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ToxSci Advance Access published online on October 6, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp243
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

P19 neuronal differentiation and retinoic acid metabolism as criteria to investigate atrazine, nitrite and nitrate developmental toxicity

Mathieu Solari*, Joanne Paquin{dagger}, Philippe Ducharme{dagger} and Monique Boily*,§

* Département des Sciences Biologiques, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montréal, Québec, H3C 3P8, Canada {dagger} Département de Chimie, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montréal, Québec, H3C 3P8, Canada

§ Corresponding author: Dr Monique Boily, PhD, Département des Sciences Biologiques, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montréal, Québec, H3C 3P8, Canada, Phone : 514-987-3000 (5605), Fax : 514-987-4647, Email : boily.monique{at}uqam.ca

Received July 24, 2009; revision received September 14, 2009; accepted September 16, 2009


  Abstract

Atrazine and nitrogenous fertilizers are agrochemical contaminants frequently detected in water systems in North America. Several studies reported their ability to affect amphibian and mammalian development. Retinoids, supplied in the diet or synthesized by cells, are essential to embryogenesis. Disturbance of their homeostasis may lead to teratogenic effects. Retinoic acid (RA) is a major retinoid regulator of cell proliferation and differentiation. Previous studies reported alterations of retinoid stores in bullfrogs of Yamaska River subwatersheds (Québec, Canada), a region of intensive agricultural activities associated with atrazine, nitrate and nitrite contaminants. These contaminants could affect RA metabolism and RA-mediated processes. Mouse P19 embryonic stem cells, which can differentiate to neurons in response to RA, were used to test this hypothesis. Cells were cultured in the absence or presence of contaminants during neuroinduction with RA, and assayed by flow cytometry for expression of SSEA1 (embryonic marker) and βIII-tubulin (neuronal marker). Cell cultures were also analysed for RA metabolism by HPLC. Downregulation of SSEA1 paralleled βIII-tubulin upregulation in a RA concentration-dependent manner. Atrazine, nitrate and nitrite did not affect differentiation at environmentally-encountered micromolar concentrations. However, low molar nitrite prevented RA-induced SSEA1 downregulation, and decreased βIII-tubulin appearance. Decreased cell viability/proliferation accompanied these differentiation effects. P19 cells metabolized RA to polar retinoids. RA metabolism was not affected at any concentration of atrazine, nitrate or nitrite. Environmentally-relevant levels of these contaminants thus had no gross effect on neurodifferentiation and RA catabolism of embryonic stem cells. P19 cell-based bioassays may provide valuable tools in monitoring developmental toxicity.

Key Words: agrochemical contaminants; retinoids; bioassay; flow cytometry; HPLC.

Email: mathieu35{at}hotmail.com, Email: paquin.joanne{at}uqam.ca, Email: ducharme.philippe{at}courrier.uqam.ca


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