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The reproductive toxicity of lead was investigated in NMRI mice exposed to 0.5% lead acetate in drinking water from day 1 of intra-uterine life until 60 days after birth. Compared with control mice, the weights of lead- exposed fetuses and subsequently of the lead-exposed weaned pups, male and female, diminished by 11 and 13% respectively. The lead-exposed male and female offspring of lead-exposed dams were mated with unexposed females and males, to examine the effect of lead exposure on reproductive function. Male fertility was not affected but reduced female fertility was observed: litters were smaller and a smaller number of implantation sites was found in lead-exposed females. In lead-exposed males, the weights of the body, testes and epididymes diminished by about 13%, and seminal vesicle and ventral prostate weights, by about 29%. Testicular histology and the number and mor phology of epididymal spermatozoa were normal. The lev els of plasma FSH, LH and testosterone, and of testicular testosterone, were not modified. These results suggest that the hypothalamic-pituitary-testicular axis is not adverse ly affected by the above lead exposure, and that therefore the decreased seminal vesicle and ventral prostate weights might not be the consequence of reduced testosterone lev els. The hypothesis that lead has a direct effect on these organs as well as a secondary effect resulting from possi bly reduced food consumption by lead-exposed mice can not be excluded. Consequently, in male NMRI mice, expo sure to lead might affect reproductive function by acting directly and/or indirectly on accessory sex organs.

To clarify the mechanism of the action of lead on male reproductive function, adult male rats were injected intraperitoneally (i.p.) with lead acetate (8 mg/kg/day of lead), 5 days a week for 35 days. Despite this high dose, germ cells and Sertoli cells did not appear to be major targets of lead. However, lead determination in the reproductive organs showed that the accessory sex glands are such a target. Epididymal function was unchanged. In lead-exposed rats, plasma and testicular testosterone dropped by about 80%, but plasma luteinizing hormone (LH) only dropped by 32%. After luteinizing hormone releasing hormone (LHRH) stimulation of the pituitary, the plasma LH level reached the control one, but plasma testosterone remained significantly reduced by 37%. The sharp decrease in the testosterone:LH ratio in lead-exposed rats, combined with the significant reduction of intertubular tissue volume in the testes, indicate impaired Leydig cell function.

1 The effects of lead poisoning during pregnancy were tested on female Sprague-Dawley rats that inhaled 5 mg m-3 lead oxide for 13 days during gestation. At the end of gestation, the respective blood lead levels of dams and fetuses were 71.1 and 83.2 μg 100 ml-1, indicating lead poisoning. 2 In the 90 day-old male offspring of the exposed dams, testis weight and histology, and epididymal weight and sperm reserve, were all similar to those of control males. Spermatozoa mobility and morphology were normal. 3 Also similar to control values were the pituitary weight in these male offspring, their plasma FSH, LH and testosterone levels, and the weight of their ventral prostate and seminal vesicles, the targets of the sexual hormones. 4 When male and female offspring of exposed dams were mated, their fertility was normal, with no increase in prenatal death or malformations, and no changes in the size or sex ratio of litters. 5 These results indicate that, under our experimental conditions, lead oxide inhalation by rats during pregnancy did not perturb reproductive function in their male offspring.

Ninety-day-old Sprague-Dawley rats were intoxicated for 70 d with lead, given either as 0.3% lead acetate in drinking water or by inhalation as 5 mg m-3 lead oxide. Direct or transmitted lead toxicity for the male reproductive system was assessed in the rats and their offspring from pituitary and genital organ weights after exposure, the numbers of Sertoli and germ cells, the number, motility and morphology of epididymal spermatozoa, the levels of plasma testosterone, LH and FSH and fertility tests. Whole blood lead levels were similar after lead ingestion and after inhalation (58.0 ± 1.7 μg dl-1 vs. 51.1 ± 1.8 μg dl-1). Lead acetate ingestion did not affect the reproductive system or fertility of rats. Inhalation of lead oxide did not affect fertility either, but seminal vesicle weight dropped significantly, which might suggest an alteration in the pattern of testosterone secretion. In the male progeny of sires that inhaled lead, the number of epididymal spermatozoa decreased but this did not interfere with fertility. Our results show that for the doses studied, lead inhalation and lead ingestion do not produce strikingly different effects on the male rat's reproductive system. Differences between the present findings and those of others might be due to difference of rat strain or of age at exposure.

