Maternal exposure to butyl paraben impairs testicular structure and sperm quality on male rats

Parabens are hormonally active chemicals widely used as preservatives in foods and are frequently detected in human fluids and tissues. Therefore, the objective of this study was to determine the effects of maternal butyl paraben (BP) exposure on male sexual development. Pregnant Wistar rats received corn oil (control group), or BP at doses of 10, 100, or 200 mg/kg, subcutaneously, from gestational day 12 until postnatal day 21. Our results demonstrated that developmental BP exposure significantly increased the number of adult Leydig cells and the circulating concentrations of testosterone and attenuated FSH and LH concentrations at 200 mg/kg. BP exposure adversely affected spermatogenesis kinetics at doses of 10 and 200 mg/kg and provoked a decrease in the immunostaining of EsR1 and AR at 200 mg/kg. The sperm motility was impaired at the 10 mg/kg dose, and sperm head abnormalities were increased in all BP dose groups. We suggest that BP impairs testicular structure and function in the rat, affecting sperm quality. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1273–1289, 2017.     

萘普替尼对雄性大鼠睾丸形态结构和附睾精子质量的影响

目的 探究萘普替尼对雄性大鼠睾丸形态结构及附睾精子质量的影响。方法 将30只雄性SD大鼠随机分为30和70 d两组,每组又分为对照组和萘普替尼低、高剂量组（0.75、3.00 mg/kg）,ig给药,每天给药1次,给药体积10 mL/kg。每天进行1次症状观察,每周称量一次体质量,大鼠分别于给药35和70 d后次日处死,肉眼检查各脏器有无异常,检测双侧睾丸质量和横径、附睾尾精子数量和活力,睾丸固定进行组织病理学检查。结果 萘普替尼高剂量组动物均从给药第14天开始,出现腹泻、脱毛、口鼻眼处有红色分泌物,随着给药天数的增加,症状加重;给药70 d组其中1只动物于给药60 d开始出现血尿症状。给药35 d组大鼠从给药21 d开始,给药70 d组从14 d开始,高剂量大鼠体质量明显低于同期对照组（P<0.01）。与对照组比较,给药组雄鼠的双侧睾丸绝对质量和脏器指数、睾丸横径、附睾尾精子数量和活力及睾丸组织病理学检查并未随给药剂量的增加和给药时间的延长而出现明显变化。结论 萘普替尼对雄性大鼠的睾丸组织及精子质量无明显影响。     

Lead exposure reduces sperm quality and DNA integrity in mice

Toxicity of lead on male reproductive functions has raised wide public concern as environmental lead contamination remains common worldwide. Conflicting and controversial data are available regarding effects of lead on male fertility. More importantly, our knowledge on effects of lead on sperm DNA integrity is significantly limited. Thus, further studies should focus on this issue. In the current study, adult male mice were exposed to a series of lead acetate concentrations in drinking water for six weeks. Following administration, lead levels in blood, testicles, and epididymis were measured, and potential changes in morphology of testis and epididymis due to lead exposure were identified. We also analyzed sperm parameters, including sperm density, viability, motility, and morphology, to evaluate quality of sperm collected from epididymis. Especially, hypothetical influence of lead on sperm DNA integrity was also evaluated by terminal deoxynucleotidyltransferase‐mediated dUTP‐biotin nick end labeling, alkaline comet assay, and sperm chromatin structure assay. Lead exposure possibly exerted no effect on growth of mice because these animals acquired similar body weight gain during the experimental period. However, high lead concentrations (0.5% and 1%) in drinking water affected sperm motility and increased percentage of spermatozoa with abnormal morphology. In groups treated with 0.25%, 0.5%, and 1% lead acetate, percentages of sperm cells showing DNA breaks and chromatin structure damage significantly increased. Altogether, lead exposure not only exhibits adverse effects on sperm physiological parameters, but also impairs DNA structure and integrity. These effects may lead to significant decline in male fertility.     

Effects of acute and chronic exposure to cobalt on male reproduction in mice

Chronic exposure of male mice to cobaltous chloride dramatically affected their reproductive potential, while acute administration had minimal effects. Acute exposure, followed by evaluation weekly over a 7-week period, revealed no significant changes in epididymal sperm concentration or testicular weight. However, small but significant decreases in fertility at weeks 2 and 3 of the study were observed. Sperm motility was depressed only during the first week of the study. In chronic studies, cobalt affected fertility in a time- and dose-dependent manner. There was a decrease in testicular weight, epididymal sperm concentration, and fertility. Sperm motility was also depressed. Serum testosterone levels were dramatically increased in cobalt treated animals, while FSH and LH serum levels were normal. It appears that cobalt is directly or indirectly interfering with spermatogenesis and with local regulatory mechanisms in testosterone synthesis.     

