Polyaromatic hydrocarbon driven developmental toxicity is dependent on the aryl hydrocarbon receptor: A case study with benzo(a)pyrene

Regulatory Toxicology and Pharmacology, vol. 172, pp. 106219

Abstract

Petroleum substances (PS) are complex hydrocarbon substances that present major challenges for toxicity assessment under REACH regulations. In vivo prenatal developmental toxicity (PNDT) testing is often mandated but remains resource-intensive, underscoring the need for New Approach Methodologies (NAMs) such as mechanistic read-across and in vitro models. The toxicity of PS is largely attributed to their polycyclic aromatic hydrocarbon (PAH) content, known to act through activation of the aryl hydrocarbon receptor (AhR). AhR activation induces cytochrome P450 enzymes that metabolize PAHs into reactive intermediates capable of eliciting developmental toxicity. To investigate the role of AhR in this adverse outcome pathway, we orally exposed wild-type and AhR-knockout (AhR-KO) Sprague-Dawley rats to Benzo[a]Pyrene (BaP), a prototypical PAH. BaP exposure caused marked embryonic resorptions and delayed ossification in wild-type rats, effects absent in AhR-KO animals, demonstrating that BaP-induced developmental toxicity is predominantly AhR-dependent. Transcriptomic profiling of blood, kidney, liver, and thymus revealed distinct AhR-mediated expression of Cyp1a1/1a2 in wild-type rats, whereas AhR-KO rats upregulated alternative detoxification pathways (Cyp2b2, Cyp3a23-3a1). These findings confirm AhR as the molecular initiating event in PAH-driven developmental toxicity and support the application of mechanistic data to enable efficient, less animal-intensive hazard assessment of petroleum substances.

Authors 6

1. Lize Deferme

   Concawe

   Affiliation as printed

   Member of Concawe, Brussels, Belgium; ExxonMobil Petroleum and Chemical BV, Machelen, Belgium

2. Neslihan Aygün Kocabaş

   Concawe

   Affiliation as printed

   Member of Concawe, Brussels, Belgium; TotalEnergies Refining & Chemicals, Seneffe, Belgium

3. Colin M. North
   Affiliation as printed

   ExxonMobil Biomedical Sciences Inc., Annadale, NJ, USA

4. Francois van Otterdijk Aachen Charles River Laboratories

   Charles River Laboratories (Netherlands)

   Affiliation as printed

   Charles River Laboratories, 's-Hertogenbosch, the Netherlands

5. George W. Hinkal

   Concawe

   Affiliation as printed

   Concawe, Brussels, Belgium. Electronic address: health@concawe.eu

6. Florian Caiment

   Maastricht University

   Affiliation as printed

   Department of Translational Genomics, GROW Research Institute for Oncology and Developmental Biology, Maastricht University, Maastricht, 6229 ER, the Netherlands