Paternal cyclophosphamide treatment of rats causes fetal loss and malformations without affecting male fertility

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Abstract
The use of cytotoxic, mutagenic and carcinogenic agents as treatment for various types of cancer may be particularly hazardous in men of reproductive age as there exists the possibility that this may lead to congenital malformations in the progeny. Such agents can affect fertility and other aspects of male reproductive function, for example, treatment with anti-cancer drugs such as cyclophosphamide has been associated with oligozoospermia, azoospermia and increased levels of serum follicle-stimulating hormone (FSH). Depending on the cumulative dose and the duration of treatment, spermatogenesis often returns but this may take years. The relevance of the effects of such chemicals on the male reproductive system to the offspring is poorly understood. We have set out to determine whether present tests of male reproductive function (that is, endocrine status, numbers of spermatozoa, fertility) can predict deleterious effects of a paternally administered agent on the offspring. Here, we report that chronic administration in rats of low doses of the widely used drug cyclophosphamide had minimal effects on the male reproductive system and fertility, but resulted in malformations and retardation of growth in the surviving fetuses and a high frequency of fetal death. Thus, adverse effects on the fetus cannot be predicted from the effects of a drug on the male reproductive system.