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Int. J. Mol. Sci. 2016, 17(11), 1830; doi:10.3390/ijms17111830

Programmed Effects in Neurobehavior and Antioxidative Physiology in Zebrafish Embryonically Exposed to Cadmium: Observations and Hypothesized Adverse Outcome Pathway Framework

1
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands
2
Centre for Environmental Quality, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands
*
Author to whom correspondence should be addressed.
Academic Editor: Juliette Legler
Received: 30 August 2016 / Revised: 14 October 2016 / Accepted: 24 October 2016 / Published: 2 November 2016
(This article belongs to the Special Issue Zebrafish: A Model for Toxicological Research)
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Abstract

Non-communicable diseases (NCDs) are a major cause of premature mortality. Recent studies show that predispositions for NCDs may arise from early-life exposure to low concentrations of environmental contaminants. This developmental origins of health and disease (DOHaD) paradigm suggests that programming of an embryo can be disrupted, changing the homeostatic set point of biological functions. Epigenetic alterations are a possible underlying mechanism. Here, we investigated the DOHaD paradigm by exposing zebrafish to subtoxic concentrations of the ubiquitous contaminant cadmium during embryogenesis, followed by growth under normal conditions. Prolonged behavioral responses to physical stress and altered antioxidative physiology were observed approximately ten weeks after termination of embryonal exposure, at concentrations that were 50–3200-fold below the direct embryotoxic concentration, and interpreted as altered developmental programming. Literature was explored for possible mechanistic pathways that link embryonic subtoxic cadmium to the observed apical phenotypes, more specifically, the probability of molecular mechanisms induced by cadmium exposure leading to altered DNA methylation and subsequently to the observed apical phenotypes. This was done using the adverse outcome pathway model framework, and assessing key event relationship plausibility by tailored Bradford-Hill analysis. Thus, cadmium interaction with thiols appeared to be the major contributor to late-life effects. Cadmium-thiol interactions may lead to depletion of the methyl donor S-adenosyl-methionine, resulting in methylome alterations, and may, additionally, result in oxidative stress, which may lead to DNA oxidation, and subsequently altered DNA methyltransferase activity. In this way, DNA methylation may be affected at a critical developmental stage, causing the observed apical phenotypes. View Full-Text
Keywords: developmental origins of health and disease (DOHaD); programming; epigenetics; DNA methylation; cadmium; glutathione; S-adenosyl-methionine; oxidative stress; adverse outcome pathway (AOP); zebrafish developmental origins of health and disease (DOHaD); programming; epigenetics; DNA methylation; cadmium; glutathione; S-adenosyl-methionine; oxidative stress; adverse outcome pathway (AOP); zebrafish
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Ruiter, S.; Sippel, J.; Bouwmeester, M.C.; Lommelaars, T.; Beekhof, P.; Hodemaekers, H.M.; Bakker, F.; van den Brandhof, E.-J.; Pennings, J.L.A.; van der Ven, L.T.M. Programmed Effects in Neurobehavior and Antioxidative Physiology in Zebrafish Embryonically Exposed to Cadmium: Observations and Hypothesized Adverse Outcome Pathway Framework. Int. J. Mol. Sci. 2016, 17, 1830.

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