Correlation of sperm and endocrine measures with reproductive success in rodents.
This paper compares the statistical precision and biological sensitivity of multiple indices of reproductive function to infertility in the male rodent. The studies discussed include those that examined reproductive function in the male following perinatal exposure to reproductive toxicants and others in which the compounds were administered to young-adult males, often with very diverse results. For example, some chemicals that alter sex differentiation reduce fertility by affecting breeding performance alone (polychlorinated biphenyls (PCBs), fenarimol, or losulazine), without altering sperm and testicular measures. Others also markedly alter sex differentiation of the genitalia, the accessory glands and the testis in addition to their effects on central nervous system (CNS) sex differentiation and mating behavior (testosterone, flutamide, cyproterone acetate, tamoxifen, estradiol and diethylstilbestrol (DES)). In contrast, prenatal exposure to compounds that alter primary germ cell survival (busulphan, congo red) induce partial gonadal/germ cell agenesis without altering sex differentiation. These chemicals dramatically reduce testicular sperm production in the male offspring, and the most severely affected males are infertile. In a series of studies conducted in our laboratory, young male rats were exposed to known reproductive toxicants in a dose related manner from puberty, through young adulthood and breeding. We have found that the profile of effects varies considerably depending upon the chemical's mechanism of toxicity. When a compound produced infertility through direct effects of testicular function (Carbendazim (MBC) and dibutyl phthalate (DBP)), then testis weight, testicular histology, and testicular sperm head counts provided sensitive indicators of toxicity. In general, dramatic reductions in sperm production are required to induce infertility and these changes were accompanied by elevated serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and changes in human chorionic gonadotropin (hCG)-stimulated testosterone synthesis. Chemicals that have hormonal activity, alter the internal endocrine environment, or directly effect CNS function induce a completely different profile of effects. For example, estrogen administration alters the function of the seminal vesicle and the endocrine system, and reduces epididymal sperm reserves; while testicular measures are relatively unaffected. Since very different spectrums of effects are produced by different compounds, no single endpoint will consistently be the most sensitive indicator of reproductive toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
Gray
L E
LE
Developmental and Cellular Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
Ostby
J
J
Ferrell
J
J
Sigmon
R
R
Cooper
R
R
Linder
R
R
Rehnberg
G
G
Goldman
J
J
Laskey
J
J
D000818:Animals; D001562:Benzimidazoles / Q000633:toxicity; D002219:Carbamates; D003224:Congo Red / Q000633:toxicity; D003993:Dibutyl Phthalate / Q000633:toxicity; D005298:Fertility / Q000187:drug effects*; D008297:Male; D008731:Methoxychlor / Q000633:toxicity; D051379:Mice; D051381:Rats; D013094:Spermatozoa / Q000187:drug effects*; D013737:Testis / Q000187:drug effects*
D001562:Benzimidazoles; D002219:Carbamates; D003993:Dibutyl Phthalate; D003224:Congo Red; C006698:carbendazim; D008731:Methoxychlor