Neonatal Exposure to Genistein Reduces Expression of Estrogen Receptor Alpha and Androgen Receptor in Testes of Adult Mice.

Abstract

Abstract.We investigated the long-term estrogenic influence of genistein on the male reproductive system in mice. Newborn ICR male mice were treated with genistein (10, 100, or 1000 , tg/mouse) for neonatal 5 days. As positive control, administration of diethylstilbestrol (0.5-50 pg/mouse) was carried out. In mice exposed to genistein,we examined weight of testes, sperm counts, sperm motility, and mRNA expression levels of estrogen receptor a (ERa) and androgen receptor (AR) at 4, 8 or 12 weeks after birth. Moreover, at 12 weeks of age, we evaluated protein level of ERa. In our conventional reproductive-toxicological study (weight of testes, sperm counts and sperm motility), neonatal transient exposure to genistein did not show adverse effects on the male reproductive system in 4, 8 or 12 week old mice. However, in mice treated with genistein mRNA expression levels of ERa and AR were reduced at 8 weeks. This reduction was recovered at 12 weeks in mice treated with a lower dose (10 ICg) of genistein but not in those with higher doses (100 pg and 1000 rig). In addition, ERa protein levels tended to decrease in 12 weeks of adulthood.Our results exhibited that the disruption of gene expression continued for long term such as 3 months after administration of genistein, even if no effect was found at conventional reproductive-toxicological level. We have shown that neonatal administration of weak estrogenic compound (genistein) affects male reproductive organs at molecular levels in adulthood.

Application of toxicogenomic analysis to risk assessment of delayed long-term effects of multiple chemicals including endocrine disruptors in human fetuses

“…Table 1 is a summary of the data from our experiments and others Komiyama et al 2002;McLachlan et al 2001;Newbold 2001;Newbold et al 1984Newbold et al , 2002Shibayama et al 2001). The table shows the effects of neonatal exposure to DES or genistein in experimental animals at three different end points (gene expression level, reproductive disorder level, and cancer level).…”

“…Our group conducted animal experiments to investigate the long-term alteration of gene expression affected by neonatal exposure to estrogenic compounds in mouse testis Komiyama et al 2002;Shibayama et al 2001). Male and female reproductive organs including testis and uterus are vulnerable to estrogenic compounds.…”

“…In our experiments, DES caused several adverse effects as reported before by conventional experimental methods. Furthermore, using molecular level analysis, we were able to detect long-term alteration of gene expression (Shibayama et al 2001).…”

Progression of the Dose-Related Effects of Estrogenic Endocrine Disruptors, an Important Factor in Declining Fertility, Differs between the Hypothalamo-Pituitary Axis and Reproductive Organs of Male Mice

“…The diminished immunoexpressions of AR and ERα were considered to be due to reductions in the amount or activity of these factors, and may have been responsible for the observed reproductive dysfunction. In a previous study, in which a daily subcutaneous administration of DES (0.5, 5 and 50 µg) was carried out neonatally for 5 days from the day of birth, there was a decrease of both AR and ERα mRNA at 12 weeks of age (especially in the animals receiving 5 and 50 µg treatment) [28]. In the present study, the plasma LH and testosterone levels in the group receiving IUE+NE 0.1 µg were significantly lower than those of the control group, whereas there were no remarkable changes of the AR and ERα immunoexpression or in the expression of the AR, ERα and StAR genes.…”

“…The fetal and neonatal period has a clinical window that is particularly sensitive to exposure to exogenous estrogenic compounds. Furthermore, long-term changes, including molecular alterations, have been observed after exposure to endocrine disrupting chemicals during these early developmental periods [13,28]. In addition, it has been reported that neonatal exposure of animals to estrogenic compounds caused disorders of the male reproductive tract [24], reduction of testosterone [3], testicular atrophy and carcinoma [17,21], increased rate of breast cancer [8], uterine adenocarcinoma and various cervicovaginal lesions [18,20].…”