Brain developmental neurotoxicity

Repeat-dose neurotoxicity studies may identify behavioral effects or impaired nerve functions that can interfere with mating or maternal care. Developmental neurotoxicity studies have been conducted for specific pesticide classes, following requirements of US-EPA. If such a study is available it can be examined not only for the study-specific endpoints on the developing brain but also compared to the prenatal toxicity study and the two-generation smdy with respect to general endpoints of pre- and postnatal development, respectively. 

Slotkin, T.A., Levin, E.D. and Seidler, F.J. (2006) Comparative developmental neurotoxicity of organophosphate insecticides effects on brain development are separable from systemic toxicity. Environ. Health Perspect., 114 (5), 746-751. 

The exposure period in the developmental neurotoxicity study is during gestation and lactation, but not during the juvenile period until sexual maturation. The brain still undergoes development during the juvenile period, but effects induced during this period are... 

Most developmental neurotoxicity studies have focused on general impairment of behaviour, but some studies have also found evidence for effects on sexual dimorphic behaviour. Hormones play a central role in central nervous system development, including the sexual differentiation of the brain. Studies on hormones and various endocrine disrupting chemicals (particularly those with estrogenic or antiandrogenic effects) have shown that the developing brain may be susceptible to disturbances in sexual behaviour. Therefore, effects on one sex but not the other should not be dismissed, but must be evaluated in the context of effects on sexual differentiation of the brain. 

The toxicity to the nervous system depends on the delivered dose and exposiue duration. In the case of pregnant women, pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern PAH disposition within the mother and the nervous system of children. Moreover, unique physiological features, such as the presence of a placental barrier and the gradual development of the blood-brain barrier influence PAH disposition and thus modulate developmental neurotoxicity. Because CNS effects are dependent upon windows of susceptibility when the lowest dose and shortest duration of exposure to environmental PAHs will have the greatest negative impact on brain development, a susceptibility exposure paradigm has proven to be the most reliable model in which to study developmental insult. The intent of this chapter was to review... 

Slotkin, T.A., Seidler, F.J., Fumagalli, F. (2008). Targeting of neurotiophic factors, their receptors, and signaling pathways in the developmental neurotoxicity of organophosphates in vivo and in vitro. Brain. Res. Bull. 76 424—38. 

The definition of neurotoxicity also indicates a potential difference between the developing and the mature nervous system, to underscore the fact that developmental neurotoxicity is an important aspect of neurotoxicology. Most known human neurotoxicants are indeed developmental neurotoxicants.4 In most, but not all cases, the developing nervous system is more sensitive to adverse effects than the adult nervous system, as indicated, for example, by the most deleterious effects of ethanol, methylmercury, or lead when exposure occurs in utero or during childhood. Furthermore, the blood-brain barrier (BBB), which protects the mature nervous system from the entry of a number of substances, appears to be poorly developed at birth and during the first few years of life.6... 

Dam K, Seidler FJ, Slotkin TA. Transcriptional biomarkers distinguish between vulnerable periods for developmental neurotoxicity of chlorpyrifos Implications for toxicogenomics. Brain Res Bull 2003 59(4) 261-5. 

Garcia, S.J., F.J. Seidler, T.L. Crumpton and T.A. Slotkin. Does the developmental neurotoxicity of chlorpyrifos involve glial targets Macromolecule synthesis, adenylyl cyclase signaling, nuclear transcription factors, and formation of reactive oxygen in C6 glioma cells. Brain Res. 891 54-68, 2001. 

Crumpton. T. L, Seidlcr, F. J., and Slotkin, T. A. (2000). Developmental neurotoxicity of chlorpyrifos in vivo and in vitro Effects on nuclear transcription factors involved in cell replication and differentiation. Brain fie.s, 857, 87-98,... 

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