral substituted PCBs and the other for ortho-substituted PCBs by overlaying the PCB molecule on T4 (Fig. 4). The binding potencies of several PCBs seem to follow their biological activities such as decreases in PC12-cellular dopamine content and PKC translocation in neuronal cells [27,127,130,224] with some exceptions where differential effects of PCBs on circulating TH are observed based on coplanarity. PCB congeners that are non-coplanar such as 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) decrease circulating T4 levels to a greater extent (>90%) than coplanar PCBs such as 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) [37].
Organohalogen compounds are global environmental pollutants. They are highly persistent, bioaccumulative, and cause adverse effects in humans and wildlife. Because of the widespread use of these organohalogens in household items and consumer products, indoor contamination may be a significant source of human exposure, especially for children. One significant concern with regard to health effects associated with exposure to organohalogens is endocrine disruption. This review focuses on PCBs and PBDEs as old and new organohalogens, respectively, and their effects on two neuroendocrine systems; thyroid hormones and the arginine vasopressin system (AVP). Regarding neuroendocrine effects of organohalogens, there is considerable information on the thyroid system as a target and evidence is now accumulating that the AVP system and associated functions are also susceptible to disruption. AVP-mediated functions such as osmoregulation, cardiovascular function as well as social behavior, sexual function and learning/memory are discussed. For both thyroid and AVP systems, the timing of exposure seems to play a major role in the outcome of adverse effects. The mechanism of organohalogen action is well understood for the thyroid system. In comparison, this aspect is understudied in the AVP system but some similarities in neural processes, shown to be targeted by these pollutants, serve as promising possibilities for study. One challenge in understanding modes of action within neuroendocrine systems is their complexity stemming, in part, from interdependent levels of organization. Further, because of the interplay between neuroendocrine and neural functions and behavior, further investigation into organohalogen-mediated effects is warranted and may yield insights with wider scope. Indeed, the current literature provides scattered evidence regarding the role of organohalogen-induced neuroendocrine disruption in the neuroplasticity related to both learning functions and brain structure but future studies are needed to establish the role of endocrine disruption in nervous system function and development.

View all citing articles on Scopus

View full text

Regular ArticleIncreased (3H) Phorbol Ester Binding in Rat Cerebellar Granule Cells by Polychlorinated Biphenyl Mixtures and Congeners: Structure-Activity Relationships

Abstract

Regular Article
Increased (³H) Phorbol Ester Binding in Rat Cerebellar Granule Cells by Polychlorinated Biphenyl Mixtures and Congeners: Structure-Activity Relationships