Maternal exposure to a human based mixture of persistent organic pollutants (POPs) affect gene expression related to brain function in mice offspring hippocampus

Oddvar Myhre,Karin E Zimmer,Alexandra M Hudecova,Kristine E.A Hansen,Abdolrahman Khezri,Hanne F Berntsen,Vidar Berg,Jan L Lyche,Siddhartha Mandal,Nur Duale,Erik Ropstad

doi:10.1016/j.chemosphere.2021.130123

Abstract

Male and female mice pups were exposed to a low and high dose of a human relevant mixture of persistent organic pollutants (POPs) during pregnancy and lactation. Most compounds detected in the dams were found in offspring brains. The mice offspring exhibited changed expression of hippocampal genes involved in cognitive function (Adora2a, Auts2, Crlf1, Chrnb2, Gdnf, Gnal, Kcnh3), neuroinflammation (Cd47, Il1a), circadian rhythm (Per1, Clock), redox signalling (Hmox2) and aryl hydrocarbon receptor activation (Cyp1b1). A few genes were differentially expressed in males versus females. Mostly, similar patterns of gene expression changes were observed between the low and high dose groups. Effects on learning and memory function measured in the Barnes maze (not moving, escape latency) were found in the high dose group when combined with moderate stress exposure (air flow from a fan). Mediation analysis indicated adaptation to the effects of exposure since gene expression compensated for learning disabilities (escape latency, walking distance and time spent not moving in the maze). Additionally, random forest analysis indicated that Kcnh3, Gnal, and Crlf1 were the most important genes for escape latency, while Hip1, Gnal and the low exposure level were the most important explanatory factors for passive behaviour (not moving). Altogether, this study showed transfer of POPs to the offspring brains after maternal exposure, modulating the expression level of genes involved in brain function.

Highlights

Halogenated persistent organic pollutants (POPs) are of concern to human health and wildlife because of their potential toxicity
We explore whether the human based POP mixture affects the expression of hippocampal genes relevant to neuronal function and development in mouse offspring and to which extent such changes are reflected in behaviour and cognition
We considered the first principal component as the mediator in a causal mediation analysis to test whether the effect of exposure on behavioural outcomes were mediated through gene expression (Imai et al, 2010)

Summary

Introduction

Halogenated persistent organic pollutants (POPs) are of concern to human health and wildlife because of their potential toxicity. Many are structurally closely related and share common characteristics, most notably their persistence and ubiquitous distribution in the environment, their potential for bioaccumulation in living organisms and for bio-magnification in the food chain (de Wit, 2002; Carpenter, 2006; Yogui and Sericano, 2009; Butt et al, 2010; Letcher et al, 2010; Salamova and Hites, 2011) This has led to POPs being banned from production via the Stockholm Convention or regulated through REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals), a huge number of chemicals that we are exposed to in our daily life are not even tested for toxic properties. There is a need to focus on the effects of human relevant mixtures

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Conclusion