Sex-dependent effects of early-life paracetamol exposure on behavior and monoamines in the rat central nervous system.

The effects of prenatal and early postnatal paracetamol exposure on behavior and neurotransmission in offspring remain poorly understood. The aim of this study was to investigate the consequences of paracetamol administration during fetal and early postnatal development period in rats. A total of 43 offspring prenatally exposed to paracetamol were assigned to experimental groups based on dose (10 or 30 mg/kg b.w.) and stratified by sex. Paracetamol was administered throughout the entire prenatal period and during the first three months of postnatal life, with treatment continuing during the behavioral assessments. These included the Novel Object Recognition test, Staircase test, Hole Board, and Morris Water Maze, which were conducted to evaluate exploratory behavior, motor function, anxiety, and memory. Neurochemical analyses of neurotransmitters level in forebrain regions (prefrontal cortex, hippocampus, hypothalamus, striatum), hindbrain regions (cerebellum, medulla oblongata), and spinal cord were performed using high-performance liquid chromatography (HPLC). The behavioral response to paracetamol differed between sexes. Paracetamol exposure enhanced exploration and produced a moderate anxiolytic effect, which was more pronounced in females and increased dose-dependently. Furthermore, sex-dependent impairments in spatial memory recall were observed in the Water Maze test, particularly in females exposed to paracetamol. Biochemically, paracetamol exposure led to significant changes in dopaminergic and noradrenergic systems between the sexes, particularly in the hypothalamus (e.g., increased noradrenaline and dopamine turnover and their metabolites in males) and medulla oblongata (e.g. decreased noradrenalin turnover in males) indicating a sex-specific neurochemical response. These findings suggest that paracetamol exposure during critical developmental periods may influence cognitive function and neurotransmitter regulation in a sex-dependent manner, with female and male offspring demonstrating different neurobehavioral outcomes.