The effect of chlorine position on the distribution and excretion of four hexachlorobiphenyl isomers

doi:10.1016/0041-008X(80)90351-8

Toxicology and Applied Pharmacology

Volume 53, Issue 3, May 1980, Pages 377-388

https://doi.org/10.1016/0041-008X(80)90351-8 Get rights and content

Abstract

The distribution and excretion of four symmetrical polychlorinated biphenyl (PCB) isomers, 2,3,5,2′,3′,5′-hexa-; 2,3,6,2′,3′,6′-hexa-; 2,4,5,2′,4′,5′-hexa-; and 2,4,6,2′-4′,6′-hexachlorobiphenyl, were studied in the male rat. The study of three of these hexachlorobiphenyl isomers permitted an assessment of the importance of each unchlorinated position in the absence of adjacent unsubstituted carbon atoms on the biphenyl rings. The study of 2,3,6,2′,3′,6′-hexachlorobiphenyl allowed an assessment of the importance of adjacent unsubstituted carbon atoms in an otherwise highly chlorinated PCB. 2,3,6,2′,3′,6′-Hexachlorobiphenyl was rapidly metabolized and excreted relative to the hexachlorobiphenyls which did not have adjacent unsubstituted carbon atoms. The other hexachlorobiphenyls were very slowly metabolized by the male rat and have extremely long half-lives in this species. The results of these studies demonstrate the importance of adjacent unsubstituted carbon atoms to the metabolism of PCBs and imply that when the position of PCB chlorination is such as to inhibit the formation of an arene oxide intermediate then PCB metabolism proceeds very slowly. These studies allo indicate that in the absence of adjacent unsubstituted carbon atoms, the preferred mechanism of PCB metabolism may be by the insertion of a hydroxyl group at the meta position.