Perinatal exposure to low doses of tributyltin chloride reduces sperm count and quality in mice

Exposure to endocrine disruptors (EDs) during early development might lead to adverse health outcomes later in life. Tributyltin (TBT), a proven ED, is widely used in consumer goods and industrial products. Herein we demonstrate the effects of low doses of tributyltin chloride (TBTCl) on reproduction of male KM mice. Pregnant mice were administered by gavage with 0, 1, 10, or 100 μg TBTCl/kg body weight/day from day 6 of pregnancy through the period of lactation. TBTCl dramatically decreased sperm counts and motility on postnatal days (PNDs) 49 and 152. Meanwhile, a significant increase in sperm abnormality was observed in exposed mice on PND 49, but comparable to that in the control on PND 152. The histopathological analysis of testes of treated animals showed a dose‐dependent increase in sloughing of germ cells in seminiferous tubules. Mice treated with 10 μg TBTCl/kg exhibited decreased intratesticular 17β‐estradiol (E2) levels on PND 49, and then followed by an obvious recovery on PND 152. While, no significant differences in serum E2, testosterone (T) levels and intratesticular T levels were detectable between control and TBTCl‐exposed offspring at the sacrifice. These results suggest that perinatal TBTCl exposure is implicated in causing long lasting alterations in male reproductive system and these changes may persist far into adulthood. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 44–52, 2015.     

Arsenic trioxide exposure impairs testicular morphology in adult male mice and consequent fetus viability

ABSTRACT

The acute promyelocytic leukemia (APL) is a rare disease, affecting 0.1/100,000 individuals globally. Despite significant advances in APL therapy, some patients still experience relapsed disease. Currently, arsenic trioxide (As₂O₃) was found to be effective in relapsed APL treatment and considered as standard treatment for these cases. However, it has been shown that exposure to As₂O₃ may exert adverse effects on the male reproductive system since this substance might also induce apoptosis of other important cell types including stem cells. Studies demonstrated that treatment with this metallic substance decreased plasma levels of testosterone and interfered with sperm parameters such as concentration, motility, and viability. In addition, As₂O₃ was found to produce significant damage to spermatocytes, which may be associated with testicular toxicity and consequent inhibition of spermatogenesis. The aim of this study was to determine sub-chronic treatment effects of As₂O₃ on sperm and testicular morphology, androgen receptor (AR) immunoreactivity in testes and epididymis, in addition to evaluation of fertility parameters in adult male mice. Thirty adult Swiss mice were divided into three experimental groups: control; received distilled water (vehicle) while treated received 0.3 or 3 mg/kg/day As₂O₃ subcutaneously, for 5 days per week, followed by 2 days of interruption, for 5 weeks. Results showed that As₂O₃ (1) decreased spermatozoa number, (2) produced seminiferous epithelium degeneration and exfoliation of germ cells tubule lumen (3) altered nucleus/cytoplasm proportion of Leydig cells and (4) reduced AR immunoreactivity in both Leydig and epithelial epididymal cells. Further, fetal viability tests demonstrated an increase in post-implantation loss in females that were mated with As₂O₃-treated males. Data indicate that As₂O₃ exposure altered the spermatogenic process and subsequently fetal viability.     

Lower sperm quality and testicular and epididymal structural impairment in adult rats exposed to rosuvastatin during prepuberty

The increase of obesity, bad eating habits and the lack of physical exercises are highly related to dyslipidemias. Rosuvastatin is a lipid‐lowering drug and has been indicated to prevent cardiovascular diseases and to treat dyslipidemias due to its higher efficiency to reduce serum cholesterol concentrations. This study aimed to evaluate the reproductive adverse effects on sexual maturity due to rosuvastatin exposure in juvenile male rats during prepuberty. Three groups were randomly formed with newly weaned rats: control, whose rats received saline solution 0.9% and rosuvastatin at doses of 3 or 10 mg kg^–1 day^–1, administered orally by gavage, from postnatal day 21 until preputial separation (average of 45 days for controls and 49 days for statin‐treated animals), indicative of puberty onset. Male rats were maintained until sexual maturity and were killed on postnatal day 110. In the rosuvastatin‐treated groups, the results showed diminished follicle‐stimulating hormone, luteinizing hormone and testosterone concentrations, increased estradiol and prolactin concentrations, histopathologic alterations on testis and epididymis and decreased sperm quality. Moreover, statin‐exposed groups showed decreased expression of androgen receptor on testis and epididymis and lower expression of aquaporin‐9 on epididymal epithelium. In conclusion, administration of rosuvastatin to prepubertal male rats provoked long‐term hormonal deregulation and impaired reproduction at adulthood.     