BACKGROUND Hormonal treatments lasting 2–6 months inhibit spermatogenesis in men and have been proposed as germ cell protection against anticancer therapy. Because it is unthinkable to delay anticancer treatments, the authors investigated the protection afforded against irradiation of rats by 22 days of hormonal pretreatment. METHODS Adult Sprague–Dawley rats were assigned to an untreated control group (C) or to one of 5 treatments: medroxyprogesterone acetate plus testosterone only (M), 3 or 5 gray of irradiation (R3 and R5), or hormonal treatment prior to 3 or 5 gray of irradiation (MR3 and MR5). Mating trials were conducted 1, 24, 45, 65, 86, and 109 days after treatment. At 122 days, genital organ weights, testis histology, and epididymal spermatozoa were evaluated. RESULTS Irradiation reduced sperm production and had a clastogenic effect on postmeiotic germ cells. No protective effect of steroid treatment was observed. Moreover, testis weight, tubule diameter, the repopulating index, and the sperm head count decreased more in the MR5 group than in the R5 group. Mating tests showed decreases in positive vaginal smears and fertility at both 45 and 65 days, and an increase in resorption at 109 days. CONCLUSIONS These results indicate that hormonal pretreatment potentiates irradiation damage to germ cells, especially stem cells, as regards survival and genomic alterations, probably because of increased lipoperoxidation of late spermatids. Cancer 1999;85:1313–22. © 1999 American Cancer Society.

Lead is known to impede the male reproductive function, however, the mechanisms through which the adverse effects are mediated are not clearly elucidated. In order to get insight into those mechanisms, we have examined the effects of lead on the biosynthesis of steroid hormones by Leydig cells in the rat. To determine whether lead has a direct action on Leydig cells, we have compared the concentrations of testosterone secreted by Leydig cells in ex vivo experiments after animals had been injected with high doses of lead and in vitro experiments with Leydig cells from normal rats maintained in culture in presence or absence of lead. In ex vivo experiments male Sprague-Dawley rats were injected i.p. with lead acetate (8 mg lead/kg/day, 5 days a week for S weeks) or with sodium acetate. Testosterone production by Leydig cells isolated and maintained in culture for 48 h was then assessed under basal conditions or after stimulation by human chorionic gonadotrophin (hCG). Both basal and hCG-stimulated testosterone production dropped by 59% and 37%, respectively, with Leydig cells from lead-exposed rats. For in vitro experiments, cultures of Leydig cells from control rats were exposed to various concentrations of lead acetate for different periods. Dose and time-dependent reductions of testosterone level were observed in the culture medium. The effective doses of hCG for maximal and half-maximal testosterone production did not change, indicating that the sensitivity of Leydig cells to hCG was not impaired by exposure to lead in vitro. Progesterone production was also decreased after this exposure. The negative effect of lead on testosterone and progesterone production was correlated with the lower expression of the enzymes cytochromes P450scc (CYP11 A1) and P450c17 (CYP17) and 3β-hydroxysteroid dehydrogenase (3β-HSD) involved in steroid hormone biosynthesis, as shown by immunohistochemistry. Ultrastructural alterations of the smooth endoplasmic reticulum observed after lead administration might be correlated with the lower expression of the microsomal enzymes P450cl7 and 3β-HSD. Our results indicate that lead can adversely affect the Leydig cell function by impairing directly steroidogenesis.

Lead is an environmental pollutant which has received much attention, partly because of the particular sensitivity of children to this element. As regards the consequences of exposure to lead during fetal life or childhood, epidemiological studies have so far focused on its neuropsychological effects and little is known about the consequences of fetal or childhood exposure for reproduction. With respect to animals, the reproductive toxicity of lead in males exposed during prenatal life or the suckling period has only been considered in a few studies. Four such studies concerned the rat, the most current model of lead toxicity for male reproduction; two of studies considered the long term effects (i.e. during adulthood) of moderate in utero lead exposure, another covered the prenatal and neonatal periods and focused on the possible impact of lead intoxication on steriodogenesis before weaning, while the remaining study dealt with pituitary hormone level at the end of lead gavage in newborns. None of these investigations compared the effects of exposure during prenatal life to those of exposure via lactation, or the early effects (at about weaning time) to the long-term consequences during adulthood. Because of the paucity of data on these points, we conducted two experiments:more » in one, rats were exposed to lead prenatally, and in the other via maternal milk. In both cases male reproductive function at weaning and adulthood was examined. 12 refs., 1 fig., 2 tabs.« less

