Endocrine Modulation of Reproduction

The ability of foreign compounds to affect the functioning ofvarious endocrine systems is currently thought responsible fora wide variety of effects. The presentations in this Symposiumreviewed the evidence for and against the involvement of endocrinesystems in several different aspects of reproduction. The mechanismbehind the ability of a triazine herbicide to cause enhancedappearance of mammary tumors in one strain of female rats isreviewed by Stevens. The data suggest that enhanced aging, notdirect mammary modulation, is responsible. Dietary phytoestrogens,the mediators of their actions, their effects in various biologicalsystems, and the relationships between phytoestrogen producersand consumers are all provocatively and succinctly reviewedby Hughes. Kelce presents the strategy used to dissect the modeand mechanisms of action of a fungicide that opened a new awarenessin reproductive toxicology: the possibility of xenobiotics beingantiandrogens. Finally, to heighten our understanding of theinterplay among hormonal systems in vivo, Hess reviews the datathat show that androgens are not the only hormones importantin the development of the male reproductive system: the pituitaryis shown to play a critical role at specific stages of development.The breadth of these presentations, and the implications oftheir findings, should make us pause and realize how much thereis still to discover about the interaction between the reproductivesystem and anthropogenic compounds.     

Toxicity Sudies of Acetone Administered in the Drinking Water of Rodents

Toxicity Studies of Acetone Administered in the Drinking Waterof Rodents. DIETZ, D. D., LEININGER, J. R., RAUCKMAN, E. J.,THOMPSON, M. B., CHAPIN, R. E., MORRISSEY, R. L., AND LEVINE,B. S. (1991). Fundam Appl. Toxicol 17, 347–360. Two- andthirteen-week toxicity studies were conducted using male andfemale F344/N rats and B6C3F1 mice. Animals were exposed tothe following concentrations of acetone in their drinking water:two-week studm 0; 5000; 10,000; 20,000; 50,000; or 100,000 ppmacetone. Thirteen-week rat and female mouse studies 0; 2500;5000; 10,000; 20,000; or 50,000 ppm acetone. Thirteen week malemice were exposed to 0; 1250; 2500; 5000; 10,000; or 20,000ppm acetone. Depressed body weight gain was restricted to the50,000 and 100,000 ppm exposure groups. Male and female miceexposed respectively to 20,000 or 50,000 ppm acetone for 2 weeksdeveloped hepatocellular hypertrophy. This change was not apparentafter 13 weeks of exposure although relative and alsolute liverweight was increased in high dose female mice. Bone marrow hypoplasiawas observed In 5/5 high dose (100,000 ppm) male rats duringthe 2-week studies. Treatment of male rats for 13 weeks resultedin a variety of mild and subtle hematological changes that oftenoccurred at relatively low levels of exposure (5000 ppm) andresembled those seen during the clinical condition of megaloblasticanemia Changes characteristic of hypogonadism (depressed spermmotility and cauda epididymal and epididymal weight and elevatedincidence of abnormal sperm) were observed in male rats raceiving50,000 ppm acetone for 13 weeks. The incidence and severityof a kidney laion that is morphologically similar to the spontaneouslyoccurring nephropathy among aging F-344 rats were increasedat 20,000 and 50,000 ppm acetone, respectively, in 13-week malerats. In summary, the effects of acetone were either subtlein nature or occurred during very high levels of exposure confirmingacetone's low level of toxicity. The daily levels of acetoneexposure were often several-fold greater than possibly encounteredby humans during the accidental consumption of contaminatedgroundwater (250 ppm; 5 mg/day) and frequently exceeded maximumlevels reported following acute toxic exposures (2,500 mg/kg).     

Subchronic (13-Week) Toxicity Studies of Oral Phenolphthalein in Fischer 344 Rats and B6C3F1 Mice

