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Book ChapterDOI

Male Reproductive System

01 Jan 2013-pp 2493-2598
TL;DR: The male reproductive system provides a multitude of potential sites for toxicologic disturbance, and a thorough knowledge of the structure and physiology of the system, as well as the kinetics and organization of spermatogenesis, is essential to understand toxicologic disturbances.
Abstract: Much of the work of the pathologist in understanding male reproductive toxicity comes from trying to understand the initial site of toxicant action – that is, distinguishing the initial effects from the follow-on events. These changes can happen because of, or completely independent of, initial impacts on male reproductive hormones. Fortunately, the patterns of response and the holistic evaluation of a wide variety of different but complementary data allow for considerable confidence in assigning an initiating site of action. This chapter will review the anatomy and physiology as well as successful strategies for understanding toxicities in this complicated and sublime multi-organ system.
Citations
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Journal ArticleDOI
TL;DR: An in-depth analysis of the state of the science on several topics critical to evaluating the relationship between the MOA for PPARα agonists and the human relevance of related animal tumors produces a range of outcomes, depending partly on the quality and quantity of MOA data available from laboratory animals and related information from human data sources.
Abstract: Widely varied chemicals--including certain herbicides, plasticizers, drugs, and natural products--induce peroxisome proliferation in rodent liver and other tissues. This phenomenon is characterized by increases in the volume density and fatty acid oxidation of these organelles, which contain hydrogen peroxide and fatty acid oxidation systems important in lipid metabolism. Research showing that some peroxisome proliferating chemicals are nongenotoxic animal carcinogens stimulated interest in developing mode of action (MOA) information to understand and explain the human relevance of animal tumors associated with these chemicals. Studies have demonstrated that a nuclear hormone receptor implicated in energy homeostasis, designated peroxisome proliferator-activated receptor alpha (PPARalpha), is an obligatory factor in peroxisome proliferation in rodent hepatocytes. This report provides an in-depth analysis of the state of the science on several topics critical to evaluating the relationship between the MOA for PPARalpha agonists and the human relevance of related animal tumors. Topics include a review of existing tumor bioassay data, data from animal and human sources relating to the MOA for PPARalpha agonists in several different tissues, and case studies on the potential human relevance of the animal MOA data. The summary of existing bioassay data discloses substantial species differences in response to peroxisome proliferators in vivo, with rodents more responsive than primates. Among the rat and mouse strains tested, both males and females develop tumors in response to exposure to a wide range of chemicals including DEHP and other phthalates, chlorinated paraffins, chlorinated solvents such as trichloroethylene and perchloroethylene, and certain pesticides and hypolipidemic pharmaceuticals. MOA data from three different rodent tissues--rat and mouse liver, rat pancreas, and rat testis--lead to several different postulated MOAs, some beginning with PPARalpha activation as a causal first step. For example, studies in rodent liver identified seven "key events," including three "causal events"--activation of PPARalpha, perturbation of cell proliferation and apoptosis, and selective clonal expansion--and a series of associative events involving peroxisome proliferation, hepatocyte oxidative stress, and Kupffer-cell-mediated events. Similar in-depth analysis for rat Leydig-cell tumors (LCTs) posits one MOA that begins with PPARalpha activation in the liver, but two possible pathways, one secondary to liver induction and the other direct inhibition of testicular testosterone biosynthesis. For this tumor, both proposed pathways involve changes in the metabolism and quantity of related hormones and hormone precursors. Key events in the postulated MOA for the third tumor type, pancreatic acinar-cell tumors (PACTs) in rats, also begin with PPARalpha activation in the liver, followed by changes in bile synthesis and composition. Using the new human relevance framework (HRF) (see companion article), case studies involving PPARalpha-related tumors in each of these three tissues produced a range of outcomes, depending partly on the quality and quantity of MOA data available from laboratory animals and related information from human data sources.

