dinitrobenzenes and Infertility--Male

This review focuses of industrial chemicals that research has indicated may adversely affect human male reproductive capacity. The study of male reproductive toxicity is impeded by a dearth of clinical endpoints. Males lack an obvious and easily measurable reproductive cycle, and the primary clinical indicator, semen analysis, offers unsure clues to reproductive performance. However, progress is being made in developing and evaluating tests to identify chemical hazards and estimate human health risks. Agents with confirmed adverse effects of male reproduction include carbon disulfide, dibromocklopropane, lead, and oral contraceptives. Agents with inconclusive effects include anesthetic gases, arsenic, benzene, boron, cadmium, carbaryl, chlordecone, chloroprene, DNT and TDA, ethylene dibromide, manganese, mercury, pesticides, PCP, radiation ionizing and nonionizing, solvents, dioxin, and vinyl chloride. Finally, agents with no observed adverse effects include epichlorohydrin, glycerine, benzoic acid, and polybrominated biphenyls. The literature suggests a need for further research in the following areas: 1) chemicals that are reactive and capable of covalent interactions in biological systems, 2) chemicals defined as mutagens and/or carcinogens in short-term laboratory tests, 3) chemicals demonstrated to cause aneuploidy or other chromosomal aberrations, 4) chemicals that affect sperm motility in vitro, 5) chemicals that share hormonal activity or affect hormone action, and 6) chemicals that act directly or indirectly to affect the hypothalamo-pituitary-gonadal axis.

Topics: Anesthetics; Arsenic; Benzene; Boron; Cadmium; Carbaryl; Carbon Disulfide; Chlordecone; Contraceptives, Oral, Hormonal; Dinitrobenzenes; Ethylene Dibromide; Humans; Infertility, Male; Lead; Male; Manganese; Methylmercury Compounds; Occupational Diseases; Pentachlorophenol; Pesticides; Polychlorinated Dibenzodioxins; Propane; Reproduction; Solvents; Vinyl Chloride

Theophylline (THP) and 1,3-dinitrobenzene (DNB) are thought to induce infertility by incapacitating the nurturing Sertoli cells and causing germ cell apoptosis in the testicular seminiferous epithelium, respectively. We hypothesized that THP and DNB exposure would alter the expression of the genes within the ubiquitin-proteasome pathway (UPP), implicated in spermatogenesis and epididymal sperm quality control. Rats were fed 0 or 8000 ppm of THP and necropsied on Days 18, 30, and 42 or administered 0, 2, or 6 mg/kg DNB via oral gavage and necropsied on Day 7. Tissues were collected from the testis and the caput, corpus, and cauda regions of the epididymis for transcriptional profiling by semiquantitative RT-PCR, real-time RT-PCR, and histopathology. Target UPP genes included those encoding for constitutive the 20S proteasomal core subunits Psmb1 (beta1), Psmb2 (beta2), and Psmb5 (beta5); the inducible 20S core subunits Psmb9 (LMP2), Psmb8 (LMP7), and Psmb10 (LMP10); and Ube1 (ubiquitin-activating enzyme E1), Ube2d3 (ubiquitin-conjugating enzyme E2), and Uchl1 (ubiquitin C-terminal hydrolase PGP9.5). Spermatozoa were collected from the cauda epididymis for analysis by light microscopy and flow cytometric evaluation of sperm surface ubiquitin. These data show that reprotoxic exposure alters the tissue-specific expression of UPP genes in the testis and epididymis, which may contribute to the aberrant spermatogenesis and epididymal processing of both normal and defective spermatozoa. Transcriptional profiling and flow cytometric analysis of the UPP thus captures the prodromal effects of reproductive toxicity not captured by conventional histology and functional cytology. Complementing seminal analysis with these measures may be useful in screening drug-induced toxicity or environmental infertility.

Topics: Animals; Dinitrobenzenes; Epididymis; Gene Expression Profiling; Infertility, Male; Male; Proteasome Endopeptidase Complex; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spermatogenesis; Spermatozoa; Testis; Theophylline; Ubiquitin

Weanling male Sprague-Dawley rats were gavaged 5 d/wk with 1,3-dinitrobenzene (m-DNB) at dosages of 0, 0.75, 1.5, 3.0, and 6.0 mg/kg X d. Males were bred to untreated females during treatment wk 10 and were killed during treatment wk 12. Although males dosed with 3 mg/kg X d inseminated the females and evidence of mating was observed in males dosed with 6 mg/kg X d, none of the males in these groups sired litters. Diminished sperm production (reduced testicular sperm head counts), decreased cauda epididymal sperm reserves, nonmotile spermatozoa, atypical sperm morphology, decreased weights of the testes and epididymides, seminiferous tubular atrophy, and incomplete spermatogenesis were also observed in these groups. Sperm production was also decreased in males dosed with 1.5 mg/kg X d. Changes in the spleen included increased weight at dosages of 1.5 mg/kg X d or higher and splenic hemosiderosis, which ranged from slight in rats treated with 0.75 mg/kg X d to moderately severe in those dosed with 6 mg/kg X d. The data indicate that m-DNB is a potent testicular toxicant in the male rat, capable of producing extensive damage to reproductive tissues and reproductive failure. Limited data on four rats that received 6 mg/kg X d and were allowed a 5-mo posttreatment recovery period suggested that the testicular effects are at least partially reversible.

Topics: Animals; Dinitrobenzenes; Infertility, Male; Male; Nitrobenzenes; Organ Size; Rats; Reproduction; Sperm Count; Spermatogenesis; Testis