Leptin-Mediated Modulation of Steroidogenic Gene Expression in Hypoxic Zebrafish Embryos: Implications for the Disruption of Sex Steroids

Yu, Richard Man Kit; Chu, Daniel Ling Ho; Tan, Tianfeng; Li, Vincent Wai Tsun; Chan, A. H. C.; Giesy, John P.; Cheng, Shuk Han; Wu, Rudolf S.S.; Kong, Richard Yuen Chong

doi:10.1021/es301758c

Cited by 32 publications

(20 citation statements)

References 41 publications

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“…Our study showed the same mortality rate (50%) at 5 mM and 10 mM concentrations, although the concentrations we used were higher than those used by Reinardy et al At this mortality rate, we conducted our study of residual live larvae. Kajimura and Yu used the concentrations of CoCl 2 used in the present study to induce HIF-1α expression [ 58 , 59 ]. Therefore, our strategy for collecting live larvae and measuring the expression of neovascularization-related genes such as vegfaa and vegfr2 in CoCl 2 -treated embryos is reasonable, although the expression level of vegf may come from extra-ocular tissues.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced Retinal Neovascularization in Zebrafish Embryos: A Potential Model of Retinopathy of Prematurity

Chang

Kao

et al. 2015

PLoS ONE

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Retinopathy of prematurity, formerly known as a retrolental fibroplasia, is a leading cause of infantile blindness worldwide. Retinopathy of prematurity is caused by the failure of central retinal vessels to reach the retinal periphery, creating a nonperfused peripheral retina, resulting in retinal hypoxia, neovascularization, vitreous hemorrhage, vitreoretinal fibrosis, and loss of vision. We established a potential retinopathy of prematurity model by using a green fluorescent vascular endothelium zebrafish transgenic line treated with cobalt chloride (a hypoxia-inducing agent), followed by GS4012 (a vascular endothelial growth factor inducer) at 24 hours postfertilization, and observed that the number of vascular branches and sprouts significantly increased in the central retinal vascular trunks 2–4 days after treatment. We created an angiography method by using tetramethylrhodamine dextran, which exhibited severe vascular leakage through the vessel wall into the surrounding retinal tissues. The quantification of mRNA extracted from the heads of the larvae by using real-time quantitative polymerase chain reaction revealed a twofold increase in vegfaa and vegfr2 expression compared with the control group, indicating increased vascular endothelial growth factor signaling in the hypoxic condition. In addition, we demonstrated that the hypoxic insult could be effectively rescued by several antivascular endothelial growth factor agents such as SU5416, bevacizumab, and ranibizumab. In conclusion, we provide a simple, highly reproducible, and clinically relevant retinopathy of prematurity model based on zebrafish embryos; this model may serve as a useful platform for clarifying the mechanisms of human retinopathy of prematurity and its progression.

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Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced Retinal Neovascularization in Zebrafish Embryos: A Potential Model of Retinopathy of Prematurity

Chang

Kao

et al. 2015

PLoS ONE

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“…increases hepatic lep mRNA expression in fish (Chu et al 2010, Yu et al 2012. Given the anorexigenic effects of leptin in rainbow trout (Murashita et al 2008, Aguilar et al 2010, the inverse relationship between hepatic lep-a1 mRNA expression and food intake in C. salmositica-infected fish and the increase in plasma leptin-A1 levels during acute infection suggest that leptin contributes to the regulation of food intake at peak parasitemia.…”

Section: Discussionmentioning

confidence: 99%

Hypoxemia-induced leptin secretion: a mechanism for the control of food intake in diseased fish

