The effects of the phytoestrogen genistein on the postnatal development of the rat.
The present studies report the effects on neonatal rats of oral exposure to genistein during the period from birth to postnatal day (PND) 21 to generate data for use in assessing human risk following oral ingestion of genistein. Failure to demonstrate significant exposure of the newborn pups via the mothers milk led us to subcutaneously inject genistein into the pups over the period PND 1-7, followed by daily gavage dosing to PND 21. The targeted doses throughout were 4 mg/kg/day genistein (equivalent to the average exposure of infants to total isoflavones in soy milk) and a dose 10 times higher than this (40 mg/kg genistein). The dose used during the injection phase of the experiment was based on plasma determinations of genistein and its major metabolites. Diethylstilbestrol (DES) at 10 micro g/kg was used as a positive control agent for assessment of changes in the sexually dimorphic nucleus of the preoptic area (SDN-POA). Administration of 40 mg/kg genistein increased uterus weights at day 22, advanced the mean day of vaginal opening, and induced permanent estrus in the developing female pups. Progesterone concentrations were also decreased in the mature females. There were no effects in females dosed with 4 mg/kg genistein, the predicted exposure level for infants drinking soy-based infant formulas. There were no consistent effects on male offspring at either dose level of genistein. Although genistein is estrogenic at 40 mg/kg/day, as illustrated by the effects described above, this dose does not have the same repercussions as DES in terms of the organizational effects on the SDN-POA.
Lewis
Richard W
RW
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, United Kingdom. dick.lewis@syngenta.com
Brooks
Nigel
N
Milburn
Gillian M
GM
Soames
Anthony
A
Stone
Susan
S
Hall
Michael
M
Ashby
John
J
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D004971:Estrus / Q000187:drug effects; D005260:Female; D019833:Genistein / Q000008:administration & dosage / Q000633:toxicity*; D006128:Growth / Q000187:drug effects*; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D007279:Injections, Subcutaneous; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011301:Preoptic Area / Q000187:drug effects / Q000473:pathology; D011374:Progesterone / Q000097:blood; D051381:Rats; D012727:Sex Characteristics; D012741:Sexual Maturation / Q000187:drug effects; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D014621:Vagina / Q000187:drug effects / Q000254:growth & development
D006131:Growth Inhibitors; D011374:Progesterone; D019833:Genistein