title: Chronic estradiol exposure induces oxidative stress in the hypothalamus to decrease hypothalamic dopamine and cause hyperprolactinemia.
abstract: Estrogens are known to cause hyperprolactinemia, most probably by acting on the tuberoinfundibular dopaminergic (TIDA) system of the hypothalamus. Dopamine (DA) produced by TIDA neurons directly inhibits prolactin secretion and, therefore, to stimulate prolactin secretion, estrogens inhibit TIDA neurons to decrease DA production. However, the mechanism by which estrogen produces this effect is not clear. In the present study, we used a paradigm involving chronic exposure to low levels of estradiol-17β (E(2)) to mimic prolonged exposures to environmental and endogenous estrogens. We hypothesized that chronic exposure to low levels of E(2) induces oxidative stress in the arcuate nucleus (AN) of the hypothalamus that contains TIDA neurons and causes nitration of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of DA. This results in a significant decrease in DA and consequently, hyperprolactinemia. To investigate this, adult, intact female cycling rats were implanted with slow-release E(2) pellets (20 ng/day) for 30, 60, or 90 days and were compared with old (16-18 mo old) constant estrous (OCE) rats. Chronic E(2) exposure significantly increased the expression of glial fibrillary acidic protein and the concentrations of interleukin-1β (IL-1β) and nitrate in the AN that contains perikarya of TIDA neurons and increased nitration of TH in the median eminence (ME) that contains the terminals. These levels were comparable to those seen in OCE rats. We observed a significant decrease in DA concentrations in the ME and hyperprolactinemia in an exposure-dependent manner similar to that seen in OCE rats. It was concluded that chronic exposure to low levels of E(2) evokes oxidative stress in the AN to inhibit TIDA neuronal function, most probably leading to hyperprolactinemia.
authors.affiliation: Neuroendocrine Research Laboratory, Dept. of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State Univ., East Lansing, 48824, USA. mohankumar@cvm.msu.edu
authors.forename: Sheba M J
authors.initials: SM
authors.lastname: MohanKumar
authors.forename: Badrinarayanan S
authors.initials: BS
authors.lastname: Kasturi
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Shin
authors.forename: Priya
authors.initials: P
authors.lastname: Balasubramanian
authors.forename: Ebony T
authors.initials: ET
authors.lastname: Gilbreath
authors.forename: Madhan
authors.initials: M
authors.lastname: Subramanian
authors.forename: Puliyur S
authors.initials: PS
authors.lastname: Mohankumar
mesh_terms: D000367:Age Factors; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015536:Down-Regulation; D004343:Drug Implants; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D004971:Estrus; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006966:Hyperprolactinemia / Q000139:chemically induced* / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011388:Prolactin / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D004343:Drug Implants; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D009569:Nitric Oxide; D004958:Estradiol; D011388:Prolactin; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine