Dioxin-like and non-dioxin-like PCBs differentially regulate the hepatic proteome and modify diet-induced nonalcoholic fatty liver disease severity

Jin, Jian; Wahlang, Banrida; Shi, Hongxue; Hardesty, Josiah; Falkner, K. Cameron; Head, Kimberly Z.; Srivastava, Sudhir; Merchant, Michael L.; Shesh, N.; Cave, Matthew C.; Prough, Russell A.

doi:10.1007/s00044-020-02581-w

Cited by 29 publications

(23 citation statements)

References 51 publications

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“…There was a high prevalence of obesity in ACHS-I. Based on the results, we postulate that PCB exposures may modify diet-induced fatty liver disease via epigenetic mechanisms in humans, as recently demonstrated using an animal exposure model ( Jin et al. 2020 ).…”

Section: Discussionsupporting

confidence: 67%

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Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey

Cave

Pinkston

Shesh

et al. 2022

Environ Health Perspect

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Background: Polychlorinated biphenyl (PCB) exposures have been associated with liver injury in human cohorts, and steatohepatitis with liver necrosis in model systems. MicroRNAs (miRs) maintain cellular homeostasis and may regulate the response to environmental stress. Objectives: We tested the hypothesis that specific miRs are associated with liver disease and PCB exposures in a residential cohort. Methods: Sixty-eight targeted hepatotoxicity miRs were measured in archived serum from 734 PCB-exposed participants in the cross-sectional Anniston Community Health Survey. Necrotic and other liver disease categories were defined by serum keratin 18 (K18) biomarkers. Associations were determined between exposure biomarkers (35 ortho-substituted PCB congeners) and disease biomarkers (highly expressed miRs or previously measured cytokines), and Ingenuity Pathway Analysis was performed. Results: The necrotic liver disease category was associated with four up-regulated miRs (miR-99a-5p, miR-122-5p, miR-192-5p, and miR-320a) and five down-regulated miRs (let-7d-5p, miR-17-5p, miR-24-3p, miR-197-3p, and miR-221-3p). Twenty-two miRs were associated with the other liver disease category or with K18 measurements. Eleven miRs were associated with 24 PCBs, most commonly congeners with anti-estrogenic activities. Most of the exposure-associated miRs were associated with at least one serum hepatocyte death, pro-inflammatory cytokine or insulin resistance bioarker, or with both. Within each biomarker category, associations were strongest for the liver-specific miR-122-5p. Pathways of liver toxicity that were identified included inflammation/hepatitis, hyperplasia/hyperproliferation, cirrhosis, and hepatocellular carcinoma. Tumor protein p53 and tumor necrosis factor were well integrated within the top identified networks. Discussion: These results support the human hepatotoxicity of environmental PCB exposures while elucidating potential modes of PCB action. The MiR-derived liquid liver biopsy represents a promising new technique for environmental hepatology cohort studies. https://doi.org/10.1289/EHP9467

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Section: Discussionsupporting

confidence: 67%

“…2017 ) including in ACHS ( Pittman et al. 2020a , 2020b ) and animal liver disease models ( Jin et al. 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey

Cave

Pinkston

Shesh

et al. 2022

Environ Health Perspect

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“…Chronic or acute inflammation can change collagen density [ 57 ] and PCBs have been linked to changes in collagen mRNA abundance and fiber density [ 58 , 59 , 60 ]. To test whether developmental PCB exposure changes collagen density in young mice, bladders were stained using picrosirius red (PSR) and stained fibers visualized under a Texas red filter ( Figure 5 A,B).…”

Section: Resultsmentioning

confidence: 99%

The Bladder Is a Novel Target of Developmental Polychlorinated Biphenyl Exposure Linked to Increased Inflammatory Cells in the Bladder of Young Mice

Kennedy

Spiegelhoff

Wang

et al. 2021

Toxics

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Bladder inflammation is associated with several lower urinary tract symptoms that greatly reduce quality of life, yet contributing factors are not completely understood. Environmental chemicals are plausible mediators of inflammatory reactions within the bladder. Here, we examine whether developmental exposure to polychlorinated biphenyls (PCBs) leads to changes in immune cells within the bladder of young mice. Female mice were exposed to an environmentally relevant mixture of PCBs through gestation and lactation, and bladders were collected from offspring at postnatal day (P) 28–31. We identify several dose- and sex-dependent PCB effects in the bladder. The lowest concentration of PCB (0.1 mg/kg/d) increased CD45+ hematolymphoid immune cells in both sexes. While PCBs had no effect on CD79b+ B cells or CD3+ T cells, PCBs (0.1 mg/kg/d) did increase F4/80+ macrophages particularly in female bladder. Collagen density was also examined to determine whether inflammatory events coincide with changes in the stromal extracellular matrix. PCBs (0.1 mg/kg/d) decreased collagen density in female bladder compared to control. PCBs also increased the number of cells undergoing cell division predominantly in male bladder. These results implicate perturbations to the immune system in relation to PCB effects on the bladder. Future study to define the underlying mechanisms could help understand how environmental factors can be risk factors for lower urinary tract symptoms.

