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Interleukin-1β-induced inflammation and acetaminophen during infancy: Distinct and interactive effects on
Christopher Harshaw1, Anna G Warner1
1Department of Psychology, University of New Orleans, New Orleans, LA, United States of America.
Insights
Early-life exposure to acetaminophen (APAP) combined with immune activation (interleukin-1β) causes long-term, sex-specific neurodevelopmental changes in mice, impacting social behavior and anxiety.
Area of Science:
- Neuroscience
- Developmental Biology
- Toxicology
Background:
- Epidemiological studies link early-life acetaminophen (APAP) exposure to neurodevelopmental disorders.
- Rodent models show APAP alters brain and behavior, but often without simulating immune activation or fever common in infants.
- Immune activation, frequently co-occurring with APAP exposure, may modify APAP's neurodevelopmental impact.
Purpose of the Study:
- To investigate the combined effects of early-life immune activation (using interleukin-1β, IL-1β) and APAP exposure on neurodevelopment in a rodent model.
- To determine if a 'two-hit' model (IL-1β + APAP) produces distinct or interactive sex-specific long-term behavioral outcomes relevant to neurodevelopmental disorders.
Main Methods:
- Postnatal day 5, 8, and 11 C57BL/6J mouse pups received three administrations of either IL-1β or saline, followed 45 minutes later by either APAP or vehicle.
- Adult mice underwent a battery of tests assessing social-emotional behavior and repetitive behaviors.
- Behavioral outcomes were analyzed for sex-specific effects and interactions between IL-1β and APAP treatments.
Main Results:
- Early-life IL-1β alone caused sex-specific shifts in repetitive behavior and emotional hyperthermia.
- Early-life APAP alone increased social caution in males.
- Combined IL-1β + APAP exposure ('two-hit') resulted in significant sex-specific effects: adult females showed increased anxiety-related thigmotaxis, while adult males exhibited heightened avoidance of unfamiliar social partners.
Conclusions:
- Early-life immune activation and APAP exposure have both distinct and interactive effects on neurodevelopment.
- The 'two-hit' model reveals enduring, sex-specific behavioral alterations relevant to neurodevelopmental disorders.
- These findings underscore the importance of considering co-occurring immune activation when assessing the neurodevelopmental risks of early-life APAP exposure.
Abstract:
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.
