Inhibition of central nervous system aromatase activity: a mechanism for fenarimol-induced infertility in the male rat.
Fenarimol (alpha-(2-chlorophenyl)-alpha(4-chlorophenyl)-5-pyrimidine-methanol), a pyrimidine carbinol agricultural fungicide, was previously reported to cause a dose-related decrease in fertility in rats (K. S. Hirsch, E. R. Adams, D. G. Hoffman, J. K. Markham, and N. V. Owen (1986), Toxicol. Appl. Pharmacol. 86, 391-399). Based on the results of a number of reproduction studies (K. S. Hirsch, E. R. Adams, D. G. Hoffman, J. K. Markham, and N. V. Owen (1986), Toxicol. Appl. Pharmacol. 86, 391-399), the infertility appeared to be associated with an impairment of male sexual behavior. When [14C]fenarimol was administered to the dam, high concentrations of radioactivity were observed in the neonatal hypothalamus, which functions in the development and subsequent expression of male sexual behavior. In the present studies fenarimol exhibited neither antiandrogenic nor antiestrogenic activities. The compound did, however, prevent the increase in nuclear estrogen receptors in the brain which normally occurs in the male during the early postnatal period. These results suggested that fenarimol might be acting to inhibit estrogen biosynthesis (via the aromatase enzyme complex) within the central nervous system. [3H]Testosterone was administered to neonatal rats, and the tritiated metabolites were isolated. Testosterone and dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) concentrations were similar in all treatment groups. Tritiated estrogens were detected in the brain cell nuclei from control neonates but not in neonates exposed to fenarimol. Fenarimol was also observed to inhibit rat ovarian aromatase activity in vitro. These data indicate that the decrease in male sexual behavior and the infertility associated with exposure to fenarimol were, most likely, due to inhibition of aromatase activity within the central nervous system.
Hirsch
K S
KS
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285.
Weaver
D E
DE
Black
L J
LJ
Falcone
J F
JF
MacLusky
N J
NJ
D000818:Animals; D047072:Aromatase Inhibitors; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005260:Female; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007248:Infertility, Male / Q000139:chemically induced*; D007700:Kinetics; D008297:Male; D010052:Ovariectomy; D010902:Pituitary Gland / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism
D047072:Aromatase Inhibitors; D004967:Estrogens; D011743:Pyrimidines; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; C033789:fenarimol