Antimitotic Drugs in the Male Rat Behavioral Abnormalities in the Second Generation

Abstract

The second generation descended from rats treated either with cyclophosphamide alone or with both cyclophosphamide and vinblastine were investigated. As in the first generation, the offspring were evaluated for mean litter size, sex ratio, frequency of gross external malformations and, within the first 4 months of life, growth and mortality. When they reached adulthood, between 12 and 16 weeks of age, the offspring were also tested for spontaneous activity and learning capacity. At birth, the progeny of the treated grandfathers did not show malformations or any other obvious disorder. However, when compared with the control population, the experimental animals showed significantly decreased success rates in a learning task, whatever the learning performance of their parents. Furthermore, decreased spontaneous activity was observed in the male subjects from unsuccessful parents. The similarities between the anomalies found in the first and the second generations argue for the induction of mutations by antimitotic drugs. This hypothesis and the subtle differences between generations and between sexes are discussed.

Radiation-induced transgenerational instability

“…In these studies, the offspring of irradiated parents were analysed using a spectacular variety of phenotypic traits, ranging from the incidence of cancer to behaviour patterns (Auroux et al, 1988) and fertilisation rate (Burruel et al, 1997). It should be noted that the genetic component of some phenotypic characteristics examined in these publications is either low or unknown, which substantially complicates their interpretation.…”

Paternal Exposure to Drugs and Environmental Chemicals: Effects on Progeny Outcome

“…Observed malformations included open eyes, omphalocele, generalized edema, syndactyly, gigantism and dwarfism; these F 2 generation malformations were similar to those found in the F 1 generation (Trasler et al, 1986). Some of the behavioral abnormalities caused by paternal cyclophosphamide treatment also persisted in subsequent generations (Auroux et al, 1988(Auroux et al, , 1990. Nagao and Fujikawa (1996) suggested that the types of malformations induced by male-mediated developmental toxicants such as ethylnitrosourea are the same as those that occur spontaneously.…”

Exposure to Chemotherapy During Childhood or Adulthood and Consequences on Spermatogenesis and Male Fertility

“…This disruption of zygotic gene expression disturbs the kinetics of embryonic development and could explain the losses of early embryos fathered by males treated by alkylating agents [145]. In addition to embryo losses, studies performed in rats have shown a rise in postnatal mortality in litters descended from cyclophosphamide-treated fathers and grandfathers [146,147]. Moreover, one-to two-week cisplatin treatment was sufficient to induce growth retardations in the offspring sired by treated males.…”