Polyaromatic Hydrocarbon Driven Developmental Toxicity is Dependent on the Aryl Hydrocarbon Receptor: A case study with Benzo(a)Pyrene

Petroleum substances are complex mixtures of hydrocarbons with vast structural diversity, posing significant challenges for toxicity assessment. To evaluate their safety under the REACH legislation, in vivo toxicological tests, particularly prenatal developmental toxicity assessments, are mandated. However, these tests are resource-intensive. Given the substantial number of compositionally and biologically similar petroleum substances, a more efficient approach is essential to meet regulatory requirements while supporting the industry's competitiveness and innovation. Petroleum substance toxicity is frequently attributed to the presence of polycyclic aromatic hydrocarbons (PAHs). PAHs' underlying mechanism of action involves the aryl hydrocarbon receptor (AhR) activation as a molecular initiating event followed by cytochrome P450 induction, which in turn catalyzes the transformation of PAH to epoxide-containing reactive metabolites. To evaluate the dependence of this adverse outcome pathway, an AhR-knockout (AhR-KO) rat model was orally exposed to Benzo[a]Pyrene (BaP), a prototypical PAH. This study offers valuable insights into the AhR-dependent and -independent maternal toxicity and fetal developmental effects of BaP exposure, employing transcriptomic assessments to enhance the comprehension of the underlying mechanisms across four distinct tissues: blood, kidney, liver, and thymus. This research contributes toward a more efficient approach to assessing the safety of diverse petroleum substances, in alignment with regulatory objectives and the interests of the industry.