Cadmium exposure increases susceptibility to testicular autoimmunity in mice

Cadmium, one of various environmental toxicants, is known to suppress systemic immunity and to injure the testicular capillary endothelia with resultant necrosis of testicular tissues in mice and rats treated with high doses. Recently, it also became evident that cadmium can affect the integrity of the blood–testis barrier (BTB), the endocrine function of Leydig cells, apoptosis of germ cells and systemic immunity, even on treatment with a low dose that does not induce spermatogenic disturbance. Experimental autoimmune orchitis (EAO), i.e., an organ‐specific autoimmunity of the testis, can be induced by repeated immunization with testicular antigens, and its pathology is characterized by lymphocytic inflammation and spermatogenic disturbance. In the present study, we investigated the morphological and functional changes of testes in mice treated with a low dose of cadmium chloride (CdCl₂) and also examined its toxicity as to susceptibility to EAO. The results showed that exposure to 3 mg CdCl₂ kg^?1 body weight did not affect the spermatogenic state. However, the BTB at the tubuli recti and the rete testis, but not the seminiferous tubules, was slightly weakened, and intra‐testicular mRNA expression of interleukin (IL)‐6, tumor necrosis factor‐α and IL‐1β was significantly increased by the CdCl₂ treatment. Furthermore, immunization with testicular antigens after the CdCl₂ exposure significantly augmented the EAO severity. Therefore, exposure to a low dose of CdCl₂ induces no significant disturbance of spermatogenesis, however, it does change the immunological microcircumstances in the testis, resulting in increased susceptibility to testicular autoimmunity. Copyright © 2012 John Wiley & Sons, Ltd.     

Effects of exposure to nanoparticle-rich diesel exhaust on adrenocortical function in adult male mice

To investigate the effects of nanoparticle-rich diesel exhaust (NR-DE) on adrenocortical function, seven-week-old male mice were divided into four groups and exposed to either whole NR-DE at low (41.73 μg/m³, 8.21 × 10⁵ particles/cm³), high (152.01 μg/m³, 1.80 × 10⁶ particles/cm³) concentrations, filtered diesel exhaust (F-DE) or clean air for 8 weeks (5 h/day, 5 days/week). After 8 weeks of exposure, the animals were euthanized under pentobarbital anesthesia and the blood samples were collected to detect serum progesterone and corticosterone. In addition, adrenal glands were excised, and adrenal cells were cultured in the absence or presence of rat adrenocorticotropic hormone (ACTH) (10⁻¹⁵ to 10⁻¹⁰ M) for 4 h. There were no significant differences in the body weight, absolute and relative adrenal gland weight among the groups. Serum concentration of corticosterone and progesterone was not changed significantly. Administration of ACTH resulted in a dose-dependent increase in corticosterone and progesterone release in mice-exposed to low-concentration NR-DE and clean air. Moreover, corticosterone and progesterone concentrations in adrenal cells increased significantly in mice-exposed to low-concentration NR-DE basal and administrated with ACTH (10⁻¹⁵ to 10⁻¹¹ M for corticosterone; 10⁻¹⁴ to 10⁻¹¹ M for progesterone) compared with the control mice. In contrast, the concentration of corticosterone and progesterone decreased significantly in mice-exposed to high-concentration NR-DE or F-DE basal and administrated with ACTH (10⁻¹² to 10⁻¹⁰ M for corticosterone; 10⁻¹⁵ to 10⁻¹⁰ M for progesterone) compared with the control mice. These results suggest that exposure to NR-DE or F-DE may disrupt adrenocortical function in adult male mice.     

