Parabens are a group of para-hydroxybenzoic acid (p-HBA) esters widely used in pharmaceutical industries. Their safety is well documented in mammalian models, but little is known about their toxicity in non-mammal species. In addition, chlorinated and brominated parabens resulting from wastewater treatment have been identified in effluents. In the present study, we explored the cytotoxic effects (EC₅₀) of five parabens: methylparaben (MP), ethylparaben (EP), propylparaben (PP), butylparaben (BuP), and benzylparaben (BeP); the primary metabolite, 4-hydroxybenzoic acid (4-HBA), and three of the wastewater chlorinated/brominated byproducts on fish and human cell lines. In general, higher cytotoxicity was observed with increased paraben chain length. The tested compounds induced toxicity in the order of 4-HBA < MP < EP < PP < BuP < BeP. The halogenated byproducts led to higher toxicity with the addition of second chlorine. The longer chain-parabens (BuP and BeP) caused a concentration-dependent decrease in cell viability in fish cell lines. Intriguingly, the main paraben metabolite, 4-HBA, proved to be more toxic to fish hepatocytes than human hepatocytes by 100-fold. Our study demonstrated that the cytotoxicity of some of these compounds appears to be tissue-dependent. These observations provide valuable information for early cellular responses in human and non-mammalian models upon exposure to paraben congeners.

Chemical pollution threatens organismal integrity, affecting growth, reproduction, behavior, and overall fitness, ultimately leading to shifts in biodiversity and the provisioning of ecosystem services. In response to chemical exposure, organisms use specific regions of their genome coding for different defense mechanisms—this collection of genes is termed the “chemical defensome”. Specifically, genes associated with efflux transporters, transcription factors, antioxidant systems, and biotransformation pathways, among others, are expressed to reduce toxicity. These sub-individual processes are, for the most part, widely conserved across taxa and play a critical role in enabling organisms to cope with polluted environments. Additionally, we argue that behavioral responses—particularly spatial avoidance—should be recognized as an individual-level defense mechanism and incorporated into an extended chemical defensome framework. Expanding and reinforcing the concept of the chemical defensome beyond traditional studies at the genome level, as well as developing strategies to synthesize existing data, offers a valuable opportunity to link gene composition to physiological and behavioral responses, thereby addressing key research needs in environmental toxicology. These include: estimating the impact of chemical mixtures across different exposure scenarios, identifying the main drivers of intra- and interspecific sensitivity to pollution, and assessing large-scale ecological processes, such as biodiversity losses, in polluted habitats in a more integrated manner. In ecotoxicology and environmental risk assessment, understanding not only how chemical pollutants exert toxicity but also how organisms counteract these effects is essential. Indeed, investigating chemical-induced shifts in defense mechanisms can improve predictions of adverse outcomes at higher levels of biological organization and can inform more effective chemical management and regulatory strategies.

Divergence in the activity of biotransformation pathways could lead to species sensitivity differences to chemical stress. To explore this hypothesis, we evaluated the biotransformation capacity of five fish species that are representatives of Swiss biodiversity assemblages and that inhabit watercourses surrounded by different land use. We report important interspecific differences regarding the presence and activity of major biotransformation pathways, such as the invasive pumpinkseed ( Lepomis gibbosus ) displaying micropollutant clearance between 3- and 7–fold higher than native species (e.g. Salmo trutta, Squalius cephalus ) collected in the same areas. These differences were exacerbated by urban and agricultural influence, which increased biotransformation potential at the enzyme level by as much as 11-fold and micropollutant clearance by approximately 2-fold compared to biotransformation levels in areas with minimal human influence. In the context of the chemical defensome, we argue that fish with low biotransformation activity carry a greater burden on chemical stress, making them less likely to cope with additional stressors and sustain their population in competition with species with a higher biotransformation capacity.