Identifying qualitative differences in PPARα signaling networks in human and rat hepatocytes and their significance for next generation chemical risk assessment methods

McMullen, Patrick D.; Bhattacharya, Sudin; Woods, Courtney G.; Pendse, Salil N.; McBride, Mary T.; Soldatow, Valerie Y.; Deisenroth, Chad; LeCluyse, Edward L.; Clewell, Rebecca A.; Andersen, Melvin E.

doi:10.1016/j.tiv.2019.02.017

Cited by 16 publications

(25 citation statements)

References 47 publications

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“…The hepatotoxic effect of phthalates via Pparα signaling networks have been observed in rodents, but not in humans [ 50 , 51 ]. To find out if the observed effects caused by phthalates on liver GJIC or MAPK-Erk 1/2 signaling pathways in oval cells in this study might be connected with Ppars, we evaluated the expression of Ppar isoforms in WB-F344 cells.…”

Section: Resultsmentioning

confidence: 99%

“…This species-specific pattern was attributed to intraspecific differences in the effects of phthalate monoesters on peroxisomal proliferation (thus on the activation of Pparα and its signaling networks). The human relevance of rodent data on phthalate-induced tumor promotion, peroxisome proliferation, and GJIC inhibition is questionable [ 50 , 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

“…For phthalates with medium- or long-side chain length, the transcriptional activation of Pparα, and subsequent downstream events such as peroxisome proliferation, represent essential mechanisms of toxicity in rodents [ 50 , 51 ]. This finding was confirmed for active phthalates from this study in appropriate ToxCast assays ( Table S2 ).…”

Section: Discussionmentioning

confidence: 99%

“…This finding was confirmed for active phthalates from this study in appropriate ToxCast assays ( Table S2 ). Peroxisomal proliferation is a species-specific process where humans are considered to be a largely non-responsive species to this mechanism of action [ 57 , 66 ], due to qualitative differences in the transcriptional networks controlled by Pparα activation [ 50 ]. However, it has also been shown that PPARα activation and peroxisomal proliferation are not essential for liver tumorigenesis induced by phthalates in humans [ 10 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

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Structure-Dependent Effects of Phthalates on Intercellular and Intracellular Communication in Liver Oval Cells

Čtveráčková

Jančula

Raška

et al. 2020

IJMS

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Humans are exposed to phthalates released from plastics, cosmetics, or food on a daily basis. Phthalates have low acute liver toxicity, but their chronic exposures could induce molecular and cellular effects linked to adverse health outcomes, such as liver tumor promotion or chronic liver diseases. The alternation of gap junctional intercellular communication (GJIC) and MAPK-Erk1/2 pathways in liver progenitor or oval cells can disrupt liver tissue homeostatic mechanisms and affect the development and severity of these adverse outcomes. Our study with 20 different phthalates revealed their structurally dependent effects on liver GJIC and MAPK-Erk1/2 signaling in rat liver WB-F344 cell line with characteristics of liver oval cells. The phthalates with a medium-length side chain (3–6 C) were the most potent dysregulators of GJIC and activators of MAPK-Erk1/2. The effects occurred rapidly, suggesting the activation of non-genomic (non-transcriptional) mechanisms directly by the parental compounds. Short-chain phthalates (1–2 C) did not dysregulate GJIC even after longer exposures and did not activate MAPK-Erk1/2. Longer chain (≥7 C) phthalates, such as DEHP or DINP, moderately activated MAPK-Erk1/2, but inhibited GJIC only after prolonged exposures (>12 h), suggesting that GJIC dysregulation occurs via genomic mechanisms, or (bio)transformation. Overall, medium-chain phthalates rapidly affected the key tissue homeostatic mechanisms in the liver oval cell population via non-genomic pathways, which might contribute to the development of chronic liver toxicity and diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Structure-Dependent Effects of Phthalates on Intercellular and Intracellular Communication in Liver Oval Cells

Čtveráčková

Jančula

Raška

et al. 2020

IJMS

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“…Indeed, studies using chimeric mice, harboring murine as well as human hepatocytes in the liver, underscore the more modest PPARa-mediated gene trans-activation in human hepatocytes compared to their murine counterparts (de la Rosa Rodriguez et al 2018). Apart from these quantitative interspecies differences, qualitative differences have also been illustrated recently, after comparisons of PPARa signaling transcriptional networks in primary human hepatocytes and rats (McMullen et al 2020). Such differences could in principle result in differential responses in humans and rats when exposed to PPARa-ligands.…”

Section: Are Ppara-mediated Effects In Rodents Relevant For Human Health?mentioning

confidence: 97%

Systemic PFOS and PFOA exposure and disturbed lipid homeostasis in humans: what do we know and what not?

