Abstract
Recent evidence indicated that alcohol exposure during the fetal period increases the susceptibility to tumor development in mammary and prostate tissues. Whether fetal alcohol exposure increases the susceptibility to prolactin-producing tumor (prolactinoma) development in the pituitary was studied by employing the animal model of estradiol-induced prolactinomas in Fischer 344 female rats. We employed an animal model of fetal alcohol exposure that simulates binge alcohol drinking during the first two trimesters of human pregnancy and involves feeding pregnant rats with a liquid diet containing 6.7% alcohol during gestational day 7 to day 21. Control rats were pair-fed with isocaloric liquid diet or fed ad libitum with rat chow diet. Adult alcohol exposed and control female offspring rats were used in this study on the day of estrus or after estrogen treatment. Results show that fetal alcohol-exposed rats had increased levels of pituitary weight, pituitary prolactin (PRL) protein and mRNA, and plasma PRL. However, these rats show decreased pituitary levels of dopamine D2 receptor (D2R) mRNA and protein and increased pituitary levels of D2R promoter methylation. Also, they show elevated pituitary mRNA levels of DNA methylating genes (DNMT1, DNMT3b, MeCP2) and histone modifying genes (HDAC2, HDAC4, G9a). When fetal alcohol exposed rats were treated neonatally with a DNA methylation inhibitor 5-Aza deoxycytidine and/or a HDAC inhibitor trichostatin-A their pituitary D2R mRNA, pituitary weights and plasma PRL levels were normalized. These data suggest that fetal alcohol exposure programs the pituitary to increase the susceptibility to the development of prolactinomas possibly by enhancing the methylation of the D2R gene promoter and repressing the synthesis and control of D2R on PRL-producing cells.
Highlights
A rapidly accumulating body of evidence indicates that many diseases must be understood in a life-long perspective, as trajectories that start at before or during conception and surface upon clinical detection decades later
We found that D2 receptor (D2R) mRNA expression was significantly reduced in pituitaries of AF rats compared to ad libitum (AD) and PF controls both at 60D and 90D after estrogen treatment (Fig 3A and 3B)
The data presented here indicate that fetal alcohol exposure resulted in hypermethylation of D2R gene promoter in adulthood, even though the exposure to ethanol ended at GD 21
Summary
A rapidly accumulating body of evidence indicates that many diseases must be understood in a life-long perspective, as trajectories that start at before or during conception and surface upon clinical detection decades later. Fetal alcohol exposure (FAE) occurs to the fetus when pregnant women drink alcohol, and causes a pattern of mental and physical defects collectively known as fetal alcohol spectrum disorders (FASD) [1]. Since the neuroendocrine-immune system is critically involved in the regulation of tumor surveillance, we have initiated studies to determine whether in utero alcohol exposure increases the offspring susceptiblity to tumorigenesis during adult life using rats as an animal model. We have recently reported that fetal alcohol exposure enhances the development of prostate carcinoma upon administration of N-nitroso-N-methylurea (NMU) with or without testosterone as carcinogens in adult offspring rats [11, 12]. The sensitivity to develop non-carcinogen induced tumors, like prolactin (PRL)-secreting pituitary adenomas (prolactinomas), in these animals has not been well studied
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