Programmed Effects in Neurobehavior and Antioxidative Physiology in Zebrafish Embryonically Exposed to Cadmium: Observations and Hypothesized Adverse Outcome Pathway Framework.
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 donorS-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.
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands.
Sander
S
Ruiter
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands.
Josefine
J
Sippel
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands.
Manon C
MC
Bouwmeester
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands.
Tobias
T
Lommelaars
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands. piet.beekhof@rivm.nl.
Piet
P
Beekhof
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands. hennie.hodemaekers@rivm.nl.
Hennie M
HM
Hodemaekers
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands. frank.bakker@rivm.nl.
Frank
F
Bakker
Centre for Environmental Quality, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands. evert-jan.van.den.brandhof@rivm.nl.
Evert-Jan
EJ
van den Brandhof
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands. jeroen.pennings@rivm.nl.
Jeroen L A
JL
Pennings
Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), Bilthoven 3720BA-1, The Netherlands. leo.van.der.ven@rivm.nl.
Leo T M
LT
van der Ven
D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D002413:Cations, Divalent; D019175:DNA Methylation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000187:drug effects* / Q000235:genetics; D004781:Environmental Exposure / Q000009:adverse effects*; D044127:Epigenesis, Genetic / Q000187:drug effects; D005001:Ethionine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress; D010641:Phenotype; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*
D002413:Cations, Divalent; D014874:Water Pollutants, Chemical; D002104:Cadmium; C012167:S-adenosylethionine; D005978:Glutathione; D000241:Adenosine; D005001:Ethionine
DNA methylation; S-adenosyl-methionine; adverse outcome pathway (AOP); cadmium; developmental origins of health and disease (DOHaD); epigenetics; glutathione; oxidative stress; programming; zebrafish