Skeletal effects of developmental lead exposure in rats

To identify possible direct and indirect mechanisms underlying the effects of lead on skeletal growth, 3 studies were conducted. In the first study, 1 male and 1 female pup/litter (n = 5 litters), were exposed ad libitum to 0 , 825, or 2475 ppm lead acetate in t drinking water from gestational day 4 to euthanasia on day 5 Tibial strength was tested by 3-point bending and pl asma levels of vitamin D metabolites were measured. A dose-dependent decrea se of the load to failure was demonstrated but only in male pups. No differ ences in plasma levels of vitamin D metabolites were observed. In the secon d study, conducted to test if hormone treatment would attenuate the lead de ficits, male and female pups were exposed to 0 or 2475 ppm lead acetate and then, from 30-60 days of age, received either saline vehicle, L-dopa, test osterone (males only), dihydrotestosterone (DHT, males only), or estradiol (females only). Lead exposure significantly reduced somatic growth, longitu dinal bone growth, and bone strength during the pubertal period. Sex steroi d replacement did not restore skeletal parameters in lead-exposed rats. L-D opa increased plasma insulin-like growth factor 1 (IGF(1)) concentrations, rates of bone growth, and bone strength measures in controls while having n o effect in lead-exposed pups. The third study was conducted at 100 days of age, when endocrine parameters have been shown to be normalized, to test f or effects of lead exposure on bone formation during tibial limb lengthenin g (distraction osteogenesis, DO). Both DO gap x-ray density and proximal ne w endosteal bone formation were decreased in the distraction gaps of the le ad-treated animals (P < 0.01). In conclusion, lead exposure reduced somatic growth, longitudinal bone growth, and bone strength during the pubertal pe riod, and these effects could not be reversed by a growth hormone (GH) axis stimulator or by sex-appropriate hormones. Finally, lead exposure appears to specifically inhibit osteoblastogenesis in vivo in adult animals.