Compensatory Mechanisms In Mouse Offspring With Inherently Weak Bones Are Suggesting A Gene‐By‐Environment Interaction In Utero

Exposure of mouse embryo to different environmental factors, including sub‐threshold teratogens, can detrimentally affect bones of the offspring later in life. We investigated to what extent the genetic differences translate into variable response to teratogen 5‐deoxy‐2'‐cytidine (5‐AZA). We used mice of 2 inbred strains, C3H/HeJ (with inherently stronger bones) and C57Bl/6J (with weaker bones). Mothers were injected with 5‐AZA or saline (control) at day 10 of pregnancy. Five offspring of mice from each strain/sex groups (C3H or C57, males and females), treated and untreated, were tested at age 3 mo (adolescent) and 6 mo (adult). Femora from 80 offspring were analyzed by Scanco μCT50. At the age of 3‐mo, treated females (C57) had significant decrease (p<0.05) of bone mineral density (BMD) or loss of trabecular thickness (C3H); treated mice demonstrated loss of cortical thickness (p<0.05). In 6‐mo‐old, BMD was slightly lower in treated C3H males and females, while treated C57 had increased trabecular thickness (p<0.05). Treated C3H males demonstrated loss of cortical thickness, had lower trabecular parameters (p<0.05). This study demonstrates that the exposure to low‐dose 5‐AZA during embryonic life affects bone structure in adult offspring. In 3‐mo‐old offspring, teratogenic exposure caused bone loss in females of both strains. In 6‐mo‐old, bone loss was observed in offspring of strong‐bones strain (C3H), but not in the offspring of weak‐bones‐strain (C57). In mice with inherently weaker bones the effect of adverse intrauterine environment triggered some compensatory mechanisms.