Early-Life Toxic Insults and Onset of Sporadic Neurodegenerative Diseases—an Overview of Experimental Studies

Abstract

The developmental origin of health and disease hypothesis states that adverse fetal and early childhood exposures can predispose to obesity, cardiovascular, and neurodegenerative diseases (NDDs) in adult life. Early exposure to environmental chemicals interferes with developmental programming and induces subclinical alterations that may hesitate in pathophysiology and behavioral deficits at a later life stage. The mechanisms by which perinatal insults lead to altered programming and to disease later in life are still undefined. The long latency between exposure and onset of disease, the difficulty of reconstructing early exposures, and the wealth of factors which the individual is exposed to during the life course make extremely difficult to prove the developmental origin of NDDs in clinical and epidemiological studies. An overview of animal studies assessing the long-term effects of perinatal exposure to different chemicals (heavy metals and pesticides) supports the link between exposure and hallmarks of neurodegeneration at the adult stage. Furthermore, models of maternal immune activation show that brain inflammation in early life may enhance adult vulnerability to environmental toxins, thus supporting the multiple hit hypothesis for NDDs' etiology. The study of prospective animal cohorts may help to unraveling the complex pathophysiology of sporadic NDDs. In vivo models could be a powerful tool to clarify the mechanisms through which different kinds of insults predispose to cell loss in the adult age, to establish a cause-effect relationship between "omic" signatures and disease/dysfunction later in life, and to identify peripheral biomarkers of exposure, effects, and susceptibility, for translation to prospective epidemiological studies.

Alteration of the brain methylation landscape following postnatal inflammatory injury in rat pups

“…It was shown that microglia of adult rats exposed to E. coli bacteria in the neonatal period had a stronger response to a secondary LPS challenge compared to naïve rats' microglia. [79][80][81] In all, 102 identical DMRs were identified between P4 and P24 for which half preserved their methylation status and the other half shifted to the opposite status. 73 Indeed, the methylation alterations in inflammatory pathways seen in this study could be a key component of a chronic low-level inflammation state, which is being increasingly recognized as central to cognitive decline, neuropsychiatric, and neurodegenerative diseases.…”

Maternal immune activation results in complex microglial transcriptome signature in the adult offspring that is reversed by minocycline treatment

“…Chronic inflammation and, in particular, MIA could be a major factor that contributes to the development of neurodegenerative disorders such as Alzheimer’s disease. 25 , 26 , 27 Lahiri et al 28 proposed a 'Latent Early-life Associated Regulation' model, postulating that latent changes in the expression of specific genes initially primed at the developmental stage of life. However, the involvement of microglia in neuropsychiatric diseases is unclear.…”

Neurodegenerative Susceptibility During Maternal Nutritional Programing: Are Central and Peripheral Innate Immune Training Relevant?

“…Experimental and clinical data support the hypothesis that inflammation itself might be a risk factor for neurodegeneration during AD (Ott et al, 1999;Bertram et al, 2007;Takahashi et al, 2007;Tartaglione et al, 2016). For instance, and Ling Z. D. et al (2004) exposed rats to LPS prenatally and then administered with a subtoxic dose of the dopaminergic (DA) neurotoxin rotenone (1.25 mg/kg per day for 14 days) when 16 months old.…”