Fetal Alcohol Exposure Reduces Dopamine Receptor D2 and Increases Pituitary Weight and Prolactin Production via Epigenetic Mechanisms.
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.
Endocrine Program, Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901, United States of America.
Omkaram
O
Gangisetty
Endocrine Program, Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901, United States of America.
Olivia
O
Wynne
Endocrine Program, Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901, United States of America.
Shaima
S
Jabbar
Department of Genetics, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901, United States of America.
Cara
C
Nasello
Endocrine Program, Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901, United States of America.
Dipak K
DK
Sarkar
D000818:Animals; D049109:Cell Proliferation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006657:Histones / Q000378:metabolism; D052682:Lactotrophs / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008934:Mitogens / Q000494:pharmacology; D009929:Organ Size; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood*; D011388:Prolactin / Q000096:biosynthesis* / Q000097:blood; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011916:Rats, Inbred F344; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D004967:Estrogens; D006657:Histones; D008934:Mitogens; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D011388:Prolactin