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.
Endocrinology Branch, NHEERL, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
J L
JL
Metcalf
S C
SC
Laws
A M
AM
Cummings
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