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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.
Fatty liver and impaired hepatic metabolism alter the congener-specific distribution of polychlorinated biphenyls (PCBs) in mice with a liver-specific deletion of cytochrome P450 reductase
2020, Environmental Pollution
Citation Excerpt :
Therefore, we compared differences in the mass percentage of PCBs congeners with a 4-, 3,4-, and 3,4,5- substitution pattern and zero or one ortho chlorine substituent (Class A); PCB congeners with two or more ortho chlorine substituents and a 2,4- or 2,3,4- substitution pattern (Class B); PCBs congeners with a 2,4,5-substitution pattern (Class C); and PCB congeners that are considered to be episodic because they are rapidly eliminated following exposure (Imsilp and Hansen, 2005). Class D congeners have adjacent, unsubstituted C-atoms and, typically, contain a 2-, 2,3-, 2,5- and 2,3,6-substitution pattern in at least one phenyl ring (Class D) (Haraguchi et al., 2005; Matthews and Tuey, 1980). Overall, the mass percentage of PCBs belonging to Class C increased relative to Aroclor 1254 in all tissues from all four exposure groups (Fig. 1; Table S5).
Polychlorinated biphenyls (PCBs) are persistent organic pollutants that are linked to adverse health outcomes. PCB tissue levels are determinants of PCB toxicity; however, it is unclear how factors, such as an altered metabolism and/or a fatty liver, affect PCB distribution in vivo. We determined the congener-specific disposition of PCBs in mice with a liver-specific deletion of cytochrome P450 reductase (KO), a model of fatty liver with impaired hepatic metabolism, and wild-type (WT) mice. Eight-week-old male WT (M_WT, n = 3), male KO (M_KO, n = 5), female WT (F_WT, n = 4), and female KO mice (F_KO, n = 4) were exposed orally to Aroclor 1254. PCBs were quantified in adipose, blood, brain, and liver tissues by gas chromatography-mass spectrometry. The ΣPCB levels followed the rank order adipose > liver ∼ brain > blood in WT and adipose ∼ liver > brain > blood in KO mice. PCB levels were much higher in the liver of KO than WT mice, irrespective of the sex. A comparison across exposure groups revealed minor genotype and sex-dependent differences in the PCB congener profiles (cos Θ > 0.92). Within each exposure group, tissue profiles showed small differences between tissues (cos Θ = 0.85 to 0.98). These differences were due to a decrease in metabolically more labile PCB congeners and an increase in congeners resistant to metabolism. The tissue-to-blood ratio of PCBs decreased for adipose, increased for the brain, and remained constant for the liver with an increase in chlorination. While these ratios did not follow the trends predicted using a composition-based model, the agreement between experimental and calculated partition coefficients was reasonable. Although the distribution of PCBs differs between KO and WT mice, the magnitude of the partitioning of PCBs from the blood into tissues can be approximated using composition-based models.
Assessment of the disposition of chiral polychlorinated biphenyls in female mdr 1a/b knockout versus wild-type mice using multivariate analyses
2010, Environment International
Polychlorinated biphenyls (PCBs) are present in the environment as complex mixtures, which make it challenging to identify PCB congeners that may be subject to active transport processes. Here we employ a transgenic mouse model in combination with multivariate analyses to investigate if chiral PCBs 91, 95, 132, 136, 149, 174, 176 and 183 are subject to active (enantioselective) transport by multidrug resistance (MDR) transporters. A synthetic PCB mixture containing these congeners was administered orally to female FVB or mdr1a/1b knockout mice. Due to the short half-life of chiral PCB congeners, mice were euthanized after 24 h and PCB concentrations and enantiomeric fractions were determined in selected tissues and excreta. Principal component analysis did not reveal differences between wild-type and mdr1a/1b knockout mice. However, Hotelling T²-test revealed significantly lower PCB concentrations and a more pronounced enantiomeric enrichment in the adipose tissue of mdr1a/1b knockout mice. These differences are due to higher body weights and higher fecal fat contents of mdr1a/1b knockout mice. Analysis of the enantiomeric fractions of PCBs 91, 95, 136, 149 and 174 showed a significant enantiomeric enrichment for all five congeners in wild-type and mdr1a/1b knockout mice. Overall, by studying a PCB mixture in a transgenic mouse model in combination with a multivariate data reduction approach, PCBs 91, 95, 136, 149 and 174 could be excluded as substrates of multidrug resistance transporters 1a/b.
Minding the calcium store: Ryanodine receptor activation as a convergent mechanism of PCB toxicity
2010, Pharmacology and Therapeutics
Chronic low-level polychlorinated biphenyl (PCB) exposures remain a significant public health concern since results from epidemiological studies indicate that PCB burden is associated with immune system dysfunction, cardiovascular disease, and impairment of the developing nervous system. Of these various adverse health effects, developmental neurotoxicity has emerged as a particularly vulnerable endpoint in PCB toxicity. Arguably the most pervasive biological effects of PCBs could be mediated by their ability to alter the spatial and temporal fidelity of Ca²⁺ signals through one or more receptor-mediated processes. This review will focus on our current knowledge of the structure and function of ryanodine receptors (RyRs) in muscle and nerve cells and how PCBs and related non-coplanar structures alter these functions. The molecular and cellular mechanisms by which non-coplanar PCBs and related structures alter local and global Ca²⁺ signaling properties and the possible short and long-term consequences of these perturbations on neurodevelopment and neurodegeneration are reviewed.
Effects of dietary wheat bran on absorption and accumulation of PCBs in rats
2008, Chemosphere
Polychlorinated biphenyls (PCBs) are toxic environmental contaminants, which tend to accumulate in the food chain. Since dietary intake is the most important exposure route, PCB body burden may be affected by taking proper dietary measures. In the present study, diets were supplemented with either wheat bran or its cellulose based placebo in order to study the effect of bran consumption on the absorption of dietary PCBs and the excretion of initially stored PCBs. During the period of PCB intake, faecal PCB excretion was elevated by consumption of wheat bran as compared to the placebo. Hence, apparent faecal PCB digestibilities as well as PCB retentions in the whole body were lower in the wheat bran consuming rats. After ending PCB consumption, dietary wheat bran had only a minor effect on faecal PCB output while accumulation in the body was not affected. When PCBs were consumed for a longer time, a small but significant reduction of apparent faecal PCB digestibility was found. However, PCB content in the body kept increasing while PCB retention as percent of intake remained almost constant. Furthermore, differences among individual PCB congeners in metabolic susceptibility and hydrophobic characteristics had an impact on their accumulation in the body.
Influence of dietary fat on the enantioselective disposition of 2,2′,3,3′,6,6′-hexachlorobiphenyl (PCB 136) in female mice
2008, Food and Chemical Toxicology
Citation Excerpt :
Overall, urinary excretion of parent PCB 136 appeared to be negligible (i.e., urinary PCB 136 levels above the limit of detection were always due to a contamination with fecal matter). Similarly, several animal studies have shown that urinary excretion is a minor route of excretion of parent PCB 136 in rats (Matthews and Tuey, 1980; Birnbaum, 1983), dogs and monkeys (Sipes et al., 1982). In rats, <2% of the total dose PCB 136 dose are excreted with the urine, mostly due to the excretion of metabolites and not of parent PCB 136 (Matthews and Tuey, 1980; Birnbaum, 1983).
Although ingestion is the major route of exposure to polychlorinated biphenyls (PCBs), dietary factors altering their absorption and excretion are only poorly understood. In the present study, (±)-PCB 136 was administered orally to female C57BL/6 mice fed an unrefined (URD, 10% fat) or high fat (HFD, 40% fat) diet to investigate the effect of the dietary fat content on the disposition of PCBs. Three days after administration, PCB levels in the adipose tissue were significantly lower in HFD animals than URD animals, partly due to a higher excretion rate of PCB 136 in the HFD group. (+)-PCB 136 was enriched in all organs and in feces. In both groups, enantiomeric fractions in feces increased each day after administration. We hypothesize that low EF (enantiomeric fraction) values in feces excreted within 24 h of exposure are due to the presence of undigested, racemic PCB. Higher EF values in feces excreted after two and three days are due to excretion of previously absorbed PCBs. Overall, our study suggests that the EF value may be a good tool to investigate the absorption and excretion of PCBs in vivo.

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The effect of chlorine position on the distribution and excretion of four hexachlorobiphenyl isomers

Abstract

Toxicol. Appl. Pharmacol.

Intestinal absorption of polychlorinated biphenyls in rats

Bull. Environ. Contam. Toxicol.

Distribution and metabolism of polychlorobiphenyls

Biphenyl hydroxylations and spectrally apparent interactions with liver microsomes from hamsters pretreated with phenobarbitone and 3-methylcholanthrene

Xenobiotica

Microsomal biphenyl hydroxylation: the formation of 3-hydroxybiphenyl and biphenyl catechol

Mol. Pharmacol.

Studies in detoxication 76. The metabolism of halogenobenzenes. 1:2:3:4-, 1:2:3:5-, and 1:2:4:5-tetrachlorobenzenes

Biochem. J.