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Polychlorinated biphenyls (PCBs), such as PCB52, are hazardous environmental contaminants present in indoor and outdoor environments. Oral PCB exposure affects the colon microbiome; however, it is unknown if inhalation of PCBs alters the intestinal microbiome. We hypothesize that sub-acute inhalation of PCB52 affects microbial communities depending on the location in the (GI) gastrointestinal tract and the local profiles of PCB52 and its metabolites present in the GI tract following mucociliary clearance and biliary or intestinal excretion. Sprague-Dawley rats were exposed via nose-only inhalation 4 h per day, 7 days per week, for 4 weeks to either filtered air or PCB52. After 28 days, differences in the microbiome and levels of PCB52 and its metabolites were characterized throughout the GI tract. PCB52 inhalation altered taxa abundances and predicted functions altered throughout the gut, with most alterations occurring in the large intestine. PCB52 and metabolite levels varied across the GI tract, resulting in differing PCB × microbiome networks. Thus, the presence of different levels of PCB52 and its metabolites in different parts of the GI tract has varying effects on the composition and predicted function of microbial communities. Future studies need to investigate whether these changes lead to adverse outcomes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Author AM is the inventor of a technology claiming the use of Prevotella histicola for the treatment of autoimmune diseases. The patent for the technology is owned by Mayo Clinic, which has given an exclusive license to Evelo Biosciences. AM received royalties from Mayo Clinic (paid by Evelo Biosciences). However, no funds or products from the patent were used in the present study. The remaining authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A semi-volatile polychlorinated biphenyl (PCB) congener, PCB52, is present in the indoor air of schools; however, the effects of inhaled PCB52 on the brain have not been investigated. This study exposed male Sprague-Dawley rats at 39 days of age and female rats at 42 days of age to PCB52 for 4 hours per day over 28 consecutive days through nose-only inhalation. Neurobehavioral tests were conducted during the last 5 days of exposure. The total estimated PCB52 exposures after 28 days were 1080±20 µg/kg BW for male rats and 1140±10 µg/kg BW for female rats. PCB52 and its metabolites were detected by gas chromatography-tandem mass spectrometry in the brain, lung, and serum, with the lung showing the highest concentrations. PCB52 levels were higher in the brains of females than males. Males showed increased exploratory behavior compared to controls, whereas females exhibited decreased exploratory behavior compared to controls in the same tests. PCB52 exposure did not impact locomotor activity or working memory. Gene expression and pathway analysis in the striatum and cerebellum suggest that PCB52 inhalation causes mitochondrial dysfunction. No significant differences were observed by immunohistochemical evaluation in the density and percent area of total cells, astrocytes, or microglia in the striatum and cerebellar cortex. Our results indicate multilevel effects of inhaled PCB52 on the rat brain, from gene expression to behavioral effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Elevated airborne PCB levels in older schools are concerning due to their health impacts, including cancer, metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular issues, neurodevelopmental diseases, and diabetes. During a four-week inhalation exposure to PCB52, an air pollutant commonly found in school environments, adolescent rats exhibited notable presence of PCB52 and its hydroxylated forms in their livers, alongside changes in gene expression. Female rats exhibited more pronounced changes in gene expression compared to males, particularly in fatty acid synthesis genes regulated by the transcription factor SREBP1. In vitro studies with human liver cells showed that the hydroxylated metabolite of PCB52, 4-OH-PCB52, but not the parent compound, upregulated genes involved in fatty acid biosynthesis similar to in vivo exposure. These findings highlight the sex-specific effects of PCB52 exposure on livers, particularly in females, suggesting a potential pathway for increased MASLD susceptibility., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Inhalation of PCB-contaminated air is increasingly recognized as a route for PCB exposure. Because limited information about the disposition of PCBs following inhalation exposure is available, this study investigated the disposition of 2,2',5,5'-tetrachlorobiphenyl (PCB52) and its metabolites in rats following acute, nose-only inhalation of PCB52. Male and female Sprague-Dawley rats (50-58 days of age, 210 ± 27 g; n = 6) were exposed for 4 h by inhalation to approximately 14 or 23 μg/kg body weight of PCB52 using a nose-only exposure system. Sham animals (n = 6) were exposed to filtered lab air. Based on gas chromatography-tandem mass spectrometry (GC-MS/MS), PCB52 was present in adipose, brain, intestinal content, lung, liver, and serum. 2,2',5,5'-Tetrachlorobiphenyl-4-ol (4-OH-PCB52) and one unknown monohydroxylated metabolite were detected in these compartments except for the brain. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis identified several metabolites, including sulfated, methoxylated, and dechlorinated PCB52 metabolites. These metabolites were primarily found in the liver (7 metabolites), lung (9 metabolites), and serum (9 metabolites) due to the short exposure time. These results demonstrate for the first time that complex mixtures of sulfated, methoxylated, and dechlorinated PCB52 metabolites are formed in adolescent rats following PCB52 inhalation, laying the groundwork for future animal studies of the adverse effects of inhaled PCB52.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that ubiquitously exist in the environment. PCB exposure has been linked to cancer and multi-system toxicity, including endocrine disruption, immune inhibition, and reproductive and neurotoxicity. 2,2',5,5'-Tetrachlorobiphenyl (PCB 52) is one of the most frequently detected congeners in the environment and human blood. The hydroxylated metabolites of PCB 52 may also be neurotoxic, especially for children whose brains are still developing. However, it is challenging to discern the contribution of these metabolites to PCB neurotoxicity because the metabolism of PCB is species-dependent. In this study, we evaluated the subacute neurotoxicity of a human-relevant metabolite, 2,2',5,5'-tetrachlorobiphenyl-4-ol (4-52), on male adolescent Sprague Dawley rats, via a novel polymeric implant drug delivery system grafted subcutaneously, at total loading concentrations ranging from 0%, 1%, 5%, and 10% of the implant (w/w) for 28 days. Y-maze, hole board test, open field test, and elevated plus maze were performed on exposure days 24-28 to assess their locomotor activity, and exploratory and anxiety-like behavior. 4-52 and other possible hydroxylated metabolites in serum and vital tissues were quantified using gas chromatography with tandem mass spectrometry (GC-MS/MS). Our results demonstrate the sustained release of 4-52 from the polymeric implants into the systemic circulation in serum and tissues. Dihydroxylated and dechlorinated metabolites were detected in serum and tissues, depending on the dose and tissue type. No statistically significant changes were observed in the neurobehavioral tasks across all exposure groups. The results demonstrate that subcutaneous polymeric implants provide a straightforward method to expose rats to phenolic PCB metabolites to study neurotoxic outcomes, e.g., in memory, anxiety, and exploratory behaviors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

