The cyclophosphamide, anticancer alkylating drug, is wide broad uses which causes defects in the normal female reproductive function. Previous studies showed that time- and dose-dependent effects of CPA on the ovary, specifically, its effects on follicle numbers, morphological features of ovry, ovarian biometric and estradiol production, destruction of antral follicles (Plowchalk and Mattison, 1992). The results from one study demonstrated that CPA-induced ovarian toxicity is appeared as temporal changes in both structural and functional features of the ovary also in destruction of primordial and antral follicles and depressed estaradiol production. Information of this result also gives insight into ovarian response to chemical disruption of folliculogenesis and its recovery process. CPA regarded a cytotoxic drug used in different types of cancer treatment and autoimmune diseases,which acts rapidly on dividing cells, inducing DNA cross-links and DNA single-strand breaks (Colvin, 1999).
Few experiments have explored the potential of mechanisms for the susceptibility of oocyte to chemotherapy exposure. Studies involving the investigation, ovotoxic chemical 4-vinylcyclophosphamide diepoxide (VCD) have provided evidence that oocytes may be susceptible to changes in cytoplasmic and/or mitochondrial apoptotic signal (Hu et al., 2001a,b).As regarding to the study has been done by Takai et al., ( 2003) referred that inactivation of caspase 2 or 3 reduce VCD-induced primary follicle loss, whereas elimination of Bax expression appeared to protect against VCD-induced loss both primordial and primary follicles.
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A study was done by Coderington et al.,(2007) found that the Chronic exposure of male rats to the alkylating agent CPA alters gene expression in male germ cells .The embryos from the exposed male are also showing some fine alternations by cyclophosphamide-exposed males. Sperm DNA is organized by the nuclear matrix metabolism, cell defense, or detoxification.CPA selectively induced numerous changes in cell defense and detoxification proteins, in addition, in all exist forms of the antioxidant enzyme glutathione peroxidase 4. An increase in glutathione peroxidase 4 expression appears a role for this enzyme in maintaining nuclear matrix stability and function as well as the change in composition of the nuclear matrix in response to drug exposure was a factor in altered sperm function and embryo development .into loop-domains in a sequence-specific manner.
Also many studies referred to the defects that occurred to the sperm structures due to the exposure to chemotherapeutic drug results in increased DNA damage in human spermatozoa (Chatterjee HYPERLINK "#ref-19"et al.HYPERLINK "#ref-19", 2000; Morris, 2002); also the damage has been occurred obvious abnormal sperm chromatin packaging (Manicardi HYPERLINK "#ref-48"et al.HYPERLINK "#ref-48", 1995; Manicardi HYPERLINK "#ref-49"et al.HYPERLINK "#ref-49", 1998). A commonly used anticancer drug, (CPA), is a functional alkylating agent and significant male-mediated developmental toxicant with clear stage-specific effects on male germ cells (Trasler HYPERLINK "#ref-82"et al.HYPERLINK "#ref-82", 1985; Anderson HYPERLINK "#ref-3"et al.HYPERLINK "#ref-3", 1995).The appearance of morphological normal spermatozoa revealed that the evidence of underlying anomalies exists (Bianchi HYPERLINK "#ref-15"et al.HYPERLINK "#ref-15", 1996) and may be the case in spermatozoa chronically exposed to CPA. The chronic exposure of male germ cells to CPA depends on spermiogenesis and epididymal transit so that resulting for DNA single-strand breaks, cross-links and altered in vitro spermatozoal decondensation and template function (Qiu HYPERLINK "#ref-67"et al.HYPERLINK "#ref-67", 1995a,b), morefurther in cauda epididymal sperm and to pre- and post-implantation embryo loss as well as growth retarded spring off (Trasler HYPERLINK "#ref-83"et al.HYPERLINK "#ref-83", 1986). The most damaging effects to DNA occurred during mid-spermiogenesis, as the histoneââ‚¬"protamine exchange begins (Codrington HYPERLINK "#ref-23"et al.HYPERLINK "#ref-23", 2004).
On other hand, the exposure to CPA changed the binding of protamines to DNA because of highly damage of DNA , as well as result for protamine alkylation, given that protamines are trended to be more susceptible to alkylation (Sega and Owens, 1983). Whether that case, eventually it may be faulty or incomplete protamine deposition and blockage of normal disulphide bond formation, thus preventing proper chromatin condensation and limiting fertilizing ability.
The male reproductive system is particularly sensitive to the damage induced by anticancer agents targeting rapidly dividing cells. The spermatogenic process is highly ordered and regulated; stem cells (spermatogonia) divide mitotically to form spermatocytes to initiate the process. Preleptotene spermatocytes go through two meiotic divisions to become round spermatids. During spermiogenesis, round spermatids differentiate. Changes such as chromatin remodeling, formation of the flagellum, and shedding of most of the cytoplasm take place to form mature spermatozoa (Hecht,1998).
