Interleukin-1β-induced Inflammation and Acetaminophen During Infancy: Distinct and Interactive Effects on Social-emotional and Repetitive Behavior in C57BL/6J Mice

Acetaminophen (APAP) exposure early in life has been associated with increased risk of neurodevelopmental disorders in epidemiological studies. In rodent models, early-life APAP has similarly been shown to produce long-term changes in brain and behavior, including altered activity levels and social behavior. Most rodent studies to date have, nevertheless, attempted to model early-life APAP without considering that most APAP exposure occurs in a context of immune activation and/or fever. To mimic the repeated infections common during infancy, we employed the cytokine interleukin-1β (IL-1β) to induce immune activation three times during early postnatal development (i.e., day 5, 8, and 11). On these days, C57BL/6J pups were administered either IL-1β (0.2 μg/kg) or saline vehicle followed, after 45 min, by either APAP (103.9 mg/kg) or vehicle. Mice were subsequently administered a battery of tests of social-emotional and repetitive behavior. A number of distinct long-term effects of IL-1β and APAP treatments were found, including sex-specific shifts in repetitive behavior and emotional hyperthermia following early-life IL-1β and increased social caution in males following early-life APAP. We also observed significant interaction between IL-1β and APAP: as adults, 'two-hit' IL-1β + APAP females displayed greater anxiety-related thigmotaxis across a number of tests, including an open field. 'Two hit' males, in turn, showed elevated levels of avoidance of an unfamiliar social partner during a social interaction test. Our results highlight that IL-1β-induced inflammation and APAP have both distinct effects and significant interactions during early life, with enduring sex-specific effects on phenotypes relevant to neurodevelopmental disorders.