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Transcriptomic points of departure for 6PPD-Quinone derived from human Caco-2 and HepG2 cells

ABSTRACT: N-(1,3-Dimethyl butyl)-N′-phenyl-phenylenediamine-quinone (6ppd-quinone) is of emerging concern due to its widespread presence and toxicity to aquatic species. The chemical has been detected in human biofluids though little is known about its effects on human tissues. The objective of this study was to increase understanding of 6ppd-quinone’s potential human health effects by deriving transcriptomic points of departure (tPOD) values in two human cell lines using the TPD-seq workflow. An EC20 for cytotoxicity was calculated for Caco-2 (104µg/L) but not for HepG2 cells. Even in the absence of cytotoxicity, tPOD values (20th gene, 10th percentile, mode) were calculated in Caco-2 (6.5-25µg/L) and HepG2 (0.36-35µg/L) cells. These ranges capture values from 16 statistical and bioinformatic tests that examined mapping methods (CLC and Deplexer), algorithms (Limma and DESeq2), and filters (log2FC and BMR). The most common and sensitive genes with calculable benchmark doses (BMDs) in Caco-2 (DPF2, CD44, PGAP1, GDF15, H4C16) and HepG2 (SLC5A3, DKK1, ARG2, PHLDA1, TM4SF1) cells are listed. Pathway BMDs were also calculated for Caco-2 (systemic lupus erythematosus, 9.7-18µg/L; alcoholism, 9.7-20µg/L; viral carcinogenesis, 9.3-18.1µg/L), and HepG2 (metabolic pathways, 50-60µg/L) cells. These findings highlight TPD-seq as an efficient workflow to yield quantitative and mechanistic data relevant for human health risk assessment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302559 | GEO | 2025/08/15

REPOSITORIES: GEO

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Project description:Current methods to support chemical hazard assessment face significant challenges given the rapidly growing number of compounds of emerging concern (CEC) requiring assessment. Standard testing strategies rely upon live animal testing, which are time-consuming, expensive, and ethically questionable. These concerns serve as an impetus to develop new approach methodologies (NAMs) that do not rely on live animal tests. This study explored the application of the molecular benchmark dose (BMD) approach in a 7-day embryo-larval fathead minnow (FHM) assay to derive determine transcriptomic points-of-departure (tPODs) which can be useds to predict apical BMDs of fluoxetine (FLX), a highly prescribed and potent selective serotonin reuptake inhibitor frequently detected in surface waters. Fertilized FHM embryos were exposed to graded concentrations of FLX (confirmed at <LOD, 0.19, 0.74, 3.38, 10.2, 47.5 µg/L) for 32 days. Subsets of fish were subjected to omics and locomotor analyses at 7 days post-fertilization (dpf) and to histological and biometric measurements at 32 dpf. Enrichment analyses of transcriptomics and proteomics data revealed significant perturbations in gene sets associated with serotonergic and axonal functions. BMD analysis resulted in tPOD values of 0.56 µg/L (median of the 20 most sensitive gene-level BMDs), 5.0 µg/L (tenth percentile of all gene-level BMDs), 7.51 µg/L (mode of the first peak of all gene-level BMDs) , and 5.66 µg/L (pathway-level BMD). These tPODs are protective of apical locomotor and reduced weight effects (LOEC of 10.2 µg/L) observed in this study and are well within the range of chronic apical BMDs of FLX reported in the literature. Furthermore, the distribution of gene-level BMDs followed a bimodal pattern, revealing disruption of sensitive neurotoxic pathways at low concentrations and metabolic pathway perturbations at higher concentrations. This is one of the first studies to derive tPODs for FLX using a short-term embryo assay at a life stage not considered to be a live animal under current legislations.

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Transcriptomic points of departure for 6PPD-Quinone derived from human Caco-2 and HepG2 cells

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