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Lead acetate induces cartilage defects and bone loss in zebrafish embryos by disrupting the GH/IGF-1 axis
Rui Yan1, Jie Ding1, Qianlei Yang1
1Department of Toxicology, School of Public Health, Jiangsu Key Laboratory of Preventive and Translation-al Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou 215123, China.
Abstract:
Skeletal system toxicity due to lead exposure has attracted extensive attention in recent years, but few studies focus on the skeletal toxicity of lead in the early life stages of zebrafish. The endocrine system, especially the GH/IGF-1 axis, plays an important role in bone development and bone health of zebrafish in the early life. In the present study, we investigated whether lead acetate (PbAc) affected the GH/IGF-1 axis, thereby causing skeletal toxicity in zebrafish embryos. Zebrafish embryos were exposed to lead PbAc between 2 and 120 h post fertilization (hpf). At 120 hpf, we measured developmental indices, such as survival, deformity, heart rate, and body length, and assessed skeletal development by Alcian Blue and Alizarin Red staining and the expression levels of bone-related genes. The levels of GH and IGF-1 and the expression levels of GH/IGF-1 axis-related genes were also detected. Our data showed that the LC50 of PbAc for 120 h was 41 mg/L. Compared with the control group (0 mg/L PbAc), after PbAc exposure, the deformity rate increased, the heart rate decreased, and the body length was shortened at various time periods, in the 20-mg/L group at 120 hpf, the deformity rate increased by 50 fold, the heart rate decreased by 34%, and the body length shortened by 17%. PbAc altered cartilage structures and exacerbated bone loss in zebrafish embryos; in addition, PbAc exposure down-regulated the expression of chondrocyte (sox9a, sox9b), osteoblast (bmp2, runx2) and bone mineralization-related genes (sparc, bglap), and up-regulated the expression of osteoclast marker genes (rankl, mcsf). The GH level increased and the IGF-1 level declined significantly. The GH/IGF-1 axis related genes (ghra, ghrb, igf1ra, igf1rb, igf2r, igfbp2a, igfbp3, igfbp5b) were all decreased. These results suggested that PbAc inhibited the differentiation and maturation of osteoblasts and cartilage matrix, promoted the formation of osteoclasts, and ultimately induced cartilage defects and bone loss by disrupting the GH/IGF-1 axis.
Insights
Lead acetate exposure in zebrafish embryos disrupts the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, causing skeletal defects and bone loss. This study highlights lead
Area of Science:
- Environmental Toxicology
- Developmental Biology
- Endocrinology
Background:
- Lead exposure is a known skeletal toxicant, but its effects on early-life skeletal development are understudied.
- The growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis is crucial for bone development in early life stages.
- Zebrafish embryos are a valuable model for investigating developmental toxicity.
Purpose of the Study:
- To investigate the impact of lead acetate (PbAc) on the GH/IGF-1 axis in zebrafish embryos.
- To determine if PbAc-induced disruption of the GH/IGF-1 axis leads to skeletal toxicity.
- To assess developmental and skeletal changes in zebrafish embryos following PbAc exposure.
Main Methods:
- Zebrafish embryos were exposed to lead acetate (PbAc) from 2 to 120 hours post-fertilization (hpf).
- Developmental indices (survival, deformity, heart rate, body length) were measured at 120 hpf.
- Skeletal development was assessed using Alcian Blue and Alizarin Red staining.
- Gene expression analysis of bone-related and GH/IGF-1 axis genes was performed.
- GH and IGF-1 levels were quantified.
Main Results:
- Lead acetate exposure resulted in increased deformity rates, decreased heart rates, and shortened body lengths in zebrafish embryos.
- PbAc altered cartilage structures and exacerbated bone loss, indicated by altered gene expression of chondrocyte, osteoblast, and osteoclast markers.
- Lead acetate exposure led to increased GH levels and decreased IGF-1 levels, alongside reduced expression of GH/IGF-1 axis-related genes.
Conclusions:
- Lead acetate exposure induces skeletal toxicity in zebrafish embryos by disrupting the GH/IGF-1 axis.
- PbAc inhibits osteoblast differentiation and cartilage matrix formation while promoting osteoclastogenesis.
- These disruptions ultimately lead to cartilage defects and bone loss during early development.
