Binding and activation of AhR/PPARγ lead to lipid metabolism disorders

Ruifang Fan、Shiheng Gui

Polycyclic aromatic hydrocarbons (PAHs) are a class of persistent organic pollutants derived from incomplete combustion processes, widely present in tobacco smoke, vehicle exhaust, industrial emissions, and high-temperature cooking fumes. Humans can be exposed through multiple routes including the respiratory tract, digestive tract, and skin, posing clear risks of teratogenicity, carcinogenicity, and mutagenicity. This Adverse Outcome Pathway (AOP) systematically describes how PAHs, upon exposure, bind to and activate the Aryl Hydrocarbon Receptor (AhR), inducing high mRNA expression of the phase I metabolic enzyme CYP1A1, while simultaneously triggering oxidative stress and elevated levels of pro-inflammatory factors. Through the interactive regulation between AhR and the Peroxisome Proliferator-Activated Receptor gamma (PPARγ) signaling pathways, this leads to an imbalance in the expression profile of lipid metabolism-related genes. Specifically, genes related to lipid synthesis and fatty acid transport (SREBP-1, DGAT1, FAS, CD36) are significantly upregulated, whereas genes related to fatty acid β-oxidation (PPARα, CPT1A) are significantly downregulated. The cascading effects of these molecular events ultimately drive abnormal elevations in hepatic triglyceride (TG) and total cholesterol (TC) levels, leading to lipid metabolism disorders. This AOP constructs a complete causal chain from the molecular initiating event to the adverse outcome, providing a mechanistic foundation and theoretical basis for the quantitative health risk assessment of PAHs and the targeted prevention and control of metabolic diseases.

Polycyclic aromatic hydrocarbons (PAHs) are a class of persistent organic compounds composed of two or more fused benzene rings, ubiquitous in the environment(Biache et al., 2014). They are primarily generated through incomplete combustion processes, such as vehicle exhaust, industrial emissions, tobacco smoke, and cooking fumes (Zhang and Tao, 2009), and are intrinsic to the optical properties and toxicity of combustion particles. Humans are mainly exposed to PAHs through inhalation, dietary intake, and dermal contact (Kim et al., 2013). The health effects of PAHs depend on both the exposure concentration, duration, and route, as well as the relative toxicity of individual PAHs (Mallah et al., 2022). The United States Environmental Protection Agency (USEPA) has listed 16 PAHs as priority control pollutants based on their environmental concentrations and biological toxicity (Mallah et al., 2022). Generally, PAHs are metabolized and detoxified by the liver; therefore, prolonged exposure to PAHs can exacerbate hepatic detoxification overload. As the core organ for lipid metabolism, the liver maintains lipid homeostasis through pathways including fatty acid uptake and export, de novo fatty acid synthesis, and fatty acid β-oxidation (Badmus et al., 2022). Imbalance in this regulatory network leads to intrahepatocellular lipid accumulation, accompanied by abnormal elevations in serum triglycerides (TG) and total cholesterol (TC), and may even induce cardiovascular diseases (Zhao et al., 2023). Therefore, it is necessary to assess the health risks of PAHs to the liver based on the Adverse Outcome Pathway (AOP) framework.

Since PAHs are volatile hydrocarbons produced by incomplete combustion of organic matter, previous research has focused on the damage caused by PAHs to the respiratory system, particularly the lungs. Epidemiological studies have also found that PAH exposure may increase the risk of fatty liver disease by affecting hepatic lipid metabolism (Zhou et al., 2024). Therefore, this Adverse Outcome Pathway (AOP) focuses on the association between PAH exposure and abnormal hepatic lipid metabolism. However, current in vivo and in vitro evidence exploring PAH exposure-induced abnormal hepatic lipid metabolism remains relatively scarce, and the specific mechanisms are still unclear. Moreover, existing studies have mostly focused on the exposure toxicity of individual PAH congeners, which cannot reflect real-world environmental PAH exposure scenarios. Therefore, this AOP uses the concentrations of 16 priority-controlled PAHs detected in the serum of the general population as a reference, setting three exposure concentration gradients to investigate the hepatotoxicity of PAH exposure and the molecular mechanisms by which it affects hepatic lipid metabolism.

This AOP takes AhR activation as the initiating event. PAHs can directly activate AhR, accompanied by enhanced systemic inflammation and oxidative stress, leading to significantly increased expression of PPARγ and genes related to lipid synthesis and fatty acid transport, significantly decreased expression of genes related to fatty acid β-oxidation, abnormal lipid accumulation, elevated hepatic TG and TC, and ultimately inducing abnormal lipid metabolism. Experimental results can be obtained from various models, including experimental animals and mice. Evidence from in vivo animal experiments, in vitro experiments, and computational simulations can confirm the associations between the Molecular Initiating Event (MIE) and Key Event Relationships (KERs).

References

[1]   Badmus, O.O., Hillhouse, S.A., Anderson, C.D., Hinds, T.D., Stec, D.E., 2022. Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways. Clin Sci (Lond) 136, 1347-1366.10.1042/cs20220572

[2]   Biache, C., Mansuy-Huault, L., Faure, P., 2014. Impact of oxidation and biodegradation on the most commonly used polycyclic aromatic hydrocarbon (PAH) diagnostic ratios: Implications for the source identifications. Journal of Hazardous Materials 267, 31-39.https://doi.org/10.1016/j.jhazmat.2013.12.036

[3]   Bu, K.-B., Kim, M., Shin, M.K., Lee, S.-H., Sung, J.-S., 2024. Regulation of Benzo[a]pyrene-Induced Hepatic Lipid Accumulation through CYP1B1-Induced mTOR-Mediated Lipophagy. International Journal of Molecular Sciences 25, 1324https://www.mdpi.com/1422-0067/25/2/1324