MacDonald

Alderman

Krämer

et al. 2014

Journal of Endocrinology

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Leptin is a potent anorexigen, but little is known about the physiological conditions under which this cytokine regulates food intake in fish. In this study, we characterized the relationships between food intake, O 2 -carrying capacity, liver leptin-A1 (lep-a1) gene expression, and plasma leptin-A1 in rainbow trout infected with a pathogenic hemoflagellate, Cryptobia salmositica. As lep gene expression is hypoxia-sensitive and Cryptobia-infected fish are anemic, we hypothesized that Cryptobia-induced anorexia is mediated by leptin. A 14-week time course experiment revealed that Cryptobia-infected fish experience a transient 75% reduction in food intake, a sharp initial drop in hematocrit and hemoglobin levels followed by a partial recovery, a transient 17-fold increase in lep-a1 gene expression, and a sustained increase in plasma leptin-A1 levels. In the hypothalamus, peak anorexia was associated with decreases in mRNA levels of neuropeptide Y (npy) and cocaineand amphetamine-regulated transcript (cart), and increases in agouti-related protein (agrp) and pro-opiomelanocortin A2 (pomc). In contrast, in non-infected fish pair-fed to infected animals, lep-a1 gene expression and plasma levels did not differ from those of non-infected satiated fish. Pair-fed fish were also characterized by increases in hypothalamic npy and agrp, no changes in pomc-a2, and a reduction in cart mRNA expression. Finally, peak infection was characterized by a significant positive correlation between O 2 -carrying capacity and food intake. These findings show that hypoxemia, and not feed restriction, stimulates leptin-A1 secretion in Cryptobia-infected rainbow trout and suggest that leptin contributes to anorexia by inhibiting hypothalamic npy and stimulating pomc-a2.

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“…Numerous in vivo studies have shown that fish reproduction is affected by hypoxia via alteration of the steroidogenesis pathway 7–11. Steroid hormones biosynthesis is a fundamental process for reproduction in vertebrates, and all steroid hormones are derived from cholesterol.…”

Section: Introductionmentioning

confidence: 99%

Overexpression and Knockdown of Hypoxia-Inducible Factor 1 Disrupt the Expression of Steroidogenic Enzyme Genes and Early Embryonic Development in Zebrafish

Tan

et al. 2017

Gene�Regul Syst Bio

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Hypoxia is an important environmental stressor leading to endocrine disruption and reproductive impairment in fish. Although the hypoxia-inducible factor 1 (HIF-1) is known to regulate the transcription of various genes mediating oxygen homeostasis, its role in modulating steroidogenesis-related gene expression remains poorly understood. In this study, the regulatory effect of HIF-1 on the expression of 9 steroidogenic enzyme genes was investigated in zebrafish embryos using a “gain-of-function and loss-of-function” approach. Eight of the genes, CYP11a, CYP11b2, 3β-HSD, HMGCR, CYP17a1, 17β-HSD2, CYP19a, and CYP19b, were found to be differentially upregulated at 24 and 48 hpf following zHIF-1α-ΔODD overexpression (a mutant zebrafish HIF-1α protein with proline-414 and proline-557 deleted). Knockdown of zHIF-1α also affected the expression pattern of the steroidogenic enzyme genes. Overexpression of zHIF-1α and hypoxia exposure resulted in downregulated StAR expression but upregulated CYP11a and 3β-HSD expression in zebrafish embryos. Conversely, the expression patterns of these 3 genes were reversed in embryos in which zHIF-1α was knocked down under normoxia, suggesting that these 3 genes are regulated by HIF-1. Overall, the findings from this study indicate that HIF-1–mediated mechanisms are likely involved in the regulation of specific steroidogenic genes.

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Leptin-Mediated Modulation of Steroidogenic Gene Expression in Hypoxic Zebrafish Embryos: Implications for the Disruption of Sex Steroids

Cited by 32 publications

References 41 publications

Hypoxia-Induced Retinal Neovascularization in Zebrafish Embryos: A Potential Model of Retinopathy of Prematurity

Hypoxia-Induced Retinal Neovascularization in Zebrafish Embryos: A Potential Model of Retinopathy of Prematurity

Hypoxemia-induced leptin secretion: a mechanism for the control of food intake in diseased fish

Overexpression and Knockdown of Hypoxia-Inducible Factor 1 Disrupt the Expression of Steroidogenic Enzyme Genes and Early Embryonic Development in Zebrafish

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