To study cell to cell communications within the testis of adult Sprague-Dawley rats, we used acute whole body neutron plus gamma-irradiation (0.99 Gray of neutron and 0.24 Gray of gamma-rays, 3 min; Exp A) over 7-121 days postirradiation and chronic whole body gamma-irradiation (7 cGy/day 60Co gamma-rays; Exp B) over 14-84 days of irradiation and 7-86 days postirradiation. Neither irradiation protocol had an effect on the body weight of the animals. Neutron plus gamma-rays induced dramatic damages to spermatogonia, preleptotene spermatocytes, spermatozoa, and, to a lesser extent, pachytene spermatocytes. In contrast, gamma-rays induced a selective destruction of spermatogonia. Subsequently, in both experiments a maturation-depletion process led to a marked decrease in all germ cell types. A complete or near complete recovery of the different germ cell types and spermatozoa took place during the two postirradiation periods. Under both irradiation protocols Sertoli cells number was unchanged. Androgen-binding protein and FSH levels were normal in spite of the disappearance of most germ cells from spermatogonia to early spermatids. However, the decline of androgen-binding protein as well as the rise of FSH and their subsequent recovery were highly correlated to the number of late spermatids and spermatozoa. Moreover, it appeared that spermatocytes may also interfere with the production of inhibin (Exp B). With neither irradiation was Leydig cell function altered, except in Exp B in which elevated LH levels were temporarily observed. Correlation analysis suggested a relationship between preleptotene spermatocytes and Leydig cell function. In conclusion, this study establishes that chronic gamma-irradiation is particularly useful in the study of intratesticular paracrine regulation in vivo and provides further support to the concept that late spermatids play a major role in controlling some aspects of Sertoli cell function in the adult rat.

Continuous low-dose gamma-irradiation of mature rats induced a progressive degeneration of the germ cells. Blood FSH increased by 127, 176 and 214%, respectively, after 55, 70 and 85 days of treatment when compared to FSH levels in control rats (8.50 +/- 0.60 ng/ml); conversely, serum LH and testosterone levels were unchanged. The Sertoli cell function was affected by the treatment from 70 days on, as attested by androgen binding protein (ABP) and transferrin secretions which diminished 35-40%. Serum ABP levels were not altered, whatever the duration of irradiation, even though epididymal ABP contents (as well as concentrations) diminished 34-60% when compared to those of the controls. Moreover, in purified Leydig cells, LH-stimulated intracellular cAMP levels, which were decreased by seminiferous tubule medium (STM) from control rats, were enhanced in presence of STM from treated animals. Testosterone output was stimulated 9-fold in presence of oLH and further increased (46-76%) from stages XIV-V by STM prepared from control and irradiated rats, respectively. After 85 days the STM effects on both cAMP and testosterone syntheses were zero. These results demonstrate a probable alteration of Sertoli cell function after irradiation, but also a role of the germ cells in the regulation of the synthesis of ABP, transferrin and Sertoli cell paracrine factors.

Continuous low dose irradiation induces a progressive degeneration of germ cells with a concomittant increase in blood FSH; however, the Sertoli cell function is not too much altered since serum ABP level is normal and it is likely that the decrease of epididymal ABP content is the consequence of a reduction in seminiferous tubule fluid excretion. Obviously, spermatids seems to be involved in the regulation of Sertoli cell ABP synthesis.

SummaryThe effects of a continuous exposure to cobalt gamma rays administered to rats at a daily dose of 0, 0·07, 0·12, 0·20 or 0·30 Gy for a period of up to 90 or 135 days, have been observed on their B lymphocyte populations and on their immunoglobulin serum levels. The effects increase with the daily dose and the duration of irradiation. At a daily dose of 0·07 Gy, no clear effect was observed. The depletion was almost negligible after 30 days at a daily dose of 0·12 Gy, but visible after all other doses and durations. However, a clear difference in susceptibility was observed between the marginal zone B compartment and the follicular one, the former being much more affected by the radiation than the second.