Phenolphthalein is a cathartic agent that is widely used inover-the-counter laxatives. Thirteen-week toxicity studies ofphenolphthalein were performed using F344/N rats and B₆C₃F₁mice. Rats and mice were fed ad libitum with a NIH 07 diet containing0; 3000; 6000; 12,000; 25,000; or 50,000 ppm phenolphthalein.On a milligram per kilogram body weight basis, rats and micefed 50,000 ppm phenolphthalein ingested more drug than wouldbe expected during human laxative abuse. Phenolphthalein producedlittle evidence of toxicity in rats. There was slightly lowerweight gain among the 25,000 and 50,000 ppm groups. Treatedrats showed elevated relative kidney weights (males only) andelevated absolute and relative liver weights at 12,000–50,000ppm phenolphthalein. Rat serum bile acids were depressed early(Days 5 and 6) by phenolphthalein treatment. Several treatment-relatedtoxic effects, however, were identified in mice who receivedmore phenolphthalein per unit body weight than rats. Althoughthere were no effects on body weight gain, elevated liver weightswere noted in female mice receiving 6000–50,000 ppm phenolphthalein.The primary treatment-related findings that occurred duringthe mouse studies involved the reproductive and hematopoieticsystems. Reproductive changes including depressed testis andright epididymal weights and sperm density, an elevated productionof abnormal sperm, and morphologic alterations in seminiferoustubules occurred at all levels of exposure (3000–50,000ppm). Hematopoietic changes included bone marrow hypoplasia(12,000–50,000 ppm), increased splenic hematopoiesis (malesonly, 25,000 and 50,000 ppm), and an elevated incidence of micronucleatederythrocytes (6000–50,000 ppm).     

Toxicology Studies of a Chemical Mixture of 25 Groundwater Contaminants: III. Male Reproduction Study in B6C3F1 Mice

A mixture of chemicals has been developed that models contaminatedgroundwater around hazardous waste sites. We investigated theeffects of this mixture on spermatogenesis in B6C3F₁ mice. Theanimals consumed three different concentrations of this mixturefor 90 days, after which time they were euthanatized. Althoughthere was a concentration-related decrease in the amount offluid consumed at the higher two concentrations, there wereno differences in body weight among the groups. Similarly, therewas no effect of mixture consumption upon the histology of liver,kidney, testis, epididymis, or seminal vesicles or upon theabsolute organ weights of these organs. Kidney weight relativeto body weight was increased in the high dose group. Epididymalsperm number and testicular spermatid count were not affectedby treatment. These studies show that, at exposure levels thatdecrease fluid intake and increase adjusted kidney weight, therewere no effects of this mixture on gametogenesis in male mice.     

Are Mouse Strains Differentially Susceptible to the Reproductive Toxicity of Ethylene Glycol Monomethyl Ether? A Study of Three Strains

Most rodent reproductive toxicology studies utilize strainsof high fecundity. These studies were conducted to examine thepossibility that mouse strains of differing fecundity wouldrespond differently to a known reproductive toxicant. Thirtypairs each of Swiss CD-1, C57B1, and C3H mice were cohabitedfor 14 weeks while consuming 0, 0.03, 0.10, or 0.30% EGME inthe drinking water. Litter data were collected during cohabitation.Body and organ weights, and various sperm data, were collectedat necropsy, and second-generation fertility was evaluated.The data show that the most fecund strain (Swiss) was affectedthe least by exposure to EGME, while the least fecund strain(C3H) suffered the greatest declines in fertility. These differencesmight alter interspecies extrapolation factors, or the permissibleexposure levels for humans.     

Effects of Ethylene Glycol Monomethyl Ether (EGME) on Mating Performance and Epididymal Sperm Parameters in F344 Rats

Effects of Ethylene Glycol Monomethyl Ether (EGME) on MatingPerformance and Epididymal Sperm Parameters in F344 Rats. CHAPIN,R. E., DUTTON, S. L., ROSS, M. D., and LAMB, J. C, IV. (1985).Fundam. Appl. Toxicol. 5, 182–189. Previous histologicstudies on the effects of EGME identified dividing spermatocytesas a primary target cell type in the testis. The following studieswere undertaken to assess possible effects of EGME on late-stageand epididymal spermatids, and spermatogonia. Adult male F344rats (n = 20/group) of proven fertility were dosed po with 0,50, 100, or 200 mg EGME/kg/day for 5 days. Each male was thenmated with two females/week for 8 weeks. Females were sacrificedca. 2 weeks after removal from the male, and number of liveand dead fetuses, resorption sites, and corpora lutea were noted.Additional males were treated similarly, sacrificed at weeklyintervals, and measures of epididymal sperm count, motility,and morphology were made. The fertility of males treated with200 mg EGME/kg declined at Week 4, and remained low for therest of the study. There was a modest but significant increasein the number of resorption sites at Weeks 5 and 6 in the highdose group. There was a decrease in the number of Utters siredat Week 5 after dosing in the 100-mg EGME/kg group. There weretime- and dose-related decreases in sperm concentration andmotility, primarily in the 100- and 200-mg/kg groups, as wellas concurrent elevations in the number of abnormal sperm formsin the epididymis. These studies show that EGME is a very weakinducer of dominant–lethal mutations, and produces previouslyundescribed effects on late-stage spermatids and spermatogonia.