Oral exposure to genistin, the glycosylated form of genistein, during neonatal life adversely affects the female reproductive system.
BACKGROUND
Developmental exposure to environmental estrogens is associated with adverse consequences later in life. Exposure to genistin (GIN), the glycosylated form of the phytoestrogen genistein (GEN) found in soy products, is of concern because approximately 20% of U.S. infants are fed soy formula. High circulating levels of GEN have been measured in the serum of these infants, indicating that GIN is readily absorbed, hydrolyzed, and circulated.


OBJECTIVE
We investigated whether orally administered GIN is estrogenic in neonatal mice and whether it causes adverse effects on the developing female reproductive tract.


METHODS
Female CD-1 mice were treated on postnatal days 1-5 with oral GIN (6.25, 12.5, 25, or 37.5 mg/kg/day; GEN-equivalent doses), oral GEN (25, 37.5, or 75 mg/kg/day), or subcutaneous GEN (12.5, 20, or 25 mg/kg/day). Estrogenic activity was measured on day 5 by determining uterine wet weight gain and induction of the estrogen-responsive gene lactoferrin. Vaginal opening, estrous cyclicity, fertility, and morphologic alterations in the ovary/reproductive tract were examined.


RESULTS
Oral GIN elicited an estrogenic response in the neonatal uterus, whereas the response to oral GEN was much weaker. Oral GIN altered ovarian differentiation (i.e., multioocyte follicles), delayed vaginal opening, caused abnormal estrous cycles, decreased fertility, and delayed parturition.


CONCLUSIONS
Our results support the idea that the dose of the physiologically active compound reaching the target tissue, rather than the administered dose or route, is most important in modeling chemical exposures. This is particularly true with young animals in which phase II metabolism capacity is underdeveloped relative to adults.
Jefferson
Wendy N
WN
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA. jeffers1@niehs.nih.gov
Doerge
Daniel
D
Padilla-Banks
Elizabeth
E
Woodling
Kellie A
KA
Kissling
Grace E
GE
Newbold
Retha
R
D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D004971:Estrus / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D019833:Genistein / Q000009:adverse effects / Q000097:blood; D005836:Genitalia, Female / Q000187:drug effects*; D007529:Isoflavones / Q000008:administration & dosage / Q000009:adverse effects*; D007781:Lactoferrin / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D014621:Vagina / Q000187:drug effects
D007529:Isoflavones; D012333:RNA, Messenger; C040641:genistin; D019833:Genistein; D007781:Lactoferrin