PARENT SESSION
MINISYMPOSIUM III: Adverse Effects on Reproductive Development in the Male.
Monday, July 30, 2001, 10:30 AM-12:00 PM
Westin-Confederation III
Chair: Leon E. Gray, Jr.
Speakers: Leon E Gray, Jr, Jimmy L Spearow, Philippa T Saunders
M8
GENETIC VARIATION IN SUSCEPTIBILITY TO ENDOCRINE DISRUPTION BY ESTROGENIC AGENTS.
Spearow, Jimmy1, Altafi, Rashid1, Cahill, Maureen1, O'Henley, Peter1, Stearns, Trevor1, Orozio, Lorena1, Jewison, Amber1, Barkley, Marylynn1, 1
ABSTRACT- Strains of mice differ well over 16-fold in sensitivity to the disruption of juvenile male reproductive development and spermatogenesis by estrogen. We extended previous studies to examine the genetic and physiological mechanisms that determine genetic differences in Susceptibility to Endocrine Disruption by Estrogenic agents (SEDE). Immature males of inbred C57BL/6J (B6), outbred CD-1, inbred CD9, inbred C17, wild derived outbred mus spretus (SPR), as well as CD9xB6 F1 and F2 mice were implanted subcutaneously at 3.5 weeks of age with silastic implants containing 0, 0.625, 2.5, 10, 40, or 160 
g estradiol (E2). The disruption of spermatogenesis and reproductive development were evaluated 4 weeks later by determining reproductive organ weights, histology and hormone levels. The effects of Strain, Dose of E2 and the Strain x Dose interaction were highly significant on testes and accessory gland weights (P<0.001). Large litter size selected CD-1 males were the most resistant to estrogen, showing only a slight inhibition of testes weight in response to 10 g E2, but no significant inhibition in response to 40 or 160 g E2. In contrast, other laboratory and wild strains and crosses were much more sensitive to the inhibition of testes weight by increasing doses of E2. B6 strain mice were highly sensitive to endocrine disruption by E2, showing a consistent inhibition of testes weight at and above 2.5 g E2 (P<0.0001). While F1 crosses showed heterosis for testes weight, their relative sensitivity to estrogen suggests a combination of additive and non-additive gene action controlling SEDE. Inbreeding from CD-1 in strain CD-9 increased sensitivity to endocrine disruption also suggesting non-additive gene action controlling this trait. While studies on potential endocrine and receptor mechanisms are continuing, ligand binding studies to date have detected minimal differences in the affinity of uterine estrogen receptors between untreated immature CD-1 and B6 strain mice. Estrogen sulfotransferase (EST) activity was determined in 5 week old untreated males. While liver EST activity did not differ between CD-1 and B6, testicular EST was 4.6 times higher per g testis in CD-1 than in B6 (P< 0.01). CD-1 males were also much more resistant than B6 males to the inhibition of testicular EST by increasing doses of E2. These findings demonstrate: 1) a large amount of genetic variation in susceptibility to endocrine disruption by estrogenic agents (SEDE); 2) that additive and non-additive genes control SEDE; 3) that inbreeding increases SEDE; and, 4) a large amount of genetic variation in testicular EST. These results show that inbreeding and/or loss of heterozygosity at critical loci increases SEDE. This finding suggests that small, increasingly inbred populations are likely to become even more sensitive to, and more threatened by exposure to endocrine disrupting chemicals. These findings also show that genetic variation in SEDE needs to be considered in designing bioassays for detecting chemicals with endocrine disrupting activity. (Support NSF IBN 9986077).
KEY WORDS: estrogen