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Toxicological Sciences 62, 321-329 (2001)
Copyright © 2001 by the Society of Toxicology

REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY

Skeletal Effects of Developmental Lead Exposure in Rats

Martin J. J. Ronis*,1, James Aronson{dagger},{ddagger}, Guan Gen Gao{dagger},{ddagger}, William Hogue{dagger},{ddagger}, Robert A. Skinner{dagger},{ddagger}, Thomas M. Badger* and Charles K. Lumpkin, Jr.*,{ddagger}

* Department of Pediatrics and {dagger} Department of Orthopedics, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and {ddagger} Laboratory for Limb Regeneration Research, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas 72202

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 the drinking water from gestational day 4 to euthanasia on day 55. Tibial strength was tested by 3-point bending and plasma levels of vitamin D metabolites were measured. A dose-dependent decrease of the load to failure was demonstrated but only in male pups. No differences in plasma levels of vitamin D metabolites were observed. In the second study, conducted to test if hormone treatment would attenuate the lead deficits, 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, testosterone (males only), dihydrotestosterone (DHT, males only), or estradiol (females only). Lead exposure significantly reduced somatic growth, longitudinal bone growth, and bone strength during the pubertal period. Sex steroid replacement did not restore skeletal parameters in lead-exposed rats. L-Dopa increased plasma insulin-like growth factor 1 (IGF1) concentrations, rates of bone growth, and bone strength measures in controls while having no 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 for effects of lead exposure on bone formation during tibial limb lengthening (distraction osteogenesis, DO). Both DO gap x-ray density and proximal new endosteal bone formation were decreased in the distraction gaps of the lead-treated animals (p < 0.01). In conclusion, lead exposure reduced somatic growth, longitudinal bone growth, and bone strength during the pubertal period, 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.

Key Words: lead; distraction osteogenesis; puberty; sex steroids; skeleton; growth.


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