School indoor air contaminated with polychlorinated biphenyls (PCBs) released from older building materials and paint pigments may pose health risks to children, as well as teachers and staff, by inhalation of PCBs. The health effects of long-term inhalation exposure to PCBs are poorly understood. We conducted a comprehensive toxicity assessment of 91-day repeated inhalation exposure to a lab-generated mixture of PCBs designed to emulate indoor school air, combining transcriptomics, metabolomics, and neurobehavioral outcomes. Female Sprague-Dawley rats were exposed to school air mixture (SAM+) at a concentration of 45.5 ± 5.9 μg/m 3 ∑ 209 PCB or filtered air 4 h/day, 6 days/week for 13 weeks using nose-only exposure systems. The congener-specific PCB body burden was quantified in major tissues using GC-MS/MS. The generated SAM+ vapor recapitulated the target school air profile with a similarity coefficient, cos θ of 0.91. PCB inhalation yielded 875-9930 ng/g ∑ 209 PCB lipid weight levels in tissues in the following ascending order: brain < liver < lung < serum < adipose tissue. We observed that PCB exposure impaired memory, induced anxiety-like behavior, significantly reduced white blood cell counts, mildly disrupted metabolomics in plasma, and influenced transcription processes in the brain with 274 upregulated and 58 downregulated genes. With relatively high exposure and tissue loading, evidence of toxicity from half the end points tested was seen in the rats.

Few in vivo inhalation studies have explored the toxicity of environmentally relevant mixtures of polychlorinated biphenyls (PCBs). The manufacture of industrial PCBs was banned in 1978, but PCBs continue to be formed in industrial and consumer products. Schools represent a significant source of airborne exposures to legacy and nonlegacy PCBs, placing children at risk. To evaluate the impact of these exposures, we generated an airborne mixture of PCBs, called the School Air Mixture (SAM), to match the profile of an older school from our adolescent cohort study. Female Sprague-Dawley rats were exposed either to SAM or filtered air in nose-only exposure systems, 4 h/day for 4 weeks. Congener-specific air and tissue PCB profiles were assessed using gas chromatography with tandem mass spectrometry (GC-MS/MS). PCB exposures recapitulated the target school air profile with a similarity coefficient, cos θ of 0.83. PCB inhalation yielded μg/g ∑ 209 PCB levels in tissues. Neurobehavioral testing demonstrated a modest effect on spatial learning and memory in SAM-exposed rats. PCB exposure induced oxidative stress in the liver and lungs, affected the maturational stages of hematopoietic stem cells, reduced telomerase activity in bone marrow cells, and altered the gut microbiota. This is the first study to emulate PCB exposures in a school and comprehensively evaluate toxicity.

