Copper Metabolism Disorders Affect Testes Structure and Gamete Quality in Male Mice

Abstract

In the present study, animals with a genetic defect in copper metabolism were used as a model organism to study the role of copper in reproduction and to determine whether the disturbances in copper and zinc metabolism affect the testicular tissue and gamete quality in males. Mice with an X-linked mosaic mutation (Atp7a(mo-ms)) exhibit pathological features characteristic of affected copper metabolism. This mutation usually leads to lethality of the mutant males which generally expire on about day 16. Only 4% of mutant animals survive the critical period, achieve maturity, and become fertile. To improve the mutants' viability they were treated with subcutaneous injections of cupric chloride. We measured copper and zinc concentration in the gonads of young (14-day-old) and adult (5-month-old) mutant and control males. Results indicate that copper content was increased but zinc was decreased in the mutant testes. Analysis of the morphology of the testis of the young animals indicate that apoptosis (characteristic for the gonads of young males) was increased in the gonads of the 14-day-old mutants. This process was less advanced in the group of 14-day-old copper treated control males. Apoptosis was also increased in the testes of the adult mutants. Moreover in adult mutants we observed pathological changes in testes morphology (atrophic and sclerotic tubules). Copper and zinc disorders also negatively influenced semen quality parameters, including sperm motility, head morphology, tail cytoplasmic membrane integrity, and number of viable spermatozoa. Poor semen quality of the mutant males seems to be responsible for affected in vivo fertilization efficiency. Treatment with cupric chloride did not influence semen quality except in maturation rate, which was even slower in both mutant and control males after treatment. Additionally, in mutants, copulatory plugs and fertile copulation outcome were decreased after copper treatment.

Prenatal Treatment of Mosaic Mice (Atp7a mo-ms) Mouse Model for Menkes Disease, with Copper Combined by Dimethyldithiocarbamate (DMDTC)

“…Increased body weight was also found in the group of the CuCl 2 -DMDTC- prenatally treated wild-genotype males (Figure 4). Previously we reported that postnatal CuCl 2 injection lead to significantly increasing in the body weight in wild-genotype males [11], [13]. A similar effect was observed in the pigs in which high dietary copper promotes growth and body weight and improved feed intake.…”

“…Our previous results indicated that postnatal CuCl 2 therapy of mosaic males from the second day of life improved the viability and survival substantial [12], [13]. Here we present the first description of the effect of combined (CuCl 2 and DMDTC) prenatal treatment of mosaic mice from gestation day 7 to delivery.…”

“…Copper treatment administered before the 7 th day of postnatal life improved the viability of mottled mutant males; mosaic [11], [13], brindled [16] and macular mice [9], [17]. Tanaka and co-workers found that treatment of macular mice on the 7 th day with a subcutaneous injection of high amount of copper alone (10 mg/kg) or low amount of copper (1 mg/kg) combined with an intraperitoneal injection of DMDTC (100 mg/kg) leads to 100% survival for at least 7 weeks.…”

Iron Excess Disturbs Metabolic Status and Relative Gonad Mass in Rats on High Fat, Fructose, and Salt Diets

“…The increase in calcium concentration may indicate a sharp increase in the testicular tissue of MFe rat testes, compared with the control group [39]. However, the observed decrease in copper level in the testicular tissue may have led to abnormal tissue structure and affected the quality of the sperm [40]. …”

Mfc1 is a novel copper transporter during meiosis

“…Although deficiencies in copper-dependent proteins culminate in meiotic cell developmental defects and subfertility, 3 , 4 copper homeostasis has been poorly studied during meiosis. Contributing reasons for that situation include: (1) paucity of mammalian germ cells, (2) unavailability of germ cell lines grown under copper depleted or copper sufficient conditions, (3) heterogeneity of mammalian germ cell populations and, (4) lack of information on the number and nature of molecules that serve as potential players, especially in response to changes in copper levels during meiosis 5 .…”