The inhibin B (InhB) response to the testicular toxicants mono-2-ethylhexyl phthalate (MEHP), 1,3 dinitrobenzene (DNB), or carbendazim (CBZ) following short-term repeat dosing in the male rat.
OBJECTIVE
The objective of this study was to evaluate the utility of plasma Inhibin B (InhB) as a biomarker of testicular injury in adult rats following short-term exposure to the known Sertoli cell toxicants mono-2-ethylhexyl phthalate (MEHP), 1,3 dinitrobenzene (DNB), or carbendazim (CBZ).


METHODS
Following oral gavage administration of the compounds for 2 or 7 days, the rats were evaluated for clinical signs, body weight, food consumption, organ weights, plasma hormone levels, and gross and microscopic pathology.


RESULTS
MEHP, DNB, and CBZ produced a range of testicular toxicity characterized by minimal exfoliation of germ cells as demonstrated by increased cellular debris in the epididymis (MEHP) to more severe and dose/duration responsive Sertoli cell vacuolation, germ cell degeneration, and multinucleated giant cells of germ cell origin (DNB and CBZ). The slight to moderate Sertoli and germinal cell injuries did not correlate with significant changes in plasma InhB levels following 2- or 7-day exposures. However, more severe injury to germinal epithelium following up to 7 days of exposure, but not after 2 days of exposure, correlated with decreased plasma InhB levels and less consistently with increases in plasma follicle stimulating hormone.


CONCLUSIONS
In conclusion, under the conditions of these studies, changes in InhB were not an effective early onset marker of testicular toxicity or an effective marker for slight to moderate levels of acute injury, and only reflected more severe disruption of spermatogenesis. Changes in plasma InhB and follicle stimulating hormone were poorly correlated except in some instances of moderate to marked testicular toxicity.
Non-Clinical Safety Assessment, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. wjbreslin@lilly.com
William J
WJ
Breslin
April
A
Paulman
Denise
D
Sun-Lin
Keith M
KM
Goldstein
Angela
A
Derr
D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000633:toxicity*; D002219:Carbamates / Q000008:administration & dosage / Q000633:toxicity*; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives* / Q000633:toxicity; D004136:Dinitrobenzenes / Q000008:administration & dosage / Q000633:toxicity*; D004822:Epididymis / Q000187:drug effects / Q000473:pathology; D005640:Follicle Stimulating Hormone / Q000097:blood; D007265:Inhibins / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000187:drug effects* / Q000473:pathology*
D001562:Benzimidazoles; D002219:Carbamates; D004136:Dinitrobenzenes; C422364:inhibin B; D007265:Inhibins; D005640:Follicle Stimulating Hormone; D004051:Diethylhexyl Phthalate; C017906:3-dinitrobenzene; C016599:mono-(2-ethylhexyl)phthalate; C006698:carbendazim