title: Bone loss in adult offspring induced by low-dose exposure to teratogens.
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.
authors.affiliation: Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, P.O. Box 39040, 69978, Tel Aviv, Israel. arkadyt@post.tau.ac.il
authors.forename: Arkady
authors.initials: A
authors.lastname: Torchinsky
authors.forename: Limor
authors.initials: L
authors.lastname: Mizrahi
authors.forename: Shoshana
authors.initials: S
authors.lastname: Savion
authors.forename: Ron
authors.initials: R
authors.lastname: Shahar
authors.forename: Vladimir
authors.initials: V
authors.lastname: Toder
authors.forename: Eugene
authors.initials: E
authors.lastname: Kobyliansky
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000375:Aging / Q000187:drug effects* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000633:toxicity*; D001862:Bone Resorption / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D004622:Embryo, Mammalian / Q000187:drug effects / Q000473:pathology; D005260:Female; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006614:Hindlimb / Q000187:drug effects / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism; D018878:Limb Buds / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D053244:Osteoprotegerin / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000473:pathology*; D053245:RANK Ligand / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase; D013723:Teratogens / Q000633:toxicity*; D055114:X-Ray Microtomography
chemical_list: D007527:Isoenzymes; D035683:MicroRNAs; D053244:Osteoprotegerin; D053245:RANK Ligand; D013723:Teratogens; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D001374:Azacitidine