Neurodevelopmental Consequences of Exposure to Paracetamol (Acetaminophen) and Related Drugs : Experimental studies in mice

Abstract: Paracetamol (acetaminophen) is the analgesic pharmaceutical most commonly used during pregnancy and early life. While therapeutic doses of paracetamol are considered harmless during these periods, recent findings in both humans and rodents suggest a link between developmental exposure to paracetamol and behavioral consequences later in life. Paracetamol has a known interaction with the cannabinoid receptor type 1 (CB1R) and the cyclooxygenase (COX) system; both interactions have the potential to induce developmental neurotoxicity (DNT).Central to this thesis is the use of the neonatal mouse, in which the potential DNT of paracetamol was examined after a single day’s exposure during a critical period of brain development called the brain growth spurt (BGS). This thesis investigates whether behavioral consequences can be induced by paracetamol exposure at different timepoints during the BGS and if male and female mice are equally affected. Further, it compares these effects with those of two other pharmaceuticals with analgesic properties: ibuprofen and Δ9-tetrahydrocannabinol (THC). These pharmaceuticals were included because both these drugs have pharmacodynamic similarities with paracetamol; THC, like paracetamol, interacts with the CB1R and ibuprofen, like paracetamol, interacts with the COX system.Paracetamol exposure on postnatal day (PND) 3 and 10 affected adult spontaneous behavior and habituation capability in both male and female mice. These periods are comparable, in terms of brain development, to the beginning of the third trimester and the time around birth, respectively, in humans. Exposure on PND 19, comparable to the development stage of a two-year-old human child, did not induce any adult behavioral changes. PND 10 exposure to THC, but not ibuprofen, affected adult spontaneous behavior and habituation. In addition, simultaneous exposure to a CB1R agonist enhanced the DNT of paracetamol. Interestingly, early-life exposure to both paracetamol and THC decreased transcript levels of genes encoding a receptor involved in neurogenesis and increased markers of oxidative stress. This may indicate that the two substances share common features in their respective mechanisms of DNT.This thesis provides new evidence from a human-relevant experimental design indicating that single-day exposure to paracetamol during the peak of the BGS is sufficient to affect adult spontaneous behavior, memory, learning, and cognitive function in mice. Although the high paracetamol use during pregnancy and early life is based on its advantages over other painkillers, the need for a balanced risk assessment based on the best professional judgement must be prioritized.