Folate deficiency increases genetic damage caused by alkylating agents and gamma-irradiation in Chinese hamster ovary cells.

Abstract

The effect of folate deficiency on genetic damage caused by alkylating agents and gamma-irradiation was studied in Chinese hamster ovary (CHO) cells. Mutant frequencies of 6-thioguanine-resistant and diphtheria toxin-resistant cells were not significantly increased by incubation in low-folate medium. In contrast, folate deficiency increased the mutant frequencies of 6-thioguanine-resistant cells caused by N-ethyl-N-nitrosourea or ethyl methanesulfonate by about 3-fold. Folate deficiency was associated with a 70% increase of diphtheria toxin-resistant cells after exposure to ethyl methanesulfonate. Folate deficiency alone caused DNA strand breaks equivalent to 26 cGy, as monitored by alkaline filter elution. Following 400 cGy of gamma-irradiation, folate-deficient cells manifested strand breaks equivalent to a dose of 710 cGy. CHO cells in folate-containing medium repaired breaks within 3 h, while cells in low-folate medium had an increased break frequency (P = 0.02) at 3 h and were unable to fully repair radiation-induced damage even after 9 h. These studies indicate that folate deficiency acts synergistically with alkylating agents to increase somatic mutation and with gamma-irradiation to promote DNA strand breaks in CHO cells. Folate deficiency appears to potentiate the genetic damage caused by mutagens/carcinogens by limiting DNA repair.