Methoxychlor mimics the action of 17 beta-estradiol on induction of uterine epidermal growth factor receptors in immature female rats.
Epidermal growth factor (EGF) and its receptor (EGF-R) have been implicated as mediators for estrogen induced cellular growth. This study examines whether the action of the estrogenic pesticide methoxychlor (MXC) parallels the action of 17 beta-estradiol (E2) on uterine EGF-R. Administration of 20 micrograms E2/sexually immature female rat increased 125I-EGF binding to membranes extracted from whole uteri 175% over endogenous levels, while 500 mg MXC/kg led to a 156% increase. E2 in both 20 and 40 micrograms/rat doses and 500 mg MXC/kg led to maximal stimulation over endogenous levels, 12-h posttreatment. Rats were treated with E2, MXC, or vehicle plus 100 micrograms actinomycin-D (ACT-D) or 100 micrograms cycloheximide (CYCLO) per rat to determine if mRNA transcription and translation are involved in the increased EGF-R binding following estrogenic treatment. Only ACT-D inhibited the estrogenic stimulation of EGF-R binding, resulting in a 44% decrease when given concurrently with E2 or MXC, suggesting transcription is required. Additionally, ACT-D decreased endogenous receptor levels by 55%. No other differences were detected. When EGF-R binding data were analyzed by the method of Scatchard, both E2 and MXC, at maximal dosages, elevated uterine EGF-R binding sites by over 200% after 12 h as measured by maximal binding (Bmax) with no significant difference in dissociation constant (Kd) values. These results demonstrate that both E2 and MXC can stimulate the number of EGF-R binding sites without significantly altering the receptor binding affinity (Kd). Further, this stimulation is time dependent and is affected by dose.
Metcalf
J L
JL
Endocrinology Branch, NHEERL, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
Laws
S C
SC
Cummings
A M
AM
D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive; D003513:Cycloheximide / Q000008:administration & dosage / Q000633:toxicity; D003609:Dactinomycin / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D005260:Female; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity*; D007457:Iodine Radioisotopes; D007553:Isotope Labeling; D008731:Methoxychlor / Q000008:administration & dosage / Q000633:toxicity*; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
D007306:Insecticides; D007457:Iodine Radioisotopes; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D003609:Dactinomycin; D004958:Estradiol; D003513:Cycloheximide; D066246:ErbB Receptors; D008731:Methoxychlor