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17beta-Estradiol inhibits chondrogenesis in the skull development of zebrafish embryos
Shigeko Fushimi1, Naoyuki Wada, Tsutomu Nohno
1Department of Public Health, Kawasaki Medical School, 577 Matsushima, Kurashiki 701-0192, Japan. fushimi@med.kawasaki-m.ac.jp
Abstract:
17beta-Estradiol (E2) plays important roles in the development and differentiation of the gonad and central nervous systems, but little is known regarding the effects of exogenous E2 on chondrogenesis in skeletal development. In the present study, we found that treatment with E2 1-5 days post-fertilization (dpf) at concentrations above 1.5x10(-5)M increased the mortality rate in zebrafish embryos. Morphological analysis showed that treatment with E2 1-5dpf caused abnormal cartilage formation in a dose-dependent manner at concentrations above 5x10(-6)M. E2 1-5dpf at 1.5x10(-5)M caused defects of the ethmoid plate, parallel cleft of the trabecular cartilage, and hypoplasia of Meckel's cartilage and the ceratohyal cartilage. The sensitivity of embryos to E2 depended on the developmental stage. In early chondrogenesis (1-2dpf), the embryos were highly sensitive to E2, leading to hypoplasia of the cartilage. In situ hybridization studies showed that expression levels of patched1 (ptc1) and patched2 (ptc2) receptor mRNAs were markedly decreased by exposure to 2x10(-5)M E2 1-2dpf. However, the expression levels of sonic hedgehog (shh) and tiggywinkle hedgehog (twhh) mRNAs were constant in the E2-treated embryos. In addition, the estrogen receptor antagonist ICI 182,780 did not completely abolish the effects of E2, suggesting that E2 may not inhibit chondrogenesis through its nuclear estrogen receptor. These results suggest that exposure to exogenous E2 possibly inhibits chondrogenesis via inhibition of the hedgehog (Hh) signal transduction system.
Insights
Exogenous 17beta-estradiol (E2) exposure during early zebrafish development impairs cartilage formation and skeletal development. This suggests E2 may inhibit chondrogenesis by interfering with the hedgehog signaling pathway.
Area of Science:
- Developmental Biology
- Endocrinology
- Skeletal Biology
Background:
- 17beta-estradiol (E2) is crucial for gonad and central nervous system development.
- The impact of exogenous E2 on chondrogenesis during skeletal development is largely unknown.
- Zebrafish embryos are a valuable model for studying early developmental processes.
Purpose of the Study:
- To investigate the effects of exogenous 17beta-estradiol (E2) on chondrogenesis in zebrafish skeletal development.
- To determine the dose-dependent effects and developmental timing sensitivity of E2 exposure.
- To elucidate the potential molecular mechanisms underlying E2-induced chondrogenesis defects.
Main Methods:
- Zebrafish embryos were exposed to varying concentrations of E2 at different developmental stages (1-5 days post-fertilization).
- Morphological analysis was used to assess cartilage formation and identify skeletal defects.
- In situ hybridization was employed to examine the expression of key developmental genes, including hedgehog pathway components.
- An estrogen receptor antagonist was used to investigate the role of the nuclear estrogen receptor.
Main Results:
- E2 exposure above 1.5x10(-5)M increased zebrafish embryo mortality.
- Abnormal cartilage formation, including defects in ethmoid plate, trabecular cartilage, Meckel's cartilage, and ceratohyal cartilage, occurred in a dose-dependent manner above 5x10(-6)M.
- Embryos were most sensitive to E2 during early chondrogenesis (1-2 dpf), resulting in cartilage hypoplasia.
- E2 exposure reduced the expression of patched1 (ptc1) and patched2 (ptc2) receptor mRNAs but did not alter sonic hedgehog (shh) and tiggywinkle hedgehog (twhh) mRNA levels.
- Estrogen receptor antagonism did not fully block E2's effects, suggesting non-nuclear receptor pathways may be involved.
Conclusions:
- Exogenous E2 exposure during early zebrafish development significantly inhibits chondrogenesis and causes skeletal malformations.
- The findings suggest that E2 may disrupt skeletal development by interfering with the hedgehog (Hh) signal transduction pathway.
- These results highlight the potential risks of environmental estrogens on vertebrate skeletal development.