Maternal fenvalerate exposure during pregnancy persistently impairs testicular development and spermatogenesis in male offspring

Fenvalerate, a widely used pyrethroid insecticide, has been associated with poor semen quality. As yet, little is known about the effects of prenatal fenvalerate exposure on testicular development. The present study investigated the effects of prenatal fenvalerate exposure on testicular development and spermatogenesis. The pregnant mice were administered fenvalerate (30 mg/kg) by gavage daily from gestational day (gd) 13 to gd 18. The weights of testes and epididymides were significantly decreased in mice whose mothers were exposed to fenvalerate during pregnancy. Importantly, maternal fenvalerate exposure during pregnancy markedly decreased the number of mature seminiferous tubules (stages VII and VIII) in testes of adult male offspring. In addition, maternal fenvalerate exposure during pregnancy significantly reduced the number of epididymal spermatozoa in adult male offspring. Additional experiments showed that the level of serum testosterone (T) was significantly decreased in male fetuses whose mothers were exposed to fenvalerate during pregnancy. Correspondingly, mRNA and protein levels of P450_17α, a T synthetic enzyme, were significantly decreased in fetal testes. Moreover, the disruptive effect of prenatal fenvalerate exposure on testicular T synthesis was irreversible. In conclusion, prenatal fenvalerate exposure irreversibly impairs testicular development and spermatogenesis at least into early adulthood.     

Maternal cypermethrin exposure during lactation impairs testicular development and spermatogenesis in male mouse offspring

Within the last decade, numerous epidemiological studies have demonstrated that endocrine disruptors are a possible cause for a decline in semen quality. Cypermethrin is a widely used pyrethroid insecticide, but little is known about its potentially adverse effects on male reproduction. In the present study, we investigated the effects of maternal cypermethrin exposure during lactation on testicular development and spermatogenesis in male offspring. Maternal mice were administered with cypermethrin (25 mg/kg) by gavage daily from postnatal day 0 (PND0) to PND21. Results showed that the weight of testes at PND21 was significantly decreased in pups whose mothers were exposed to cypermethrin during lactation. Maternal cypermethrin exposure during lactation markedly decreased the layers of spermatogenic cells, increased the inside diameter of seminiferous tubules, and disturbed the array of spermatogenic cells in testes of pups at PND21. In addition, maternal cypermethrin exposure during lactation markedly reduced mRNA and protein levels of testicular P450scc, a testosterone (T) synthetic enzyme. Correspondingly, the level of serum and testicular T at weaning was significantly decreased in pups whose mothers were exposed to cypermethrin during lactation. Although the expression of testicular T synthetic enzymes and serum and testicular T in adulthood had restored to control level, the decreased testicular weight and histological changes were irreversible. Importantly, the number of spermatozoa was significantly decreased in adult male offspring whose mothers were exposed to cypermethrin during lactation. In conclusion, maternal cypermethrin exposure during lactation permanently impairs testicular development and spermatogenesis in male offspring, whereas cypermethrin‐induced endocrine disruption is reversible. © 2010 Wiley Periodicals, Inc. Environ Toxicol 2011.     

Maternal lead exposure during lactation persistently impairs testicular development and steroidogenesis in male offspring

Lead (Pb) is a testicular toxicant. In the present study, we investigated the effects of maternal Pb exposure during lactation on testicular development and steroidogenesis in male offspring. Maternal mice were exposed to different concentration of lead acetate (200 or 2000 ppm) through drinking water from postnatal day (PND) 0 to PND21. As expected, a high concentration of Pb was measured in the kidneys and liver of pups whose mothers were exposed to Pb during lactation. In addition, maternal Pb exposure during lactation elevated, to a less extent, Pb content in testes of weaning pups. Testis weight in weaning pups was significantly decreased when maternal mice were exposed to Pb during lactation. The level of serum and testicular T was reduced in Pb‐exposed pups. The expression of P450scc, P450_17α and 17β‐HSD, key enzymes for T synthesis, was down‐regulated in testes of weaning pups whose mothers were exposed to Pb during lactation. Interestingly, the level of serum and testicular T remained decreased in adult offspring whose mothers were exposed to Pb during lactation. Importantly, the number of spermatozoa was significantly reduced in Pb‐exposed male offspring. Taken together, these results suggest that Pb could be transported from dams to pups through milk. Maternal Pb exposure during lactation persistently disrupts testicular development and steroidogenesis in male offspring. Copyright © 2012 John Wiley & Sons, Ltd.     