554 citations

Journal ArticleDOI
TL;DR: The overall study results indicate that even moderate exposures to Pb and Cd can significantly reduce human semen quality without conclusive evidence of impairment of male reproductive endocrine function.
Abstract: Blood lead (BPb), activity of delta-aminolevulinic acid dehydratase (ALAD), erythrocyte protoporphyrin (EP), blood cadmium (BCd), serum zinc (SZn), seminal fluid zinc (SfZn), serum copper (SCu), and parameters of semen quality and of reproductive endocrine function were measured in 149 healthy male industrial workers 20-43 years of age. The group contained 98 subjects with slight to moderate occupational exposure to Pb and 51 reference subjects. All of the subjects lived in Zagreb, Croatia. Significant (p < 0.05) correlations of BPb, ALAD, and/or EP with reproductive parameters indicated a Pb-related decrease in sperm density, in counts of total, motile, and viable sperm, in the percentage and count of progressively motile sperm, in parameters of prostate secretory function (SfZn, acid phosphatase, and citric acid in seminal fluid), and an increase in abnormal sperm head morphology, serum testosterone, and estradiol. These associations were confirmed by results of multiple regression, which also showed significant (p < 0. 05) influence of BCd, SZn, SCu, smoking habits, alcohol consumption, or age on certain reproductive parameters. These effects were mainly of lower rank and intensity as compared to Pb-related reproductive effects, whereas BCd contributed to a decrease in sperm motility and an increase in abnormal sperm morphology and serum testosterone. No significant Pb- or Cd-related influence was found on levels of the lactate dehydrogenase isoenzyme LDH-C(4) and fructose in seminal fluid or on follicle-stimulating hormone, luteinizing hormone, and prolactin in serum. The seminal fluid concentrations of Pb (SfPb) and Cd (SfCd) were measured in 118 of the 149 subjects, and a highly significant (p < 0.0001) correlation was found between BPb and SfPb levels (r = 0.571) and between BCd and SfCd levels (r = 0.490). The overall study results indicate that even moderate exposures to Pb (BPb < 400 microg/L) and Cd (BCd < 10 microg/L) can significantly reduce human semen quality without conclusive evidence of impairment of male reproductive endocrine function.

424 citations

Journal ArticleDOI
TL;DR: The Society of Toxicologic Pathology (STP) has created recommendations for weighing organs in GLP general toxicology studies lasting from 7 days to 1 year.
Abstract: The evaluation of organ weights in toxicology studies is an integral component in the assessment of pharmaceuticals, chemicals, and medical devices. The Society of Toxicologic Pathology (STP) has created recommendations for weighing organs in GLP general toxicology studies lasting from 7 days to 1 year. The STP recommends that liver, heart, kidneys, brain, testes, and adrenal glands be weighed in all multidose general toxicology studies. Thyroid gland and pituitary gland weights are recommended for all species except mice. Spleen and thymus should be weighed in rodent studies and may be weighed in non-rodent studies. Weighing of reproductive organs is most valuable in sexually mature animals. Variability in age, sexual maturity, and stage of cycle in non-rodents and reproductive senescence in female rodents may complicate or limit interpretation of reproductive organ weights. The STP recommends that testes of all species be weighed in multidose general toxicology studies. Epididymides and prostate should be weighed in rat studies and may be weighed on a case-by-case basis in non-rodent and mouse studies. Weighing of other organs including female reproductive organs should be considered on a case-by-case basis. Organ weights are not recommended for any carcinogenicity studies including the alternative mouse bioassays. Regardless of the study type or organs evaluated, organ weight changes must be evaluated within the context of the compound class, mechanism of action, and the entire data set for that study.

320 citations

Journal ArticleDOI
24 Dec 2001-BJUI
TL;DR: To determine the effect of antibiotic prophylaxis on infective complications after transrectal needle biopsy of the prostate, a large number of patients with confirmed or suspected cases of prostate cancer are treated with antibiotics.
Abstract: Objectives To determine the effect of antibiotic prophylaxis on infective complications after transrectal needle biopsy of the prostate Patients and methods Between June 1996 and September 1998, 231 patients who satisfied the inclusion and exclusion criteria entered the study; the patients were randomized into three groups Each patient underwent transrectal needle biopsy of the prostate after a cleansing enema at 06:00 hours Patients in group 1 (75) then received a placebo tablet twice a day for 3 days; those in group 2 (79) were given a single dose of ciprofloxacin (500 mg) and tinidazole (600 mg), while those in group 3 (77) were given the same combination twice a day for 3 days Urine cultures were obtained 48 h after the biopsy and blood cultures only from patients who developed fever The complications (categorized as infective or noninfective) occurring in the three groups were compared using the chi-square test Results Noninfective complications included were lower urinary tract symptoms, rectal bleeding, haematuria and perineal pain The infective complications included urinary tract infection and fever There was no significant difference among the three groups in noninfective complications (27, 29 and 31 in groups 1–3, respectively) but the incidence of infective complications (19, six and eight, respectively) was significantly higher in group 1 (P = 0003) However, the difference was significant only for urinary tract infection (P = 001) and not for fever Conclusions In selected patients a single dose of ciprofloxacin-tinidazole is adequate prophylaxis for transrectal needle biopsy of the prostate The present urinary infection rate was higher if no antibiotics were used Continuing the antibiotic prophylaxis for 3 days offered no benefit over single-dose prophylaxis