Polychlorinated biphenyls (PCBs) persist and accumulate in the ecosystem depending upon the degree of chlorination of the biphenyl rings. Airborne PCBs are especially susceptible to oxidative metabolism, yielding mono- and di-hydroxy metabolites. We have previously demonstrated that 4-chlorobiphenyl hydroquinones (4-CB-HQs) acted as cosubstrates for arachidonic acid metabolism by prostaglandin H synthase (PGHS) and resulted in an increase of prostaglandin production in vitro. In the present study, we tested the capability of 4-CB-HQ to act as a co-substrate for PGHS catalysis in vivo. BQ and 4-CB-2',5'-HQ were administered intratracheally to male Sprague-Dawley rats (2.5 μmol/kg body weight) using nanosized polyamidoamine (PAMAM) dendrimers as carriers. We found that 24 h post application, PGE2 metabolites in kidney of rats treated with 4-CB-2',5'-HQ were significantly increased compared to the controls. The increase of PGE2 metabolites was correlated with increased alveolar macrophages in lung lavage fluid. The elevation of PGE2 synthesis is of great interest since it plays a crucial role in balancing homeostasis and inflammation where a chronic disturbance may increase risk of cancer. PAMAM dentrimers proved to be an effective transport medium and did not stimulate an inflammatory response themselves.

The health risk of inhalation exposure to polychlorinated biphenyls (PCB) cannot be assessed with high confidence due to the lack of rigorous inhalation studies. One uncertainty rests on exposure regimen, as whole-body exposure systems allow oral PCB intake that confounds the exposure. We conducted contemporaneous PCB inhalation exposures with whole-body and nose-only exposure methods. Female Sprague-Dawley rats were concurrently exposed to vapor-phase PCBs (533 ± 93 μg/m(3)) generated from PCB11-supplemented Chicago Air Mixture resembling the Chicago airshed, 4 h/day, 6 days/week, for 4 weeks. Congener-specific analysis showed 1.5-fold higher ∑PCBs in the lungs of nose-only exposed than the whole-body exposed animals (p = 0.0024). Higher ∑PCB concentrations were also found in the sera, livers, brains, and adipose tissue of nose-only exposed animals (1.1-1.5-fold), but these increases were not statistically significant. Congener profiles of five tissue types were dominated by PCB 28/31 and higher-chlorinated congeners in both groups reflecting rapid metabolism of other lower-chlorinated PCBs. No toxicity was seen regarding metabolic enzyme expression, glutathione, or histopathology. However, diminished weight gain and reduced plasma total thyroxine levels were found in both groups compared with controls, after exposure to 76 μg/m(3) ∑PCBs as adjusted for continuous exposure. Hepatic lipid peroxidation was also elevated in the nose-only group. Our study shows that prolonged nose-only exposure was well-tolerated and eliminated the need for housing animals outside the vivarium, thus was preferred for long-term PCB inhalation studies.

