Abstract
Endocrine disrupting chemicals (EDCs) are environmental pollutants that mimic hormones and/or disrupt their function. Estrogenic EDCs (eEDCs) interfere with endogenous estrogen signalling pathway(s) and laboratory animal and human epidemiological studies have provided evidence for a causal link between exposure to them during embryonic/early life and neurological impairments. However, our understanding of the molecular and cellular mechanism(s) underlying eEDCs exposure effects on brain development, tissue architecture and function and behaviour are limited. Transgenic (TG) zebrafish models offer new approach methodologies (NAMs) to help identify the modes of action (MoAs) of EDCs and their associated impacts on tissue development and function. Estrogen biosensor TG zebrafish models have been applied to study eEDC interactions and resulting transcriptional activation (via a fluorescent reporter expression) across the entire body of the developing zebrafish embryo, including in real time. These estrogen biosensor TG zebrafish models are starting to deepen our understanding of the spatiotemporal actions of eEDCs and their resulting impacts on neurological development, brain function and behaviour. In this review, we first investigate the links between early life exposure to eEDCs and neurodevelopmental alterations in model organisms (rodents and zebrafish) and humans. We then present examples of the application of estrogen biosensor and other TG zebrafish models for elucidating the mechanism(s) underlying neurodevelopmental toxicities of eEDCs. In particular we illustrate the utility of combining estrogen biosensor zebrafish models with other TG zebrafish models for understanding the effects of eEDCs on the brain, spanning cellular processes, brain circuitry, neurophysiology and behaviour. Finally, we discuss the future prospects of TG zebrafish models as experimental models for studying more complex scenarios for exposure to contaminant mixtures on neurological development and function.
Highlights
ENVIRONMENTAL ESTROGENIC EDCSEstrogens are steroid hormones that play important roles in the development and physiological function of reproductive organs and a very wide range of other organs (Simerly et al, 1997; Wang et al, 2001; Wang et al, 2003; McCarthy, 2008; Bondesson et al, 2015)
Estrogens can bind to membrane-bound estrogen receptors, called G-protein coupled estrogen receptors (GPERs); activating the non-canonical estrogen signalling for intracellular calcium mobilisation, cAMP production and MAP kinase-mediated phosphorylation cascades (Périan and Vanacker, 2020)
Using tg (ERE:Gal4ff;UAS:GFP) and tg (ERE:mCherry;cyp19a1b: GFP) zebrafish embryos, we have shown that the olfactory bulb (OB) is one of the earliest target tissue for estrogen in the zebrafish embryo, with estrogen-mediated transcriptional activation occurring in a small number of cells in this brain tissue from early neurogenesis stage (i.e., 27 hpf) (Takesono, Takesono et al, 2022)
Summary
Estrogens are steroid hormones that play important roles in the development and physiological function of reproductive organs and a very wide range of other organs (Simerly et al, 1997; Wang et al, 2001; Wang et al, 2003; McCarthy, 2008; Bondesson et al, 2015). Given that estrogen signalling pathways are critically involved in the development of a wide variety of tissue and organ processes, including in the brain, in animals and humans (McCarthy, 2008; Bondesson et al, 2015), eEDC exposure during embryonic/early life may result in a wide range of developmental alterations, physiological dysfunctions and/or diseases and behavioural impairments in later life (Bergman et al, 2012; DiamantiKandarakis et al, 2009; Gore et al, 2015; Gore and Crews, 2009; Kuiper et al, 1997). A major purpose of this review is to illustrate the utility of zebrafish TG models as a versatile and effective NAM for testing developmental neurotoxicity of eEDC and for providing new insights into the effects of eEDCs on brain development
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