In vitro prenatal developmental toxicity induced by some petroleum substances is mediated by their 3- to 7-ring PAH constituent with a potential role for the aryl hydrocarbon receptor (AhR)

• Published in: Toxicology letters Vol. 315; pp. 64 - 76
• Main Authors: Kamelia, Lenny, de Haan, Laura, Ketelslegers, Hans B., Rietjens, Ivonne. M.C.M., Boogaard, Peter J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.10.2019
• Subjects: Aryl hydrocarbon receptor; Embryonic stem cell test; Petroleum substances; Polycyclic aromatic hydrocarbons; Prenatal developmental toxicity; UVCBs; Aryl hydrocarbon receptor; Polycyclic aromatic hydrocarbons; UVCBs; Petroleum substances; Prenatal developmental toxicity; Embryonic stem cell test
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2019.08.001

•This study evaluates the in vitro developmental toxicity potency of a series of petroleum substances extracts using alternative testing strategies.•In vitro PDT potency of petroleum substances extracts, as quantified in the EST, is mediated by their 3-7 ring PAHs with a potential role for the AhR.•A good correlation exists when comparing the in-vitro with the in-vivo PDT potencies of the petroleum substances extracts under study.•Our findings support the hypothesis that 3- to 7- ring PAHs are the primary inducers of the PDT in some petroleum substances.•The EST could also be applied for in vitro PDT testing of other UVCBs. To test the hypothesis that 3–7 ring polycyclic aromatic hydrocarbons (PAHs) are responsible for the prenatal developmental toxicity (PDT) as observed with some petroleum substances (PS), the present study evaluates the PDT potency of DMSO-extracts of 7 heavy fuel oils (HFO), varying in their PAH content, and 1 highly refined base oil (HRBO), containing no aromatics, in the embryonic stem cell test (EST). All DMSO-extracts of HFO inhibit ES-D3 cell differentiation in a concentration-dependent manner and their potency is proportional to the amount of 3–7 ring PAHs they contain. All DMSO-extracts of HFOs also show aryl hydrocarbon receptor (AhR)-mediated activities, as tested in the AhR-CALUX assay. Contrarily, the HRBO-extract tested negative in both assays. Co-exposure of ES-D3 cells with selected DMSO-extracts of PS and the AhR-antagonist trimethoxyflavone, successfully counteracted the PS-induced inhibition of ES-D3 cell differentiation, confirming the role of the AhR in mediating the observed PDT of PS extracts in the EST. A good correlation exists when comparing the in-vitro with the in-vivo PDT potencies of the PS under study. Altogether, our findings corroborate the hypothesis that PS-induced PDT is caused by 3–7 ring PAHs present in these substances and that the observed PDT is partially AhR-mediated.