Background: The production ban of polychlorinated biphenyl (PCB) technical mixtures has left the erroneous impression that PCBs exist only as legacy pollutants. Some lower-chlorinated PCBs are still being produced and contaminate both indoor and ambient air., Objectives: To inform PCB risk assessment, we characterized lung uptake, distribution, metabolism and excretion of PCB11 as a signature compound for these airborne non-legacy PCBs., Methods: After delivering [(14)C]PCB11 to the lungs of male rats, radioactivity in 34 major tissues and 5 digestive matter compartments was measured at 12, 25, 50, 100, 200 and 720min postexposure, during which time the excreta and exhaled air were also collected. [(14)C]PCB11 and metabolites in lung, liver, blood, digestive matter, urine, feces, and adipose tissues were extracted separately to establish the metabolic profile of the disposition., Results: [(14)C]PCB11 was distributed rapidly to all tissues after 99.8% pulmonary uptake and quickly underwent extensive metabolism. The major tissue deposition of [(14)C]PCB11 and metabolites translocated from liver, blood and muscle to skin and adipose tissue 200min postexposure, while over 50% of administered dose was discharged via urine and feces within 12h. Elimination of the [(14)C]PCB11 and metabolites consisted of an initial fast phase (t½=9-33min) and a slower clearance phase to low concentrations. Phase II metabolites dominated in liver blood and excreta after 25min postexposure., Conclusions: This study shows that PCB11 is completely absorbed after inhalation exposure and is rapidly eliminated from most tissues. Phase II metabolites dominated with a slower elimination rate than the PCB11 or phase I metabolites and thus can best serve as urine biomarkers of exposure., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The recent discovery of 3,3'-dichlorobiphenyl (CB11) as a byproduct of pigment manufacturing underscores the urgency to investigate its biological fate. The high level and ubiquity of atmospheric CB11 indicates that inhalation is the major route of exposure. However, few data on its uptake and elimination exist. A time course study was performed exposing male Sprague-Dawley rats to CB11 via nose-only inhalation with necropsy at 0, 4, and 8 h post exposure. An analytical method for CB11 and monohydroxylated metabolites employing pressurized liquid extraction and gas chromatography-mass spectrometry yielded efficient recovery of CB11 (73 ± 9%) and its metabolite 3,3'-dichlorobiphenyl-4-ol (4-OH-CB11) (82 ± 12%). Each rat was exposed to 106 μg/m(3) vapor-phase CB11 for 2 h and received an estimated dose of 1.8 μg. Rapid apparent first-order elimination of CB11 was found in lung, serum, and liver with half-lives of 1.9, 1.8, and 2.1 h, respectively. 4-OH-CB11 was detected in the liver but not the lung or serum of exposed animals and displayed apparent first-order elimination with a 2.4 h half-life. This study demonstrates rapid metabolism of CB11 and elimination of 4-OH-CB11 and suggests that the metabolite is not retained in the body but is susceptible to further biotransformation.

Although inhalation of atmospheric polychlorinated biphenyls (PCBs) is the most universal exposure route and has become a substantial concern in urban areas, research is lacking to determine the body burden of inhaled PCBs and consequent health effects. To reflect the Chicago airshed environment and mimic the PCB profile in Chicago air, we generated vapors from a Chicago air mixture (CAM). Sprague-Dawley rats were exposed to the CAM vapor for 1.6 h/day via nose-only inhalation for 4 weeks, 520 ± 10 μg/m(3). Congener-specific quantification in tissue and air samples was performed by gas chromatography-tandem mass spectrometry (GC/MS/MS). In contrast to the lower-chlorinated congener-enriched vapor, body tissues mainly contained tri- to hexachlorobiphenyls. Congener profiles varied between vapor and tissues and among different organs. The toxic equivalence (TEQ) and neurotoxic equivalence (NEQ) were also investigated for tissue distribution. We evaluated a variety of end points to catalogue the effects of long-term inhalation exposure, including immune responses, enzyme induction, cellular toxicity, and histopathologic abnormalities. Glutathione oxidized/reduced ratio (GSSG/GSH) was increased in the blood of exposed animals, accompanied by elevation of hematocrit. This study demonstrated that inhalation contributed to the body burden of mostly tri- to hexachlorobiphenyls and produced a distinct profile of congeners in tissue, yet minimal toxicity was found at this exposure dose, estimated at 134 μg/rat.

Despite the continued presence of PCBs in indoor and ambient air, few studies have investigated the inhalation route of exposure. While dietary exposure has declined, inhalation of the semivolatile, lower-chlorinated PCBs has risen in importance. We measured the uptake, distribution, and time course of elimination of inhaled PCB congeners to characterize the pulmonary route after short-term exposure. Vapor-phase PCBs were generated from Aroclor 1242 to a nose-only exposure system and characterized for congener levels and profiles. Rats were exposed via inhalation acutely (2.4 mg/m3 for 2 h) or subacutely (8.2 mg/m3, 2 hx10 days), after which pulmonary immune responses and PCB tissue levels were measured. Animals acutely exposed were euthanized at 0, 1, 3, 6, and 12 h post exposure to assess the time course of PCB uptake and elimination. Following rapid absorption and distribution, PCBs accumulated in adipose tissue but decayed in other tissues with half-lives increasing in liver (5.6 h)

