1. Bone loss in adult offspring induced by low-dose exposure to teratogens.
- Author
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Torchinsky A, Mizrahi L, Savion S, Shahar R, Toder V, and Kobyliansky E
- Subjects
- Acid Phosphatase metabolism, Animals, Apoptosis drug effects, Bone Resorption diagnostic imaging, Bone Resorption genetics, Bone Resorption pathology, Embryo, Mammalian drug effects, Embryo, Mammalian pathology, Female, Femur diagnostic imaging, Femur drug effects, Femur pathology, Gene Expression Profiling, Gene Expression Regulation, Developmental drug effects, Hindlimb drug effects, Hindlimb embryology, Hindlimb metabolism, Hindlimb pathology, Isoenzymes metabolism, Limb Buds drug effects, Limb Buds metabolism, Limb Buds pathology, Mice, Mice, Inbred ICR, MicroRNAs genetics, MicroRNAs metabolism, Osteoblasts drug effects, Osteoblasts metabolism, Osteogenesis drug effects, Osteogenesis genetics, Osteoprotegerin metabolism, Pregnancy, Prenatal Exposure Delayed Effects genetics, RANK Ligand metabolism, Reproduction drug effects, Tartrate-Resistant Acid Phosphatase, X-Ray Microtomography, Aging drug effects, Aging pathology, Azacitidine toxicity, Bone Resorption chemically induced, Prenatal Exposure Delayed Effects pathology, Teratogens toxicity
- Abstract
Maternal malnutrition during pregnancy was shown by numerous studies to result in the birth of offspring exhibiting altered bone characteristics, which are indicative of bone loss. We hypothesized that not only maternal malnutrition but also some developmental toxicants (teratogens) given at a dose inducing neither structural anomalies nor growth retardation can detrimentally affect skeletal health in adult offspring. To check this hypothesis, pregnant mice were exposed to a single injection of 5-aza-2-deoxycytidine (5-AZA) (a teratogen capable of inducing phocomelia of the hind limbs) at a sub-threshold teratogenic dose. Micro-computed tomography scanning revealed that femora of 5-month-old male offspring exposed in uterus to 5-AZA had trabecular microarchitecture indicative of bone loss. Furthermore, exposure to 5-AZA increased the susceptibility of offspring to postnatal chronic mild stress, which has been shown to induce bone loss in mice. While exploring possible mechanisms underlying this phenomenon, we observed that the expression of some microRNAs, which have been demonstrated as regulators of key osteoblastogenic genes, was altered in hind limb buds of embryos exposed to 5-AZA. Furthermore, the expression of receptor activator of nuclear factor kappa B ligand (RANKL) in femoral stromal/osteoblastic cells of 5-month-old offspring of 5-AZA-treated females was found to be increased. Collectively, this study implies for the first time that single low-dose exposure to a teratogen can induce bone loss in adult offspring, possibly via alteration of embryonic microRNAs and RANKL expression.
- Published
- 2012
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