The Role of Estrogen and Thyroid Hormones in Zebrafish Visual System Function

Abstract

Visual system development is a highly complex process involving coordination of environmental cues, cell pathways, and integration of functional circuits. Consequently, a change to any step, due to a mutation or chemical exposure, can lead to deleterious consequences. One class of chemicals known to have both overt and subtle effects on the visual system is endocrine disrupting compounds (EDCs). EDCs are environmental contaminants which alter hormonal signaling by either preventing compound synthesis or binding to postsynaptic receptors. Interestingly, recent work has identified neuronal and sensory systems, particularly vision, as targets for EDCs. In particular, estrogenic and thyroidogenic signaling have been identified as critical modulators of proper visual system development and function. Here, we summarize and review this work, from our lab and others, focusing on behavioral, physiological, and molecular data collected in zebrafish. We also discuss different exposure regimes used, including long-lasting effects of developmental exposure. Overall, zebrafish are a model of choice to examine the impact of EDCs and other compounds targeting estrogen and thyroid signaling and the consequences of exposure in visual system development and function.

Keywords: Danio rerio (zebrafish); T3; T4; development; estradiol; retina.

FIGURE 1

Developmental timeline. Sequence of events in zebrafish eye and retinal development (black) beginning at fertilization (0 h postfertilization—hpf) and continuing until 7 days (days) postfertilization. During this time, maternally derived transcripts for estrogen receptors (ER—red) and maternally derived thyroid hormones (TH—blue) are present in yolk. At 24 hpf, when neural retina is developing, expression of ER and aromatase (AroB) are present in retina, and expression of the genes for both thyroid receptors (thraa, thrb) begins. Expression of G-protein coupled ER (gper) begins ∼36 hpf; at 48 hpf thrb is expressed in retina. At hatching (72 hpf), there is endogenous production of both TH and estrogen. The overlap and concurrent development of thyroid, estrogen, and retinal development, suggests these hormones are important for proper retinal/visual system development. GC = ganglion cell, AC = amacrine cell, HC = horizontal cell, R = red cone, B = blue cone, BC = bipolar cell, PR = photoreceptor, OKR = optokinetic response, OMR = optomotor response.

FIGURE 2

Independent and interactive pathway components. Venn Diagram showing individual and interactive aspects of estrogen and thyroid signaling. Shared characteristics between both signaling pathways include the involvement of the hypothalamus-pituitary axis, intracellular receptors, some intracellular signaling molecules, and effects on gene transcription. Both E2 and TH are required for neurogenesis, including development of the visual system. Photoreceptors are the retinal cell type most sensitive, as TH is required for correct development and organization of cones. E2 is neuroprotective, preventing cell loss due to light-damage or disease.