Fragki

Dirven

Fletcher

et al. 2021

Critical Reviews in Toxicology

102

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Associations between per-and polyfluoroalkyl substances (PFASs) and increased blood lipids have been repeatedly observed in humans, but a causal relation has been debated. Rodent studies show reverse effects, i.e. decreased blood cholesterol and triglycerides, occurring however at PFAS serum levels at least 100-fold higher than those in humans. This paper aims to present the main issues regarding the modulation of lipid homeostasis by the two most common PFASs, PFOS and PFOA, with emphasis on the underlying mechanisms relevant for humans. Overall, the apparent contrast between human and animal data may be an artifact of dose, with different molecular pathways coming into play upon exposure to PFASs at very low versus high levels. Altogether, the interpretation of existing rodent data on PFOS/PFOA-induced lipid perturbations with respect to the human situation is complex. From a mechanistic perspective, research on human liver cells shows that PFOS/PFOA activate the PPARa pathway, whereas studies on the involvement of other nuclear receptors, like PXR, are less conclusive. Other data indicate that suppression of the nuclear receptor HNF4a signaling pathway, as well as perturbations of bile acid metabolism and transport might be important cellular events that require further investigation. Future studies with human-relevant test systems would help to obtain more insight into the mechanistic pathways pertinent for humans. These studies shall be designed with a careful consideration of appropriate dosing and toxicokinetics, so as to enable biologically plausible quantitative extrapolations. Such research will increase the understanding of possible perturbed lipid homeostasis related to PFOS/ PFOA exposure and the potential implications for human health.

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A putative adverse outcome network for neonatal mortality and lower birth weight in rodents: Applicability to per‐ and polyfluoroalkyl substances and relevance to human health

Rogers

Heintz

Thompson

et al. 2023

Birth Defects Research

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Background Some per‐ and poly‐fluoroalkyl substances (PFAS) cause neonatal mortality and lower birth weight in rodents. We constructed an Adverse Outcome Pathway (AOP) network for neonatal mortality and lower birth weight in rodents, comprising three putative AOPs. We then assessed strengths of the evidence for the AOPs and applicability to PFAS. Finally, we considered the relevance of this AOP network to human health. Methods Literature searches targeted PFAS, peroxisome proliferator‐activated receptor (PPAR) agonists, other nuclear receptors, relevant tissues, and developmental targets. We used reviews of established biology and described results of studies with prenatal PFAS exposure that assessed birth weight and neonatal survival. Molecular initiating events (MIEs) and key events (KEs) were proposed and strengths of KE relationships (KERs), applicability to PFAS, and human relevance were assessed. Results Neonatal mortality has been observed in rodents following gestational exposure to most longer chain PFAS studied, often coincident with lower birth weight. In AOP 1, PPARα activation and PPARγ activation or downregulation are MIEs; placental insufficiency, fetal nutrient restriction, neonatal hepatic glycogen deficit, and hypoglycemia are KEs leading to neonatal mortality and lower birth weight. In AOP 2, constitutive androstane receptor (CAR) and pregnane X receptor (PXR) activation upregulates Phase II metabolism, lowering maternal circulating thyroid hormones. In AOP 3, disrupted pulmonary surfactant function and PPARγ downregulation cause neonatal airway collapse and mortality from respiratory failure. Conclusions It is likely that different components of this AOP network will apply to different PFAS, largely determined by which nuclear receptors they activate. The MIEs and KEs in this AOP network can occur in humans, but differences in PPAR structure and function, and the timeline of liver and lung development, suggest that humans may be less susceptible to this AOP network. This putative AOP network elucidates knowledge gaps and research needed to better understand the developmental toxicity of PFAS.

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Identifying qualitative differences in PPARα signaling networks in human and rat hepatocytes and their significance for next generation chemical risk assessment methods

Cited by 16 publications

References 47 publications

Structure-Dependent Effects of Phthalates on Intercellular and Intracellular Communication in Liver Oval Cells

Structure-Dependent Effects of Phthalates on Intercellular and Intracellular Communication in Liver Oval Cells

Systemic PFOS and PFOA exposure and disturbed lipid homeostasis in humans: what do we know and what not?

A putative adverse outcome network for neonatal mortality and lower birth weight in rodents: Applicability to per‐ and polyfluoroalkyl substances and relevance to human health

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