Developmental Exposure to As, Cd, and Pb Mixture Diminishes Skeletal Growth and Causes Osteopenia at Maturity via Osteoblast and Chondrocyte Malfunctioning in Female Rats

被引:28
作者
Abbas, Sabiya [1 ]
Khan, Kainat [2 ,3 ]
Khan, Mohd. Parvez [2 ,3 ]
Nagar, Geet Kumar [2 ,3 ]
Tewari, Deepshikha [2 ,3 ]
Maurya, Shailendra Kumar [1 ]
Dubey, Jyoti [1 ,4 ]
Ansari, Nasreen Ghazi [5 ]
Bandyopadhyay, Sanghamitra [1 ]
Chattopadhyay, Naibedya [2 ,3 ]
机构
[1] CSIR Indian Inst Toxicol Res, Div Dev Toxicol, Lucknow 226001, Uttar Pradesh, India
[2] CSIR Cent Drug Res Inst, Div Endocrinol, Lucknow 226021, Uttar Pradesh, India
[3] CSIR Cent Drug Res Inst, Ctr Res Anabol Skeletal Targets Hlth & Illness AS, Lucknow 226021, Uttar Pradesh, India
[4] Tata Inst Fundamental Res, Natl Ctr Biol Sci, Inst Stem Cell Biol & Regenerat Med, Bangalore 560065, Karnataka, India
[5] CSIR Indian Inst Toxicol Res, Met Anal Lab, Lucknow 226001, Uttar Pradesh, India
关键词
environmental; metals; synergistic toxicity; bone; HORMONE-RELATED PROTEIN; BONE-MINERAL DENSITY; INDIAN HEDGEHOG; DRINKING-WATER; LEAD-EXPOSURE; CADMIUM; OSTEOPOROSIS; DIFFERENTIATION; APOPTOSIS; RECEPTOR;
D O I
10.1093/toxsci/kft093
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 [卫生毒理学];
摘要
We studied the effect of metal mixture (MM), comprising As, Cd, and Pb, in developing female rat skeleton from gestation day 5 until postnatal day 60 (P-60). MM resulted in synergistic inhibition in viability and differentiation of osteoblasts in vitro, likely induced by reactive oxygen species. MM, administered at their most frequently occurring concentrations present in the ground-water of India, i.e., As: 0.38 ppm, Pb: 0.22 ppm, and Cd: 0.098 ppm or 10x of the ratio to developing rats, exhibited a synergistic decrease in ex vivo mineralization of bone marrow stromal (osteoprogenitor) cells. MM group showed a dose-dependent attenuation in weight and axial lengths and shortening of tibias at P-60. Furthermore, the growth plate was shortened, which was associated with shorter proliferative and hypertrophic zones, decreased parathyroid hormone-related protein and Indian hedgehog expression in the chondrocytes, reduced primary and secondary spongiosa, and hypomineralized osteoids-a major characteristic of osteomalacia. In addition, compared with the control, MM-treated rats were clearly osteopenic based on bone mineral density, microarchitecture, biomechanical strength, and particularly the biochemical profile, that suggested high turnover bone loss. Finally, in comparison to the control, the fracture-healing ability of MM group was delayed and accompanied by inferior quality of the healed bone. Together, these data demonstrated that the mixture of As, Cd, and Pb induced synergistic toxicity to developing skeleton, thereby diminishing modeling-directed bone accrual, inducing osteopenia and dampening fracture healing.
引用
收藏
页码:207 / 220
页数:14
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