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Molecular insight on the toxicity of mixtures of Polycyclic Aromatic Hydrocarbons to improve environmental guidelines
Publication . Matos, Beatriz Isabel Manso de; Martins, Marta; Branco, Vasco; Diniz, Mário
Polycyclic aromatic hydrocarbons (PAHs) are persistent environmental pollutants with toxic,
mutagenic, and carcinogenic properties. They are usually present in the environment as a mixture of
carcinogenic and non-carcinogenic compounds, that may induce interaction effects whose mechanisms
remain poorly understood. This thesis investigates PAH toxicity using both in vitro and in vivo
approaches, focusing on key toxicological endpoints, including gene and biochemical responses related
with PAH detoxification mechanisms, oxidative stress and genotoxicity. By examining PAH
interactions within complex mixtures, in different ratios, in cellular models and whole-organism
studies, it provides insights into their mode of action and implications for environmental and human
health risk assessment.
An optimized pancreatin digestion method enabled the isolation of fish hepatocytes for PAH
toxicity assessment. Primary hepatocytes of S. aurata showed that, in general, exposure to mixtures of
phenanthrene (Phe) and benzo[a]pyrene (B[a]P) significantly altered several biochemical responses
with the Phe:B[a]P 2:1 mixture, leading to a 70% increase in DNA damage and enhanced CYP1A
expression (5-fold). In juvenile S. aurata exposed for 42 days, PAHs triggered organ-specific effects,
including oxidative stress in gills and liver, and a 7-fold increase in hepatic GST3 expression after
Phe:B[a]P 2:1 exposure. MDS analysis further identified biological response patterns, providing insight
into how fish cope with PAHs.
To assess interactions between PAHs in mixtures over Aryl Hydrocarbon Receptor (AhR)
activation, in vitro experiments using HepG2 cells were conducted. Results showed that AhR activation,
a major regulation pathway of CYP1A mediated metabolism, varied with mixture composition,
exhibiting antagonistic interactions at lower concentrations, likely due to Phe competition with other
PAH compounds.
Overall, these results highlight the complexity of PAHs mixture toxicity and its context-
dependent effects. While individual PAHs triggered distinct biochemical responses, mixtures altered
toxicity patterns. For instance, the 2:1 Phe:B[a]P mixture showed synergistic effects in fish models but
antagonistic interactions in HepG2 cells. Previous studies in PAHs mixtures toxicity suggested that they
might interact synergistically or antagonistically depending on the toxicity model. Furthermore, our
findings suggest that different ratios and types of PAHs in mixture can activate not only CYP1A1 but
another pathways, highlighting their unpredictable behaviour emphasizing the need for a more
comprehensive risk assessment approach.
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Fundação para a Ciência e a Tecnologia
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2020.09005.BD