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

Sander Ruiter,Leo Van Der Ven,Piet Beekhof,Manon Bouwmeester,Evert-Jan Van Den Brandhof,Frank Bakker,Tobias Lommelaars,Jeroen Pennings,Hennie Hodemaekers,Josefine Sippel

doi:10.3390/ijms17111830

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.

Highlights

Non-communicable diseases (NCDs) are characterized by long duration and slow progression, resulting in extensive patient suffering and treatment, and are associated with huge medical costs; the World Economic Forum predicted accumulation of NCD related costs of up to $47 trillion worldwide over the period 2011–2030 [1]
Embryotoxicity Embryotoxicity of CdCl2 at 72 hpf was observed with a critical effect dose at the 5% effect level (ClEeDve0l5E()mCoEbfDr3y02o5.t2)o–ox6fi7c3it2μy.M2o–6fi7nCμddMuCpl2ilniacdat tu7ep2elihxcppatfeerwiemxaspeneortbisms,ewernvittehsd, nwwoiitthhhantacohchirnaitgticchaaislnetghffeaescottbhdseeorosvebesadetrsvtuheedbl5esu%thbaleelftfehefacftel ct, preofbfeacbtl,yprdoubeabtloy ddeuleaytoeddedleavyeedlopdmeveenlot.pmEmenbtr.yEomsburryvoivsaulrvwivasalmwaarskmedalrykerdedlyurceedducaetd10a0t 1μ0M0 μ(M40% co(m40p%arceodmtpoa8r0ed%t–o908%0%i–n9l0o%wienrlcoownecrecnotnracteinotnras)t.ions)
The observed effects in both neurobehavioral and antioxidative physiology can be explained by either programming effects or by direct developmental toxicity

Summary

Introduction

Non-communicable diseases (NCDs) are characterized by long duration and slow progression, resulting in extensive patient suffering and treatment, and are associated with huge medical costs; the World Economic Forum predicted accumulation of NCD related costs of up to $47 trillion worldwide over the period 2011–2030 [1]. Suggest that sensitivity to develop NCDs may arise from perinatal conditions, including exposure to environmental chemicals and nutritional imbalances [2]. This paradigm is known as the developmental origins of health and disease (DOHaD) concept. Normal homeostasis in the organism is based on the programming of cell functions during embryogenesis and further early life stages. This dynamical and flexible process allows adaptations of the organism to its future environment. Due to an insult at a critical, sensitive period of early life, leads to changed cell or tissue function, and subsequently to permanent effects on structure, physiology and metabolism (homeostasis) [3]

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Discussion

Conclusion