287 citations

Journal ArticleDOI
TL;DR: The purpose of this investigation was to review the toxicity data, identify any new relevant data, and select those data to be used in dose-response modeling, and proposed revised cancer and noncancer toxicity values were estimated using the newest U.S. EPA guidelines for cancer risk assessment and non cancer hazard assessment.
Abstract: Acrylamide (ACR) is used in the manufacture of polyacrylamides and has recently been shown to form when foods, typically containing certain nutrients, are cooked at normal cooking temperatures (e.g., frying, grilling or baking). The toxicity of ACR has been extensively investigated. The major findings of these studies indicate that ACR is neurotoxic in animals and humans, and it has been shown to be a reproductive toxicant in animal models and a rodent carcinogen. Several reviews of ACR toxicity have been conducted and ACR has been categorized as to its potential to be a human carcinogen in these reviews. Allowable levels based on the toxicity data concurrently available had been developed by the U.S. EPA. New data have been published since the U.S. EPA review in 1991. The purpose of this investigation was to review the toxicity data, identify any new relevant data, and select those data to be used in dose-response modeling. Proposed revised cancer and noncancer toxicity values were estimated using the newest U.S. EPA guidelines for cancer risk assessment and noncancer hazard assessment. Assessment of noncancer endpoints using benchmark models resulted in a reference dose (RfD) of 0.83 microg/kg/day based on reproductive effects, and 1.2 microg/kg/day based on neurotoxicity. Thyroid tumors in male and female rats were the only endpoint relevant to human health and were selected to estimate the point of departure (POD) using the multistage model. Because the mode of action of acrylamide in thyroid tumor formation is not known with certainty, both linear and nonlinear low-dose extrapolations were conducted under the assumption that glycidamide or ACR, respectively, were the active agent. Under the U.S. EPA guidelines (2005), when a chemical produces rodent tumors by a nonlinear or threshold mode of action, an RfD is calculated using the most relevant POD and application of uncertainty factors. The RfD was estimated to be 1.5 microg/kg/day based on the use of the area under the curve (AUC) for ACR hemoglobin adducts under the assumption that the parent, ACR, is the proximate carcinogen in rodents by a nonlinear mode of action. When the mode of action in assumed to be linear in the low-dose region, a risk-specific dose corresponding to a specified level of risk (e.g., 1 x 10-5) is estimated, and, in the case of ACR, was 9.5 x 10-2 microg ACR/kg/day based on the use of the AUC for glycidamide adduct data. However, it should be noted that although this review was intended to be comprehensive, it is not exhaustive, as new data are being published continuously.