Occupational cadmium exposure and testicular endocrine function

Cadmium is known to cause testicular necrosis in several animal species, although there is little data on its possible effects in humans. We have investigated the effect of occupational cadmium exposure on the pituitary-testicular endocrine axis, as measured by serum testosterone, luteinizing hormone (LH) and follicular-stimulating hormone (FSH), in a well-characterized population occupationally exposed to cadmium. Over 60% of all workers, who had been exposed to cadmium oxide fumes for longer than a year, in a single factory, since 1926, were studied. Integrated cadmium exposure estimates were constructed for each subject from atmospheric measurements, together with other available company data, and these exposure estimates were validated by in-vivo neutron activation analyses of liver cadmium burdens. The lack of testicular endocrine effects was in contrast to significant dose-related changes in renal glomerular and tubular function demonstrated in the same population.     

Neonatal exposure to DES in BALB/c male mice: effects on pituitary-gonadal function

Neonatal male BALB/c mice were injected with diethylstilbestrol (DES), estradiol benzoate (E2B), testosterone propionate (TP), progesterone or DES, in combination with E2B, TP or progesterone and examined in adulthood. Body weight was reduced in males exposed to DES, TP or DES + TP, while testicular weight was reduced in animals injected with DES, E2B, TP, DES + TP or DES + progesterone. Exposure to DES and/or E2B also produced reproductive tract abnormalities and concomitant progesterone exposure did not further affect this parameter. Concomitant DES did not further alter the reduced plasma luteinizing hormone (LH) levels attributable to neonatal TP or E2B treatment. Plasma follicle-stimulating hormone (FSH) levels in intact males were increased by DES, DES + progesterone or progesterone alone. Assessment of the feedback effects of exogenous gonadal steroids on pituitary gonadotropin release in castrated adults indicated that injection of 125 micrograms TP further increased the already elevated post-castration levels of LH and FSH in mice neonatally exposed to progesterone. The increase in testosterone (T) concentration after intratesticular human chorionic gonadotropin (hCG) administration was significantly attenuated in mice neonatally exposed to DES plus E2B or to progesterone. Basal testicular T levels were significantly elevated in males exposed to DES, alone, or in combination with progesterone. Exposure to DES and TP increased hypothalamic serotonin (5-HT) levels in intact mice, while levels of 5-HT were lower after castration compared to controls. DES + E2B-treated mice had higher norepinephrine (NE) levels, and E2B-treated mice also had higher 5-HT levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of maternal cadmium exposure during late pregnant period on testicular steroidogenesis in male offspring

Cadmium (Cd) is a testicular toxicant and endocrine disruptor. In the present study, we investigated the effects of maternal Cd exposure during the late pregnant period on testicular development and steroidogenesis in male offspring. Pregnant mice were injected intraperitoneally with CdCl₂ (0.5 mg/kg) daily from gestational day (gd) 13 to gd 17. As expected, fetal weight and crown length were significantly decreased in pups whose mothers were exposed to Cd. Importantly, absolute and relative weights of testes were significantly decreased in male fetuses. In addition, maternal Cd exposure during pregnancy markedly reduced serum T level and downregulated the expression of steroidogenic acute regulatory (StAR) protein, P450scc, P45017α and 17β-HSD in testes of male fetuses. Interestingly, the level of serum and testicular T at adulthood remained decreased in male offspring of Cd-exposed mice. Correspondingly, the expression of testicular P450scc was downregulated in male adult offspring whose mothers were exposed to Cd during pregnancy. Fertility analysis found that the number of live fetuses per litter in F2 generation was significantly decreased in Cd-treated group. Additional experiment showed that placental Cd level was increased about 750 folds in dams injected with Cd. However, only traces of blood Cd was measured in fetuses whose mothers were exposed to Cd during the late pregnant period. Taken together, these results suggest that placenta could deter most of Cd from passing from dams to fetuses. The impairments on testicular steroidogenesis in male offspring could not be attributed to a direct action of Cd on fetal testes.     

