Age-related sensitivity of the nervous system to neurotoxic insults.

Complex genomic activity and environmental factors regulate neuronal plasticity, which operates during pre- and postnatal development, can be reactivated after injury, and is impaired during aging. In these contexts, the effects of chemicals are often unpredictable because the developing and aging nervous system may or may not be equally susceptible as that of the adult. Thus, the developing central nervous system may be more susceptible to the acute toxicity of certain organophosphorus esters, whereas the developing peripheral nervous system is resistant to organophosphate-induced delayed polyneuropathy. Reasons for age-related susceptibility are manifold, including both differences in toxicokinetics and toxicodynamics and in intrinsic susceptibility of the nervous system, which is related to given physiological conditions. Therefore, the identification of genetic and environmental factors regulating neuronal plasticity becomes critical to the understanding of age-related sensitivity to chemicals. The example of age-related sensitivity to organophosphate-induced delayed polyneuropathy is illustrated together with that of the promotion of axonopathies by certain esterase inhibitors, which also seem modulated according to age. The identification of the molecular targets of both organophosphate neuropathy and promotion of neuropathy might allow the understanding of processes involved in the expression of peripheral neurotoxicities according to age.