Maternal administration of cyclophosphamide induces chromosomal aberrations and inhibits cell number, histone synthesis, and DNA synthesis in preimplantation mouse embryos

Abstract

The effects of cyclophosphamide (CPA), administered to pregnant inbred CBA/Ca mice 60 h after copulation, on cell number, mitotic index, chromosome structure, histone synthesis, and DNA synthesis of 84-h blastocysts, and the subsequent development of these blastocysts cultured for a further 120 h in vitro are described. Cyclophosphamide 4, 20, and 40 mg/kg significantly increased the number of chromosomally aberrant cells, chromosomal aberrations, and chromosome breaks in the blastocysts. Chromosomal rearrangements were significantly increased in the CPA 20 and 40-mg/kg treated groups, and in the 40-mg/kg group the number of cells with ring chromosomes was significantly increased. Histone synthesis and DNA synthesis were significantly inhibited in the CPA 20 and 40-mg/kg treated groups. Blastocyst cell number in each of the treated groups was less than the controls. On subsequent culture in vitro, significantly fewer embryos in the CPA 20 and 40-mg/kg groups hatched, attached, developed trophoblast outgrowths, and expanded their inner cell masses. However, the differentiation of inner cell mass into ectoderm and endoderm was impaired by all three doses of the drug. These results demonstrate that CPA administered to pregnant mice 60 h after copulation has a clastogenic effect and interferes with synthesis of DNA and histones in the preimplantation embryo, and that the drug inhibits the subsequent development and differentiation of these embryos. Cytogenetic analysis of preimplantation embryos might be a useful adjunct to the existing methods in the evaluation of the embryotoxicity of drugs and chemicals.

Potentiating effect of caffeine on embryotoxicity of cyclophosphamide treatment in vivo during the preimplanation period

“…The unexpected synergistic embryolethal effect of exposure to CPA and CF indicates the presence of active repair mechanisms in preimplantation embryos in vivo. Therefore, active repair enzymes, rather than a lack of transfer of toxic chemicals to the fluid of the oviduct or uterus, may to some extent be responsible for the insensitivity of early embryos to agents that are embryotoxic during organogenesis [4-61. A dose-related increase of both chromosomal aberrations [19] and SCE frequency [7] in preimplantation mouse embryos has been observed after maternal administration of CPA [7], and the the usually high SCE rates in preimplantation mouse embryos have been discussed extensively [7]. In the present study, however, the increase in structural chromosomal aberrations after combined exposure of preimplantation mouse embryos to CF and CPA in vivo was not accompanied by an increased SCE frequency.…”

Upregulation of FSHR and PCNA by administration of coenzyme Q10 on cyclophosphamide‐induced premature ovarian failure in a mouse model

“…CTX can elevate the production of ROS through some signaling pathways such as PI3K/Akt/mTOR pathway, and some molecular complexes including the NADPH complex (NADPH/NADP + ) and mitochondrial electron respiratory chain . Furthermore, several studies have elucidated that the active metabolites generated during the metabolism of CTX can lead to chromosomal aberrations, sister chromatid exchange, DNA adducts, single‐strand breaks, and the formation of DNA‐DNA crosslinks . Animal studies have also shown that CTX could disrupt the ovarian follicle reserve .…”

The Immunosuppressant Fingolimod (FTY720) for the Treatment of Mechanical Force-Induced Abnormal Scars

“…Later, FTY720 was found to be a structural analog of S1P and a functional antagonist of S1PRs [49]. Unlike conventional immunosuppressive agents, FTY720 does not impair cellular DNA synthesis [50]. Our study suggests that topical application of local inflammatory lesion not only reduces macrophage numbers in the lesion but also inhibits vasculogenesis.…”