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Therefor, CPA alters male fertility activity, the incidence of azoospermia and oligospermia in adult male patients (Allen et al.,1997).Previous studies have shown that chronic paternal treatment of rats with CPA causes damage to sperm DNA (Hud et al.,1994), alters in vitro spermatozoal decondensation (Nadel et al., 1982), and results in abnormal progeny outcome (Hart et al.,). The effects of on progeny outcome depended on determination of time specific and dose amount; maximum postimplantation loss occurs 4 wk after the initiation of treatment, whereas preimplantation loss is prominent at 5ââ‚¬"6 wk after the initiation of treatment (Romrell et al.,1979). Chronic CPA treatment alters the histology features (Bellve et al.,1977), and biochemistry (Doetschman, et al.,1988), of the epididymal epithelium, but spermatogenesis is not detected. Meanwhile, abnormal spermatozoa are found in the lumen of both the epididymis and the testis after chronic CPA treatment (Bellve et al.,1977). The molecular mechanisms underlying the male-mediated developmental toxicity of CPA remain to be identified.
Identifying the effects of CPA treatment on gene expression in germ cells may give considerations into mechanisms potential the male infertility and male-mediated developmental toxicity of this drug. DNA repair, heat shock proteins, and antioxidant defense mechanisms play an important role in the stress response to alkylating drug (Blobel and Potter 1966) and in male germ cell development and functionality. One study reported that differential expression of stress response genes during spermatogenesis (Gerdes et al,.1994) and after acute exposure to cyclophosphamide (Wahl et al,.1983). Maximal abnormal effects on progeny outcome were found after low-dose chronic CPA exposure (Bellve, 1993).
Desmeules and Divine, (2006) referred that reason makes primordial oocytes are targeted by DNA-damaging agents is unknown. In addition, the tight interaction between granulosa cells and oocyte make difficult to determine which follicular cell type is affected by toxic chemicals or if effects are through disruption of the intracellular communication between cells. The alkylating potential of PM likely targets important macromolecules in follicular cells, such as DNA or critical proteins, but more research is needed to determine the specific defects that leads to follicle death. The time lag between exposure and visible effects could be due to a delay in conversion of molecular-level damage to morphological changes or in the cell death signal triggered by unsuccessful attempts to repair chemical- induced injury. Mitochondrial DNA is a possible target, because primordial oocytes were reported to have 10-1000x fewer mitochondria than oocyte in other stages (Jansen and de Boer, 1998). The exact cause of gonadal failure in this approach is still unknown. Researchers suggested that direct cytotoxic effect on follicles, possibly dependent on age or hormonal milieu (Marcello et al., 1990). Studies of leukaemia treatment in earlier age suggested that prepubertal patients who receive cyclophosphamide maintain or recover gonadal function better than similarly treated adults (Chapman and Sutcliffe, 1981).These resultes suggest that active or quiescent germinal cells may have an enhanced or reduced sensitivity, respectively, to CPA because of varying mitotic activity.
This variability in eventual results of gonadal activity after treatment with alkylating agents suggests that pharmacological suppression of gonadal function may spare the ovary any toxicity associated with these agents (Rivkees and Crawford, 1988). Meanwhile Letterie et al., (2004) explained that in the rat model, CPA induce a stimulatory effect on the ovary resulting in the greater development of both medium and large follicles. Furthermore, an ovulation conferred no protection against CPA-induced gonadal toxicity. These results suggest that in the rat model, CPA may result in ovarian failure by increasing recruitment of follicles regardless of ovulatory status or hormonal milieu.
The reports related to human, the anticancer drug CPA causes amenorrhea and premature ovarian failure in women (Howell and Shalet, 1998). Studies in rodents suggest that CPA effects on ovarian function by destroying ovarian follicles. CPA administration destroys ovarian follicles in mice and rats (Davis and Heindel, 1998; Plowchalk and Mattison, HYPERLINK "#ref-41#ref-41"1992). In despite of, the mice are more sensitive to the effects of CPA on the immature primordial and primary follicles, CPA targets granulosa cells of more mature, antral follicles in both mice and rats (Davis and Heindel, 1998 and Plowchalk and Mattison, 1992 ).Anther study has shown that the destruction of granulosa cells by CPA in rats treated in vivo occurs by the induction of apoptosis. Also, both the death receptor and the mitochondrial apoptotic pathways have been implicated in the induction of apoptosis by cyclophosphamide in developing embryos (Little and Mirkes, 2002) . However, the mechanism by which CPA induces granulosa cell apoptosis has not been investigated. The mitochondrial apoptotic pathway is initiated by damaging stimuli such as oxidative stress or DNA damage. CPA has therapeutic mechanism of action as an alkylating agent induces DNA damage.After CPA treatment has also been shown to cause oxidative stress (Murata et al., 2004). In the previous studies focused on that oxidative stress as a mediator of CPA-induced granulosa cell apoptosis (Little and Mirkes, 2002) .
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