The Fetal Basis of Adult Disease (FeBAD) hypothesis states that many adult diseases have a fetal origin. According to FeBAD, injury or environmental influences occurring at critical periods of organ development could result in """"""""programmatic"""""""" changes via alterations in gene expression or gene imprinting that may result in functional deficits that become apparent later in life. Virtually little data is available that has examined the impact of environmental exposures during early development on delayed dysfunctions or diseases in the adult brain. To bridge this gap we will examine if any associations exist between the neuro toxicant lead (Pb) and neurodegenerative diseases such as Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder which is characterized by inflammation, cell loss, and excessive deposits of aggregated beta-amyloid peptides (AI3), which are snippets of the amyloid precursor protein (APP). Abeta in both its soluble or aggregated form is known to be lethal to neuronal ceils. The predominately sporadic nature of AD suggests that the environment must play a role in neurodegeneration. Although childhood cognitive deficits produced by neonatal exposure to Pb are known to be permanent, the ability of such exposure to produce delayed neurodegenerative effects that manifest themselves much later in life has not been investigated. A potential mechanism through which Pb could promote neurodegeneration is by interfering with programmatic regulation of the APP gene established during early development. The regulatory region of the APP gene contains elements recognized by the transcription factor Spl, which is essential for the activation of the APP gene. An induction in the activity of Spl would consequentially increase the expression of the APP gene, subsequently increasing the supply of APP substrates which could be processed to generate higher levels of AI3 associated with the neuropathological symptoms of AD. The DNA-binding and transcriptional activity of Spl was found to be induced following neonatal exposure of rats to Pb. Long-term analysis of Spl DNA-binding of the same progeny of rats exposed to Pb during the postnatal stage revealed that Spl activity is maintained at resting levels for more than a year but exhibits a rise in activity 20 months later, when compared to unexposed controls. Furthermore the expression of the APP gene follows a pattern that is similar to that of Spl DNA-binding and Spl mRNA expression, while the levels of a housekeeping gene are not changed. These delayed elevations of both Spl DNA-binding and APP expression are exacerbated when postnatally-exposed animals are challenged by renewed Pb exposure during their old age. Interestingly, none of these effects are observed if exposure occurred only during old age, strongly suggesting that Pb interferes with gene imprinting, which is established during development and which is a critical for the responsiveness of the gene regulatory apparatus in the adult. Consistent with these molecular perturbations, the brains of aging animals chronically exposed to Pb exhibit pathological features of neurodegeneration (microglial activation), which are more prominent and widespread in aging rats exposed to Pb as neonates, indicating that early exposure to Pb has made the animals more susceptible to chemical stressors later in life. Therefore, we hypothesize that developmental exposure to Pb sensitizes the brain to neurodegeneration by elevating Spl activity later in life, which consequentially leads to overproduction of APP and the promotion of neurodegenerative/ inflammatory events.
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