Chlorpyrifos exposure during a critical neonatal period elicits gender-selective deficits in the development of coordination skills and locomotor activity.

The widespread use of chlorpyrifos has raised concern about the potential consequences of fetal and childhood exposure. Previous studies have shown that apparently subtoxic doses of chlorpyrifos are nevertheless capable of affecting brain development by inhibiting mitosis, eliciting apoptosis, and altering neuronal activity and reactivity. To determine whether these biochemical changes elicit behavioral abnormalities, we evaluated coordination skills and open field behaviors in developing rats. Administration of 1 mg/kg s.c. of chlorpyrifos on postnatal (PN) days 1-4 elicited deficits in reflex righting on PN3-4 and in geotaxic responses on PN5-8, an effect that was specific to females. However, the ontogeny of more complex behaviors indicated a subsequent selectivity toward males. In the periweaning period, open-field locomotor activity and rearing were markedly reduced in male rats that had been exposed to chlorpyrifos on PN1-4, whereas no effect was detected in females. The gender-selective behavioral effects were associated with greater sensitivity of males to inhibition of cholinesterase in the first few hours after chlorpyrifos treatment. In contrast to the effects seen after administration on PN1-4, shifting the period of chlorpyrifos exposure to PN11-14 had a much less notable effect, even when higher doses were used: no decreases in locomotor activity and overall increases in rearing and grooming that were not significantly gender-selective. Administration on PN11-14 did not produce differential effects on cholinesterase in males and females. These studies indicate that chlorpyrifos given during a critical neonatal period, even at levels below the threshold for overt toxicity, can elicit both immediate and delayed gender-selective behavioral abnormalities. The ultimate evaluation of the developmental neurotoxicity of chlorpyrifos will thus require long-term assessments of neurobehavioral consequences of exposure during discrete developmental periods.