Repeated exposure to iron oxide nanoparticles causes testicular toxicity in mice

The aim of this study was to determine whether repeated exposure to iron oxide nanoparticles (Fe₂O₃‐NPs) could be toxic to mice testis. Fe₂O₃‐NPs (25 and 50 mg/kg) were intraperitoneally administered into mice once a week for 4 weeks. Our study showed that Fe₂O₃‐NPs have the ability to cross the blood‐testis barrier to get into the testis. The findings showed that exposure resulted in the accumulation of Fe₂O₃‐NPs which was evidenced from the iron content and accumulation in the testis. Furthermore, 25 and 50 mg/kg Fe₂O₃‐NPs administration increased the reactive oxygen species, lipid peroxidation, protein carbonyl content, glutathione peroxidase activity, and nitric oxide levels with a concomitant decrease in the levels of antioxidants—superoxide dismutase, catalase, glutathione, and vitamin C. Increased expression of Bax, cleaved‐caspase‐3, and cleaved‐PARP confirms apoptosis. Serum testosterone levels increased with increased concentration of Fe₂O₃‐NPs exposure. In addition, the histopathological lesions like vacuolization, detachment, and sloughing of germ cells were also observed in response to Fe₂O₃‐NPs treatment. The data from our study entailed that testicular toxicity caused by Fe₂O₃‐NPs exposure may be associated with Fe₂O₃‐NPs accumulation leading to oxidative stress and apoptosis. Therefore, precautions should be taken in the safe use of Fe₂O₃‐NPs to avoid complications in the fertility of males. Further research will unravel the possible molecular mechanisms on testicular toxicity of Fe₂O₃‐NPs. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 594–608, 2017.     

Effect of human dietary exposure levels of genistein during gestation and lactation on long-term reproductive development and sperm quality in mice.

The objective of the present study was to determine the long-term reproductive effects of gestational and lactational exposure (0, 0.1, 0.5, 2.5 and 10 mg/kg/day) to genistein on male mice at levels comparable to or greater than human dietary exposures. Testicular growth, sperm count and motility, and sperm fertilizing ability in vitro was assessed in male offspring on postnatal days (PND) 105 and 315. Selected genes were also examined by real-time PCR to determine whether genistein caused changes in gene expression similar to those previously observed with diethylstilbestrol (DES). No significant treatment-related effects on male offspring body weight, anogenital distance, seminal vesicle weight or testis weight were observed. There were also no significant effects on sperm count, the percent of motile sperm or the number of motile sperm at any age. The in vitro fertilizing ability of epididymal sperm was increased significantly in the high-dose group approximately 17% (P < 0.001) on PND 105 and 315. The results indicate that developmental exposure of mice to genistein at human exposure levels does not induce adverse effects on sperm quality or changes in testicular gene expression similar to DES.     

Perfluorooctane sulfonate-induced testicular toxicity and differential testicular expression of estrogen receptor in male mice

Perfluorooctane sulfonate (PFOS, CAS#1763-23-1) causes male reproductive toxicities, but the underlying mechanisms are still unclear. In this study, 0, 0.5 and 10 mg/kg/day PFOS were given by oral gavage to adult mice for 5 weeks. In the 10 mg/kg group, serum testosterone levels decreased significantly. Sperm counts declined which might be associated with the decreased proliferation and increased apoptosis of germ cells. In relation to increased apoptosis, bax, cleaved caspase-9 and cleaved caspase-3 levels elevated significantly, indicating that PFOS induced germ cell apoptosis by activating the mitochondrial pathway. In addition, the increase in levels of testicular estrogen receptor (ER) β was observed in both 0.5 and 10 mg/kg group, whereas a decrease in ERα expression was only observed in 10 mg/kg group. These results suggested that the alterations in testicular ERs expression, together with decreased proliferation and increased apoptosis of germ cells, might be involved in PFOS-induced testicular toxicity.     

Dependence on chelating agent properties of nephrotoxicity and testicular damage in male mice during cadmium decorporation

An examination of the histopathological appearance of the kidneys of mice treated with cadmium chloride (s.c.) and simultaneously given 1 of 3 chelating agents (i.p.) reveals that the extent of nephrotoxicity is greatest when L-cysteine is the chelating agent. When either of 2 dithiocarbamates capable of mobilizing cadmium from its intracellular deposits, i.e. sodium N-methyl-D-glucamine dithiocarbamate (NaG) or sodium N-benzyl-D-glucamine dithiocarbamate (NaB) is used as the chelating agent, no morphological renal damage was evident. Under these same conditions the testes of the mice were protected to the extent of 95% by both of the dithiocarbamates, whereas the protection afforded by the L-cysteine was only about 50%. One factor governing the extent of nephrotoxicity appears to be the stability of the cadmium complexes which are formed and the manner in which this affects their behavior in vivo. Complexes which are preferentially excreted in the bile, cause little or no renal damage.