title: Developmental exposure to As, Cd, and Pb mixture diminishes skeletal growth and causes osteopenia at maturity via osteoblast and chondrocyte malfunctioning in female rats.
abstract: 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 groundwater of India, i.e., As: 0.38 ppm, Pb: 0.22 ppm, and Cd: 0.098 ppm or 10× 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.
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Lucknow, India.
authors.forename: Sabiya
authors.initials: S
authors.lastname: Abbas
authors.forename: Kainat
authors.initials: K
authors.lastname: Khan
authors.forename: Mohd Parvez
authors.initials: MP
authors.lastname: Khan
authors.forename: Geet Kumar
authors.initials: GK
authors.lastname: Nagar
authors.forename: Deepshikha
authors.initials: D
authors.lastname: Tewari
authors.forename: Shailendra Kumar
authors.initials: SK
authors.lastname: Maurya
authors.forename: Jyoti
authors.initials: J
authors.lastname: Dubey
authors.forename: Nasreen Ghazi
authors.initials: NG
authors.lastname: Ansari
authors.forename: Sanghamitra
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Naibedya
authors.initials: N
authors.lastname: Chattopadhyay
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001151:Arsenic / Q000097:blood / Q000633:toxicity; D001846:Bone Development / Q000187:drug effects*; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000139:chemically induced* / Q000196:embryology / Q000473:pathology; D002104:Cadmium / Q000097:blood / Q000633:toxicity; D019902:Chondrocytes / Q000187:drug effects* / Q000473:pathology; D045424:Complex Mixtures / Q000097:blood / Q000633:toxicity*; D004357:Drug Synergism; D005260:Female; D007854:Lead / Q000097:blood / Q000633:toxicity; D019216:Metals, Heavy / Q000097:blood / Q000633:toxicity*; D010006:Osteoblasts / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D045424:Complex Mixtures; D019216:Metals, Heavy; D002104:Cadmium; D007854:Lead; D001151:Arsenic
keywords: bone.; environmental; metals; synergistic toxicity