Gene expression as a sensitive endpoint to evaluate cell differentiation and maturation of the developing central nervous system in primary cultures of rat cerebellar granule cells (CGCs) exposed to pesticides

Effect of Pesticides on Neuronal and Glial Cell Differentiation and Maturation in Primary Cultures

“…In these studies we have demonstrated that gene expression is a relevant and promising tool to detect compounds with potential to induce DNT. Interestingly we could identify pesticides with different toxic mechanisms and at concentrations lower than those found in human plasma (Hogberg et al, 2009) suggesting that it is both a specific and sensitive endpoint.…”

“…Indeed, our in vitro approach allowed us to determine which cell type (neuronal or glial) and at which stage of development (proliferation, differentiation or maturation) was affected by the exposure to the different pesticides. Furthermore, the induced toxicity was observed at concentrations relevant to environmental exposure as compared to concentrations found in human plasma (Hogberg et al, 2009). This suggests that gene expression could be used as a sensitive endpoint for testing DNT effects of pesticides.…”

Current standing and future prospects for the technologies proposed to transform toxicity testing in the 21st century

“…The determination of adversity remains an issue for the proposed toxicity pathway-based approach, since a perturbation does not automatically lead to adverse health effects. Adversity occurs only if a perturbation is strong enough and the system can no longer Gene expression can rapidly change in response to toxic exposure, and several studies have demonstrated gene expression profiling to be a sensitive endpoint for toxicity (for example, acetaminophen-induced gene expression alterations in rat liver at doses considered non-toxic by conventional clinical endpoints (Heinloth et al, 2004) and chemical-and pesticideinduced gene expression alterations in a primary neuronal cell model at concentrations not effecting cell viability (Hogberg et al, 2009(Hogberg et al, , 2010). Such alterations in gene expression have the potential to provide insight into toxicity pathways.…”

Changes in miRNA Expression Profiling during Neuronal Differentiation and Methyl Mercury-Induced Toxicity in Human in Vitro Models

“…Therefore, to identify the possible DNT biomarkers among deregulated miRNAs, we have firstly studied the changes in miRNA expression during the process of neuronal differentiation in the neuronal cultures derived from H9 or NT-2 cell lines and then compared the miRNA expression profiles in the same cell lines observed after exposure to a non-cytotoxic concentration of methyl mercury chloride (MeHgCl). MeHgCl is a well-known DNT chemical that disturbs the process of neuronal differentiation, synapse formation and causes damage to the process of learning and memory [18][19][20]. The exposure to MeHgCl was performed during the early stages of the neuronal differentiation process (i.e., 1-36 days in vitro (DIV) for NT-2 cells and 1-10 DIV for H9 cells) since previous in vitro studies from our laboratory [19,20] and epidemiological evidence [21][22][23][24] indicate that, compared to the adult CNS, the early stages of brain development are more susceptible to toxicants.…”

“…MeHgCl is a well-known DNT chemical that disturbs the process of neuronal differentiation, synapse formation and causes damage to the process of learning and memory [18][19][20]. The exposure to MeHgCl was performed during the early stages of the neuronal differentiation process (i.e., 1-36 days in vitro (DIV) for NT-2 cells and 1-10 DIV for H9 cells) since previous in vitro studies from our laboratory [19,20] and epidemiological evidence [21][22][23][24] indicate that, compared to the adult CNS, the early stages of brain development are more susceptible to toxicants. Moreover, the early exposure of neural progenitor cells to chemicals seems to be a more vulnerable time period than the later stages of neuronal differentiation [25,26].…”