Toxicological Sciences, Vol 50, 271-279, Copyright © 1999 by Society of Toxicology
G Jahnke, M Marr, C Myers, R Wilson, G Travlos and C Price
Melatonin (MEL) is a widely used, over-the-counter sleep aid, and it has
putative contraceptive, antioxidant, antiaging, and anticancer effects. The
developmental toxicity potential for repeated oral doses of MEL had not
previously been evaluated. In the present studies, time- mated,
Sprague-Dawley-derived (CD) rats were administered MEL or vehicle by gavage
on gestation days (gd) 6-19. MEL-treated groups received 1-, 10-, 100-,
150-, or 200-mg/kg body weight/day in the screening study (15 rats/group),
and 50, 100, or 200 mg/kg/day in the definitive study (25 rats/group). In
both studies, maternal food/water consumption, body weight, and clinical
signs were monitored at regular intervals throughout gestation. At
termination (gd 20, both studies), maternal liver and gravid uterine
weights, number of ovarian corpora lutea, conceptus survival, fetal sex,
and fetal body weight were evaluated. Fetal morphological examination
included external structures (both studies) as well as visceral and
skeletal structures (definitive study). In the screening study, maternal
serum levels of 17beta- estradiol, progesterone, prolactin, and luteinizing
hormone were determined by radioimmunoassay, and mammary tissue was fixed,
stained, and evaluated for percent glandular area within the fat pad. No
maternal morbidity/mortality was found in either study. In the screening
study, aversion to treatment (> or =100 mg/kg/day) and reduced maternal
weight gain (> or =150 mg/kg/day) were noted, but reproductive/endocrine
parameters and fetal development were not affected. In the definitive
study, aversion to treatment was noted at > or =50 mg/kg/day, and mild
sedation, reduced maternal food intake, and reduced body weight gain were
found during initial treatment with 200 mg/kg/day. MEL had no effect on
prenatal survival, fetal body weight, or incidences of fetal
malformations/variations. Thus, in the definitive study, the maternal
toxicity NOAEL and LOAEL were 100 and 200 mg/kg/day, respectively, and the
developmental toxicity NOAEL was > or =200 mg/kg/day.
ARTICLES
Maternal and developmental toxicity evaluation of melatonin administered orally to pregnant Sprague-Dawley rats
Reproductive Toxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. Jahnke@NIEHS.NIH.gov
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