Reproductive toxicity and tissue concentrations of low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin in male offspring rats exposed throughout pregnancy and lactation.
The effects of low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the reproductive system of male offspring rats were examined. The dams were treated subcutaneously 2 weeks prior to mating and throughout mating, pregnancy, and lactation. They received an initial loading dose of 25, 60, or 300 ng TCDD/kg body wt, followed by a weekly maintenance dose of 5, 12, or 60 ng TCCD/kg body wt (TCDD 25/5, TCDD 60/12, and TCDD 300/60). Three dams per group were killed on Gestation Day 21 and the fetuses were removed. The concentration of TCDD in the maternal liver and fat was measured. After birth, developmental landmarks in male rats were monitored. At weaning, the concentration of TCDD in the offspring liver and testis was determined. Effects on male reproduction were studied on Postnatal Days (PND) 70 and 170. At weaning, the concentration of TCDD in the offspring liver was 0.24, 0.39, and 1.78 ng/g in the TCDD 25/5, TCDD 60/12, and TCDD 300/60 groups, respectively. In the testes, the concentration of TCDD was 0.25 ng/g in the TCDD 25/5 and TCDD 60/12 groups and 0.28 ng/g in the TCDD 300/60 group. The number of sperm per cauda epididymis was reduced in TCDD groups at puberty and at adulthood. Daily sperm production was permanently decreased as was the sperm transit rate in the TCDD-exposed male rats, thus increasing the time required by the sperm to pass through the cauda epididymis. Moreover, the male rats of the TCDD groups showed an increased number of abnormal sperm when investigated at adulthood. Similarly, mounting and intromission latencies were significantly increased in the TCDD 25/5 and TCDD 300/60 groups. In the highest dose group, serum testosterone concentration was decreased at adulthood. Likewise, in this dose group permanent changes including pyknotic nuclei and the occurrence of cell debris in the lumen were revealed. The lowest adverse effect level and the no observed effect level can be estimated to be substantially lower than the estimated daily dose of the lowest dose which is 0.8 ng/kg body wt/day. Sperm parameters were more susceptible than the other end points investigated. However, the question as to whether such doses exposed throughout gestation and lactation induce subtle changes in humans remains to be determined.
Faqi
A S
AS
Institut für Klinische Pharmakologie und Toxikologie, Freie Universität, Berlin, Germany.
Dalsenter
P R
PR
Merker
H J
HJ
Chahoud
I
I
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004822:Epididymis / Q000187:drug effects / Q000473:pathology; D005260:Female; D005865:Gestational Age; D007279:Injections, Subcutaneous; D007774:Lactation; D008099:Liver / Q000378:metabolism; D008297:Male; D009929:Organ Size; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects; D012723:Sex; D013076:Sperm Count / Q000187:drug effects; D013094:Spermatozoa / Q000002:abnormalities / Q000187:drug effects; D013737:Testis / Q000187:drug effects / Q000473:pathology
D000072317:Polychlorinated Dibenzodioxins