[4]   Elbekai, R.H., Korashy, H.M., Wills, K., Gharavi, N., El-Kadi, A.O.S., 2004. Benzo[a]pyrene, 3-methylcholanthrene and beta-naphthoflavone induce oxidative stress in hepatoma hepa 1c1c7 Cells by an AHR-dependent pathway. Free radical research 38, 1191-1200.10.1080/10715760400017319

[5]   Jiang, M., Zhao, H., 2024. Joint association of heavy metals and polycyclic aromatic hydrocarbons exposure with depression in adults. Environmental Research 242, 117807.https://doi.org/10.1016/j.envres.2023.117807

[6]   Kim, K.-H., Jahan, S.A., Kabir, E., Brown, R.J.C., 2013. A review of airborne polycyclic aromatic hydrocarbons (PAHs) and their human health effects. Environment International 60, 71-80.https://doi.org/10.1016/j.envint.2013.07.019

[7]   Li, Y., Liang, N., Tang, T., Zheng, Z., Chen, M., Mo, J., Zhang, N., Liao, S., Lei, Y., Wu, Y., Lan, C., Ding, H., Du, B., Feng, M., Wang, X., Li, X., Huang, Y., Lu, C., Tang, S., Li, X., 2023. Low-dose benzo[a]pyrene exposure induces hepatic lipid deposition through LCMT1/PP2Ac-mediated autophagy inhibition. Food Chem Toxicol 179, 113986.10.1016/j.fct.2023.113986

[8]   Liu, X., Zhang, X., Zhu, J., Zou, W., Liang, L., Zhang, J., Wen, C., Li, Y., Liu, G., Xu, X., 2025. BbF-induced liver injury in Balb/c mice: AhR activation as the conductor of metabolism, oxidative stress, lipid metabolism disorder, and inflammatory response. Free Radical Biology and Medicine 241, 617-630.https://doi.org/10.1016/j.freeradbiomed.2025.10.008

[9]   Ma, J., Zhou, Y., Liu, Y., Xiao, L., Cen, X., Li, W., Guo, Y., Kim, M., Yuan, J., Chen, W., 2019. Association between urinary polycyclic aromatic hydrocarbon metabolites and dyslipidemias in the Chinese general population: A cross-sectional study. Environmental Pollution 245, 89-97.https://doi.org/10.1016/j.envpol.2018.10.134

[10] Mallah, M.A., Changxing, L., Mallah, M.A., Noreen, S., Liu, Y., Saeed, M., Xi, H., Ahmed, B., Feng, F., Mirjat, A.A., Wang, W., Jabar, A., Naveed, M., Li, J.-H., Zhang, Q., 2022. Polycyclic aromatic hydrocarbon and its effects on human health: An overeview. Chemosphere 296, 133948.https://doi.org/10.1016/j.chemosphere.2022.133948

[11] Obanya, H.E., Omoarukhe, A., Amaeze, N.H., Okoroafor, C.U., 2019. Polycyclic Aromatic Hydrocarbons in Ologe Lagoon and Effects of Benzo[b]fluoranthene in African Catfish. J Health Pollut 9, 190605.10.5696/2156-9614-9.22.190605

[12] Pálešová, N., Maitre, L., Stratakis, N., Řiháčková, K., Pindur, A., Kohoutek, J., Šenk, P., Bartošková Polcrová, A., Gregor, P., Vrijheid, M., Čupr, P., 2023. Firefighters and the liver: Exposure to PFAS and PAHs in relation to liver function and serum lipids (CELSPAC-FIREexpo study). International Journal of Hygiene and Environmental Health 252, 114215.https://doi.org/10.1016/j.ijheh.2023.114215

[13] Wang, Y., Wong, L.Y., Meng, L., Pittman, E.N., Trinidad, D.A., Hubbard, K.L., Etheredge, A., Del Valle-Pinero, A.Y., Zamoiski, R., van Bemmel, D.M., Borek, N., Patel, V., Kimmel, H.L., Conway, K.P., Lawrence, C., Edwards, K.C., Hyland, A., Goniewicz, M.L., Hatsukami, D., Hecht, S.S., Calafat, A.M., 2019. Urinary concentrations of monohydroxylated polycyclic aromatic hydrocarbons in adults from the U.S. Population Assessment of Tobacco and Health (PATH) Study Wave 1 (2013-2014). Environ Int 123, 201-208.10.1016/j.envint.2018.11.068

[14] Wu, J., Cui, S., Li, X., Zhang, X., Yang, S., Sun, J., Jiang, X., 2025. Association between polycyclic aromatic hydrocarbons exposure and metabolic dysfunction-associated steatotic liver disease in US adults. Frontiers in Public Health Volume 13 - 2025.10.3389/fpubh.2025.1540357

[15] Zhang, Y., Tao, S., 2009. Global atmospheric emission inventory of polycyclic aromatic hydrocarbons (PAHs) for 2004. Atmospheric Environment 43, 812-819.https://doi.org/10.1016/j.atmosenv.2008.10.050

[16] Zhao, T., Li, X., Qian, H., Miao, X., Zhu, Y., Wang, J., Hui, J., Zhou, L., Ye, L., 2023. PM2.5 induces the abnormal lipid metabolism and leads to atherosclerosis via Notch signaling pathway in rats. Toxicology 485, 153415.https://doi.org/10.1016/j.tox.2022.153415

[17] Zhou, S., Guo, C., Dai, Y., Pan, X., Luo, X., Qin, P., Tan, L., 2024. Association between polycyclic aromatic hydrocarbon exposure and liver function: The mediating roles of inflammation and oxidative stress. Environmental Pollution 342, 123068.https://doi.org/10.1016/j.envpol.2023.123068