Impacts of prenatal resiquimod exposure during late gestation on rat offspring development and behavior

Maternal stress during pregnancy causes changes in circulating glucocorticoids and inflammatory cytokines that can alter fetal development. Prior studies have shown that prenatal dexamethasone impacts fetal brain development, increases anxiety-like behavior, and dysregulates neuroendocrine and autonomic function in adult rat offspring. Resiquimod (RQ) activates toll-like receptor 7, causing immune activation. The current study investigated the impact of RQ-induced maternal immune activation during late gestation on rat offspring development and behavior. Pregnant dams were weighed daily. On <i>gestation day 18</i>, dams were injected with vehicle (phosphate-buffered saline) or RQ (1 mg/kg). Early maternal caregiving behavior was assessed. Offspring were tracked by day of vaginal opening and weekly body weights as maturation milestones. Open field tests were conducted in separate cohorts of male and female offspring before (3-4 wk old) and after (8-10 wk old) the onset of puberty to assess anxiety-like behavior. RQ-injected pregnant dams had attenuated weight gain. However, this exposure did not affect early maternal caregiving behavior or litter metrics. Female offspring of RQ-injected dams experienced a significant delay (∼1 day) in vaginal opening, suggesting delayed pubertal onset. There were no effects of prenatal RQ on offspring weights or open field behaviors before puberty. Adult male and female offspring of RQ-injected dams had attenuated weight gain and increased anxiety-like behavior. The emergence of behavioral changes in adulthood suggests that late-gestation prenatal RQ impacts fetal brain development, as revealed by gonadal hormones and metabolic maturation. These changes highlight puberty as critical for exposing the effects of maternal immune activation.<b>NEW & NOTEWORTHY</b> Maternal stress during pregnancy affects offspring development and health. Data from the project show that maternal immune stress induced by resiquimod during late gestation in rats attenuated maternal weight gain and delayed female pubertal onset, increased anxiety-like behavior after puberty, and lessened weight gain over time in offspring. These results highlight puberty as critical for exposing the effects of prenatal stress and underscore the importance of tracking outcomes across development.