Zearalenone (ZON), produced by Fusarium fungi, exhibits estrogenic activity. Livestock can be exposed to ZON orally through contaminating feeds such as cereals, leading to reproductive disorders such as infertility and miscarriage via endocrine system disruption. However, the details of ZON metabolism remain unclear, and the mechanism of its toxicity has not been fully elucidated. In this study, we investigated the kinetics of ZON absorption and metabolism in rat segmented everted intestines. ZON absorption was confirmed in each intestine segment 60 min after application to the mucosal buffer at 10 µM. Approximately half of the absorbed ZON was metabolized to α-zearalenol, which tended to be mainly glucuronidated in intestinal cells. In the proximal intestine, most of the glucuronide metabolized by intestinal cells was excreted to the mucosal side, suggesting that the intestine plays an important role as a first drug metabolism barrier for ZON. However, in the distal intestine, ZON metabolites tended to be transported to the serosal side. Glucuronide transported to the serosal side could be carried via the systemic circulation to the local tissues, where it could be reactivated by deconjugation. These results are important with regard to the mechanism of endocrine disruption caused by ZON.
Extra-adrenal steroid hormone production has been reported in several tissues, the biological role of which is interesting in terms of hormonal regulation of metabolism, growth, and behavior. In this report, we describe for the first time steroidogenesis in rat salivary glands. Enzyme activities associated with corticosterone and testosterone production were detected in rat salivary glands by LC-MS analysis. In tissue homogenates of rat salivary glands, progesterone was produced enzymatically
in vitro
from pregnenolone in the presence of NADPH and NADH. Deoxycorticosterone was produced from progesterone, corticosterone from deoxycorticosterone, and testosterone from androstenedione (but not pregnenolone from cholesterol) via enzymatic reactions using the same tissue homogenates. Immunoblotting analysis indicated the expression of 11β-hydroxylase (cytochrome P450 11β1; CYP11β1), which mediated the production of corticosterone from deoxycorticosterone. However, CYP family 11 subfamily A member 1 (CYP11A1)-mediated production of pregnenolone from cholesterol was not detected in the salivary glands by immunoblotting using a specific antibody. These results indicate that corticosterone and testosterone are produced from pregnenolone in rat salivary glands. The initial substrate in salivary steroidogenesis and the roles of salivary corticosterone and testosterone are discussed.
Diethylstilbestrol (DES) is a synthetic oestrogen known to disrupt the endocrine system and to cause reproductive toxicity mediated via the hypothalamic‐pituitary‐adrenal axis; however, its molecular mechanism of action is poorly understood. In the present study, we found that, after only 1 week of exposure to DES, blood testosterone dramatically decreased and that this decrease was associated with a strong induction of prolactin (PRL). Even with the increase in PRL, the luteinising hormone and follicle‐stimulating hormone mRNAs slightly decreased. Our results show that, after 48 hours of a single dose of DES, there was a six‐fold increase in PRL expression. After exploring the upstream mechanisms, we determined that dopamine, which inhibits PRL secretion in male rats, did not decrease in the pituitary gland of DES‐treated rats, whereas vasoactive intestinal peptide (VIP), which mediates the acute release of PRL, was elevated. Serotonin (5‐HT) increased in the brain of male rats 24 hours after a single DES treatment; however, PRL, VIP or 5‐HT was not induced by DES in female rats. Our results indicate that DES induces the expression of pituitary PRL in male rats by stimulating VIP in the hypothalamus and 5‐HT in the central nervous system.
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