Prenatal Exposure to Environmental Chemicals as a Test System for Neurotoxicology

Abstract

The study of the effects of low level exposure to environmental neurotoxic agents has been one of the most important aspects of environmental research. This research has indicated that the developing organism may be more susceptible to many of these chemicals than the adult. This susceptibility varies during different stages of development, but severe behavioral, neurochemical, and neurophysiological abnormalities can be measured in adults that were exposed during neuronal development. One of the problems of toxicity testing is to correlate these behavioral alterations with the anatomical changes induced by the neonatal exposure. In our laboratory, we have evaluated the effects of 0, 5, and 8 mg/kg of methyl mercury (MeHg) administered to rats on either day 7 or day 14 of pregnancy, on the subsequent motor development, learning capability, and electrophysiological responsiveness of the visual system of the offspring. Pregnant Long-Evans rats were intubated with 5 or 8 mg/kg of MeHg either as chloride or carbonate. Control females received either corn oil or sodium carbonate alone. Mothers were weighed weekly during pregnancy. On the day of birth, the litters were reduced to 8 pups each and weighed. Weights were also determined weekly thereafter. When MeHg was administered on day 7, there was no birth weight reduction or subsequent growth retardation. At 8 mg/kg however, 40 percent of the litters were resorbed. Brain levels of mercury in the 1-day-old pups were 1.0 and 1.6 μJg/g for the 5 and 8 mg/kg groups. Pups whose mothers received 8 mg/kg were significantly more active during a 1-hour activity test on day 7 than controls, but by day 21 no significant differences in activity existed between experimental and controls groups. The adult male offspring were tested in a two-way avoidance shuttle-box to a criterion of 10 consecutive avoidances. Following this training, the animals were extinguished and then retrained to the same criterion. Animals previously exposed to 8 mg/kg took significantly more trials to learn the task than controls. The 60-day-old female offsprings (5 mg/kg group) had stainless steel screws chronically anchored to the skull over the visual cortex for the recording of visual evoked potentials (VIP). There was a 40 percent increase in the amplitude of the earliest negative component of the VIP in the mercury-exposed animals when compared to controls.

Treatment of animals on day 14 of gestation with 8 mg/kg resulted in significant reductions in birth weight and reduced weight at 9 weeks of age. Some 80 percent of these animals failed to reach criterion on the avoidance task after 400 trials. The results indicate that prenatal exposure to methyl mercury at doses that have no overt toxic effects on the mother can have permanent neural and behavioral consequences in the offspring and that the type of deficit may depend on the age of exposure as well as the dose.

These data are discussed with the known pathological effects of methyl mercury as well as a variety of agents known to affect cell proliferation during embryonic development in order to determine whether correlative measures will lead to predictive assays.