Interactive effects of cadmium and all-trans-retinoic acid on the induction of forelimb ectrodactyly in C57BL/6 mice.
BACKGROUND
Most toxicological studies have tested single chemical agents at relatively high doses, and fewer studies have addressed the toxic effects of chemical interactions. It is important to understand the toxicity of chemical mixtures in order to assess the more realistic risks of environmental and occupational exposures. A number of chemicals are known to induce a predominantly postaxial forelimb ectrodactyly in C57BL/6 mice, including acetazolamide, ethanol, cadmium, valproic acid, carbon dioxide, dimethadione, phenytoin, and 13-cis-retinoic acid and all-trans-retinoic acid (RA). In the present study, the interactive effects of coadministration of cadmium and RA on developing limbs were investigated.


METHODS
Pregnant C57BL/6 mice were treated with different intraperitoneal (IP) doses of cadmium chloride (CdCl2) and/or RA on gestational day (GD) 9.5, and fetuses were collected on GD 18 and double stained for examination of skeletal defects.


RESULTS
When RA was given simultaneously with cadmium, a significant increase in the incidence and severity of forelimb ectrodactyly (predominantly postaxial) was observed compared to the results with corresponding doses of cadmium or RA alone. When mice were exposed to subthreshold doses of both cadmium (0.5 mg/kg) and RA (1 mg/kg), the combined treatment exceeded the threshold, resulting in forelimb ectrodactyly in 19% of the fetuses. Moreover, coadministration of cadmium and RA at doses exceeding the respective thresholds showed a synergistic effect, that is, 92% of fetuses were found with the forelimb defect as opposed to 10% if the response were additive.


CONCLUSIONS
The findings demonstrate that concurrent exposure to these teratogens can have a synergistic effect and that subteratogenic doses may combine to exceed a threshold.
Lee
Grace S
GS
Molecular Toxicology Interdepartmental Program, University of California, Los Angeles School of Public Health, Los Angeles, California 90095, USA.
Liao
Xiaoyan
X
Cantor
Rita M
RM
Collins
Michael D
MD
D000818:Animals; D002104:Cadmium / Q000008:administration & dosage / Q000633:toxicity*; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D005552:Forelimb / Q000002:abnormalities / Q000187:drug effects* / Q000196:embryology; D005865:Gestational Age; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D013723:Teratogens / Q000633:toxicity*; D014212:Tretinoin / Q000008:administration & dosage / Q000633:toxicity*
D013723:Teratogens; D002104:Cadmium; D014212:Tretinoin