Assays of Altered Behavioral Development in the Mouse

As noted in Chapter 2, developmental defects include functional as well as structural defects, but functional defects are less well diagnosed and less well understood. Behavioral defects comprise a large category of functional defects. The testing of environmental agents in animals for behavioral defects as an outcome of prenatal exposure is sometimes done, but not routinely. If an agent is suspected to have neurotoxic effects, a developmental neurotoxicity battery is required, and the suspected agents are mostly pesticides, fungicides, and rodenticides (see Makris et al. 1998; EPA 1998f).

In the developmental neurotoxicity tests, pregnant rodents are treated with the agent from day 6 after conception until 10 days after birth to include transfer of the chemical in the milk, and then the pups are tested in various ways from day 4 to day 60. Tests include a functional observational battery (FOB) and specialized behavioral tests.

The FOB includes cage-side observations of arousal; autonomic signs; convulsion; tremors; gait; mobility; posture; rearing; stereotypy; responses to touch, approach, tail pinch, and clicks; foot splaying; grip strength; righting reflex; body temperature; and body weight. The specialized tests include those of motor function, sensory function, and cognitive function. Motor-function tests involve tests of grip strength, swimming endurance, use of the suspension rod and rotorod, discriminative motor function, gait, righting reflex, and various ratings of spasms or tremors. Sensory-function evaluations include discrimination conditioning and reflex modification related to auditory, visual, somatosensory, and olfactory inputs and pain sensitivity. Cognitive-function tests include habituation of the startle reflex and classical conditioning related to the nictitating membrane, flavor aversion, passive avoidance, and olfactory conditioning.

Twelve chemicals, mostly pesticides, were tested by the above protocol, reviewed retrospectively as a group, and various developmental neurotoxic effects were distinguishable (Makris et al. 1998). Concordance was found between structural alterations of the nervous system and behavioral defects. The difficulties of interpreting the developmental causes of behavioral defects were discussed.

In the effort to assess functional defects, the committee favors greater inclusion of behavioral tests with other tests of toxicants. It would be useful to calibrate these tests with mice of known genetic defects affecting aspects of neurodevelopment. Null knockout mutants in homozygous and heterozygous condition could be used. The importance of modifier genes in the genetic background of each transgenic mouse line cannot be underestimated. It would also be useful to calibrate the tests with animals treated with doses of toxicants just below the level giving detectable structural defects in CNS development.



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