Neurotoxic effects of secalonic acid D in mice during subchronic postnatal exposure

Abstract

To establish a dose-response of neurotoxic effects to daily oral doses of the mycotoxin secalonic acid D (SAD), as well as to correlate the neonatal behavioral responses to smaller doses of SAD with the attendant neurochemical effects in mice, 5 neonates of each sex were placed with each mother and 4 litters were treated orally with 0 to 5 mg/kg of SAD daily from postnatal day (PND) 3 through 35. Body weights, toxic signs, and mortality were used to arrive at a no observable effect level (NOEL). Performance in several behavioral tests and changes in regional norepinephrine and dopamine levels in the brains of neonates treated with SAD at NOEL (1.25 mg/kg/day) or below were evaluated at selected times during SAD exposure. Doses as low as 1.25 mg/kg/day reversibly reduced body weights in both sexes on PND 12 and 13 compared to controls, whereas doses of 2.5 mg/kg/day or greater were lethal (LD 50 of 2.5 mg/kg/day). Toxic signs observable in neonates receiving 2.5 mg/kg/day or more of SAD included fine body tremors, uncoordinated movements, hindlimb weakness, circling, loss of righting reflex, paddling, and terminal coma. Ontogeny of cliff avoidance (PND 5, 7, and 9), hindlimb grip response (PND 14, 17, and 20), olfactory discrimination (PND 8 through 11) and swimming (PND 13 through 21) were significantly delayed by SAD exposure: some even at 0.625 mg/kg/day. Dopamine levels significantly increased on PND 13 and decreased on PND 20 only in the olfactory lobe of SAD-exposed neonates. Norepinephrine levels were unchanged in all the brain regions examined. These results suggest a NOEL of <0.625 mg/kg/day for SAD in mouse neonates and a role for regional alterations in dopamine levels in SAD-induced behavioral deficits.