Pharmacokinetic characterisation of a valproate Autism Spectrum Disorder rat model in a context of co-exposure to -Hexabromocyclododecane

Assessing the role of alpha-hexabromocyclododecane alpha-HBCDD as a factor of susceptibility for Autism Spectrum disorders by using valproic acid-exposed rat model (VPA) required characterizing VPA pharmacokinetic in the context of alpha-HBCDD-co-exposure in non-pregnant and pregnant rats. The animals were exposed to alpha-HBCDD by gavage (100 ng/kg/day) for 12 days. This was followed by a single intraperitoneal dose of VPA (500 mg/kg) or a daily oral dose of VPA (500 mg/kg) for 3 days. Exposure to alpha-HBCDD did not affect the pharmacokinetics of VPA in pregnant or non-pregnant rats. Surprisingly, VPA administration altered the pharmacokinetics of alpha-HBCDD. VPA also triggered higher foetal toxicity and lethality with the PO than IP route. alpha-HBCDD did not aggravate the embryotoxicity observed with VPA, regardless of the route of exposure. Based on this evidence, a single administration of 500 mg/kg IP is the most suitable VPA model to investigate alpha-HBCDD co-exposure.