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“…another receptor, the EGFR, in NASH in vitro (Hardesty et al 2017(Hardesty et al , 2018 and in murine liver (Hardesty et al 2017(Hardesty et al , 2019a(Hardesty et al , 2019bJin et al 2020). Similarly, classes of EGFR inhibitors have been associated with liver injury (Qian et al 2020) in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

“…Aroclor 1260 includes dioxin-like PCBs such as PCB-157 but primarily consists of nondioxin-like PCBs such as PCB-181 and PCB-154 (Wahlang et al 2014a). Both PCB classes have been associated with fatty liver disease in cohort studies (Clair et al 2018) and animal models (Jin et al 2020;Wahlang et al 2019a). In addition to AhR activation, several modes of action affecting hepatic lipid metabolism, cell death/proliferation, inflammation, and fibrosis have been identified for PCBs.…”

Section: Introductionmentioning

confidence: 99%

Effect of Epidermal Growth Factor Treatment and Polychlorinated Biphenyl Exposure in a Dietary-Exposure Mouse Model of Steatohepatitis

Hardesty

Wahlang

Prough

et al. 2021

Environ Health Perspect

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BACKGROUND: Polychlorinated biphenyls (PCBs) are signaling disrupting chemicals that exacerbate nonalcoholic steatohepatitis (NASH) in mice. They are epidermal growth factor receptor (EGFR) inhibitors that enhance hepatic inflammation and fibrosis in mice. OBJECTIVES: This study tested the hypothesis that epidermal growth factor (EGF) administration can attenuate PCB-related NASH by increasing hepatic EGFR signaling in a mouse model. METHODS: C57BL/6 male mice were fed a 42% milk fat diet and exposed to Aroclor 1260 (20 mg=kg) or vehicle for 12 wk. EGF (0:2 lg=g) or vehicle were administered daily for 10 d starting at study week 10. Liver and metabolic phenotyping were performed. The EGF dose was selected based on results of an acute dose-finding study (30 min treatment of EGF at 0.2, 0.02, 0:002 lg=g of via intraperitoneal injection). Hepatic phosphoproteomic analysis was performed using liver tissue from this acute study to understand EGFR's role in liver physiology. RESULTS: Markers of EGFR signaling were higher in EGF-treated mice. EGF + PCB-exposed mice had lower hepatic free fatty acids, inflammation, and fibrosis relative to PCB-only exposed mice. EGF-treated mice had higher plasma lipids, with no improvement in hepatic steatosis, and an association with higher LXR target gene expression and de novo lipogenesis. EGF-treated mice showed more severe hyperglycemia associated with lower adiponectin levels and insulin sensitivity. EGF-treated mice had higher hepatic HNF4a, NRF2, and AhR target gene expression but lower constitutive androstane receptor and farnesoid X receptor target gene expression. The hepatic EGF-sensitive phosphoproteome demonstrated a role for EGFR signaling in liver homeostasis. DISCUSSION: These results validated EGFR inhibition as a causal mode of action for PCB-related hepatic inflammation and fibrosis in a mouse model of NASH. However, observed adverse effects may limit the clinical translation of EGF therapy. More data are required to better understand EGFR's underinvestigated roles in liver and environmental health.

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Dioxin-like and non-dioxin-like PCBs differentially regulate the hepatic proteome and modify diet-induced nonalcoholic fatty liver disease severity

Cited by 29 publications

References 51 publications

Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey

Circulating MicroRNAs, Polychlorinated Biphenyls, and Environmental Liver Disease in the Anniston Community Health Survey

The Bladder Is a Novel Target of Developmental Polychlorinated Biphenyl Exposure Linked to Increased Inflammatory Cells in the Bladder of Young Mice

Effect of Epidermal Growth Factor Treatment and Polychlorinated Biphenyl Exposure in a Dietary-Exposure Mouse Model of Steatohepatitis

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