Abstract: Background: The production ban of polychlorinated biphenyl (PCB) technical mixtures has left the erroneous impression that PCBs exist only as legacy pollutants. Some lower-chlorinated PCBs are still being produced and contaminate both indoor and ambient air. Objectives: To inform PCB risk assessment, we characterized lung uptake, distribution, metabolism and excretion of PCB11 as a signature compound for these airborne non-legacy PCBs. Methods: After delivering [14C]PCB11 to the lungs of male rats, radioactivity in 34 major tissues and 5 digestive matter compartments was measured at 12, 25, 50, 100, 200 and 720min postexposure, during which time the excreta and exhaled air were also collected. [14C]PCB11 and metabolites in lung, liver, blood, digestive matter, urine, feces, and adipose tissues were extracted separately to establish the metabolic profile of the disposition. Results: [14C]PCB11 was distributed rapidly to all tissues after 99.8% pulmonary uptake and quickly underwent extensive metabolism. The major tissue deposition of [14C]PCB11 and metabolites translocated from liver, blood and muscle to skin and adipose tissue 200min postexposure, while over 50% of administered dose was discharged via urine and feces within 12h. Elimination of the [14C]PCB11 and metabolites consisted of an initial fast phase (t½ =9–33min) and a slower clearance phase to low concentrations. Phase II metabolites dominated in liver blood and excreta after 25min postexposure. Conclusions: This study shows that PCB11 is completely absorbed after inhalation exposure and is rapidly eliminated from most tissues. Phase II metabolites dominated with a slower elimination rate than the PCB11 or phase I metabolites and thus can best serve as urine biomarkers of exposure. [Copyright &y& Elsevier]

Although inhalation of atmospheric polychlorinated biphenyls (PCBs) is the most universal exposure route and has become a substantial concern in urban areas, research is lacking to determine the body burden of inhaled PCBs and consequent health effects. To reflect the Chicago airshed environment and mimic the PCB profile in Chicago air, we generated vapors from a Chicago air mixture (CAM). Sprague-Dawley rats were exposed to the CAM vapor for 1.6 h/day via nose-only inhalation for 4 weeks, 520 ± 10 μg/m3. Congener-specific quantification in tissue and air samples was performed by gas chromatography-tandem mass spectrometry (GC/MS/MS). In contrast to the lower-chlorinated congener-enriched vapor, body tissues mainly contained tri- to hexachlorobiphenyls. Congener profiles varied between vapor and tissues and among different organs. The toxic equivalence (TEQ) and neurotoxic equivalence (NEQ) were also investigated for tissue distribution. We evaluated a variety of end points to catalogue the effects of long-term inhalation exposure, including immune responses, enzyme induction, cellular toxicity, and histopathologic abnormalities. Glutathione oxidized/reduced ratio (GSSG/GSH) was increased in the blood of exposed animals, accompanied by elevation of hematocrit. This study demonstrated that inhalation contributed to the body burden of mostly tri- to hexachlorobiphenyls and produced a distinct profile of congeners in tissue, yet minimal toxicity was found at this exposure dose, estimated at 134 μg/rat. [ABSTRACT FROM AUTHOR]

Despite the continued presence of PCBs in indoor and ambient air, few studies have investigated the inhalation route of exposure. While dietary exposure has declined, inhalation of the semivolatile, lower-chlorinated PCBs has risen in importance. We measured the uptake, distribution, and time course of elimination of inhaled PCB congeners to characterize the pulmonary route after short-term exposure. Vapor-phase PCBs were generated from Aroclor 1242 to a nose-only exposure system and characterized for congener levels and profiles. Rats were exposed via inhalation acutely (2.4 mg/m³ for 2 h) or subacutely (8.2 mg/m³, 2 h × 10 days), after which pulmonary immune responses and PCB tissue levels were measured. Animals acutely exposed were euthanized at 0, 1, 3, 6, and 12 h post exposure to assess the time course of PCB uptake and elimination. Following rapid absorption and distribution, PCBs accumulated in adipose tissue but decayed in other tissues with half-lives increasing in liver (5.6 h) < lung (8.2 h) < brain (8.5 h) < blood (9.7 h). PCB levels were similar in lung, liver, and adipose tissue, lower in brain, and lowest in blood. Inhalation of the airborne PCB mixture contributed significantly to the body burden of lower-chlorinated congeners. Congeners detected in tissue were mostly ortho-substituted ranging from mono- to pentachlorobiphenyls. Selective uptake and elimination led to accumulation of a distinct congener spectrum in tissue. Minimal evidence of toxicity was observed. [ABSTRACT FROM AUTHOR]