Abstract
The long term skeletal effects of antenatal exposure to teratogen 5-deoxy-2′-cytidine (5-AZA) were studied using two inbred strains, C3H/HeJ (C3H, with inherently stronger bones) and C57Bl/6J (C57, with weaker bones). We previously reported that in-utero exposure to 5-AZA resulted in loss of bone quality in 3- and 6-mo-old C3H offspring. In this study, we further examined whether the long-term effects of an acute teratogenic exposure are still evident in older mice. Bone phenotypes of 12 mo-old mice exposed to a single injection of 5-AZA on day 10 of their mother's pregnancy were evaluated by micro-computed tomography and compared to the untreated controls.The main observation of this study is that 5-AZA-induced loss of bone length was registered in 12-mo-old C57 and C3H males. As expected, we did not find differences in the 3rd lumbar vertebra since in-utero exposure to 5-AZA was shown to affect the limb buds but not the axial skeleton. Trajectory of changes in bone phenotypes from ages 3 mo through 6 mo to 12 mo was also compared; 5-AZA-exposed C57 males had consistently lower femoral length and trabecular BMD than age-matched controls. In summary, by characterizing teratogen-exposed C57 and C3H mice, we further confirmed that the adaptive response to antenatal insults continue into mid-life of the mice as well as there is a sex-specificity of these responses.
Highlights
Antenatal response to intrauterine stress (Oberbauer, 2015) is an inherent trait of an organism
We previously reported that strain genetics influences the response to 5-deoxy-2′-cytidine (5-AZA) in C3H/HeJ (C3H) and C57Bl/6J (C57) mice and contemplated about the potential mechanisms of strain and sex effects observed in young/adult animals (Raygorodskaya et al, 2016)
It was originally shown that 5mo-old offspring of ICR mice exposed to a single injection of 5-AZA at a sub-threshold teratogenic dose on day 10 of pregnancy exhibit femoral trabecular microarchitecture indicative of bone loss, while such a dose does not affect maternal homeostasis (Torchinsky et al, 2012)
Summary
Antenatal response to intrauterine stress (Oberbauer, 2015) is an inherent trait of an organism. Our choice of 5-AZA was dictated by the fact that teratological studies in mice have revealed that 5-AZA injected on day 10 of gestation induces phocomelia (absence of the long bones of the limb) in a dose-dependent fashion (Torchinsky et al, 2012). This exposure time of 5-AZA approximately matched the very beginning of osteoblastogenesis (Maes et al, 2007). Elucidating whether antenatal and early-life stress affect the adult skeleton is highly relevant to our understanding of genome-by-environment impact on bone mineral density (BMD) throughout life
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