269 citations

References
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Journal ArticleDOI
TL;DR: In the present work, the cellular associations were defined by the stage of development of the spermatids, which themselves were characterized by their staining reaction to the “periodic acid-Schiff” technique (hereafter referred to as PAFSA).
Abstract: Any area of any seminiferous tubule of the rat contains a few spermatogonia along the basement membrane, one or several layers of spermatocytes farther in, and groups of spermatids next to the lumen of the tubule. The present work is a systematic study of the various modes of association of these cells in what is known as the seminiferous epithelium. In the rat, development of any one generation of spermatogonia, spermatocytes, or spermatids is closely integrated with that of other generations present in the same area of the tubule. Thus, the cel!s are not arranged a t random, but are organized into well-defined cellular associations. I t was realized in the 1890’s that the various cell associations must succeed one another in time in any given area of the seminiferous tubule, and that the sequence must repeat itself indefinitely. The complete series of successive cellular associations has been named the “ spermatogenic cycle” by von Ebnerl and Regaud.? This designation is somewhat misleading and, more recently, has been used to describe the whole of spermat~genesis.~ To avoid confusion, the more exact designation “cycle of the seminiferous epithelium” or, simply, “cycle” will be used instead. The cycle of the seminiferous epithelium may be defined as that series of changes occurring in a given area of the seminiferous epithelium between two successive appearances of the same cellular association. The number of cellular associations identified by various authors within a cycle ot the seminiferous epithelium shows large (TABLE 1.) The discrepancies may be explained by the fact that many stages of development of the cells cannot be characterized with precision in preparations stained with hematoxylin. In the present work, the cellular associations were defined by the stage of development of the spermatids, which themselves were characterized by their staining reaction to the “periodic acid-Schiff”, also called “periodic acid-fuchsin sulfurous acid” technique (hereafter referred to as PAFSA). The stages through which the developing spermatids progress can be easily identified by this technique, as shown in a previous paper,l0 in which the bibliography of the subject may be found. Spermiogenesis may thus be divided into 19 stages, numbered from 1 to 19 (FIGURES 1-19). During the first 8 stages of the development of young spermatids, the seminiferous epithelium also contains a generation of older spermatids, which are released when the younger generation completes Stage 8. During the next few stages of development, the remaining spermatids are the only ones present, but when they reach Stage 15, a new generation again arises

1,625 citations

Journal ArticleDOI
Dean P. Jones1
TL;DR: From a mechanistic standpoint, oxidative stress may be better defined as a disruption of redox signaling and control and adoption of such a definition could redirect research to identify key perturbations of red Oxidative stress-related disease processes and lead to new treatments for oxidative stressed disease processes.
Abstract: Oxidative stress is often defined as an imbalance of pro-oxidants and antioxidants, which can be quantified in humans as the redox state of plasma GSH/GSSG. Plasma GSH redox in humans becomes oxidized with age, in response to oxidative stress (chemotherapy, smoking), and in common diseases (type 2 diabetes, cardiovascular disease). However, data also show that redox of plasma GSH/GSSG is not equilibrated with the larger plasma cysteine/cystine (Cys/CySS) pool, indicating that the "balance" of pro-oxidants and antioxidants cannot be defined by a single entity. The major cellular thiol/disulfide systems, including GSH/GSSG, thioredoxin- 1 (-SH2/-SS-), and Cys/CySS, are not in redox equilibrium and respond differently to chemical toxicants and physiologic stimuli. Individual signaling and control events occur through discrete redox pathways rather than through mechanisms that are directly responsive to a global thiol/disulfide balance such as that conceptualized in the common definition of oxidative stress. ...

1,438 citations

Journal ArticleDOI
TL;DR: The kinetics of sperMatogenesis in mammals are reviewed with special emphasis on the seminiferous epithelium cycle and spermatogonial renewal .
Abstract: The kinetics of spermatogenesis in mammals are reviewed with special emphasis on the seminiferous epithelium cycle and spermatogonial renewal . 2 features of the spermatogenic process are that for a given species each step of spermatogenesis has a constant duration and that many spermatogonial stem cells enter spermatogenesis simultaneously and almost synchronously. The seminiferous epithelium composed of 5 or 6 generations of germ cells form cellular associations of fixed compositi on. Spermatids at a given step of spermiogenesis are always associated with spermatocytes and spermatogonia at given steps of development. These cellular groupings were taken to represent stages of a cycle of the seminferous epithelium. The number of stages composing the cycle vary with the species and the criteria used to characterize them. The classifications of cell associations are particulary useful in investigations of the mode of renewal of the spermatogonial population. The stem cells that belong to the Type A category may be classified as "reserve" and "renewing" stem cells. The former appear to be actively involved in the production of spermatocytes in normal adult animals but the latter initiate at each cycle of the seminiferous epithelium a series of mitoses during which they renew themselves and simultaneously give rise to "differentiating" spermatogonia. The "nodal" or key mitosis that result appear to be equivalent in type and not bivalent.

1,266 citations