Micronucleus induction in the bone marrow of rats by pharmacological mechanisms. I: glucocorticoid receptor agonism

Abstract

A novel selective glucocorticoid receptor (GR) agonist, AZD2906, was found to increase the incidence of micronucleated immature erythrocytes (MIE) in the bone marrow of rats given two oral doses at the maximum tolerated level. Because GR agonists as a class are considered not to be genotoxic and AZD2906 showed no activity in the standard in vitro tests or in vivo in a rat liver comet assay, investigative studies were performed to compare AZD2906 with a reference traditional GR agonist, prednisolone. Emphasis was placed on blood and bone marrow parameters in these studies because GR activation has been reported to induce erythropoiesis which, in turn, is known to increase MIE in the bone marrow. Both compounds induced almost identical, small increases in micronucleus frequency at all doses tested. Directly comparable changes in haematological and bone marrow parameters were also seen with significant decreases in lymphoid cells in both compartments and significant increases in numbers of circulating neutrophils. Although no evidence of increased erythropoiesis was seen as increased immature erythrocyte numbers either in the blood or in the bone marrow, histopathological examination showed focal areas in the bone marrow where the erythroid population was enriched in association with an atrophic myeloid lineage. This could have been due to direct stimulation of the erythroid lineage or a secondary effect of myelosuppression inducing a rebound increase in erythropoiesis into the vacant haematopoietic cell compartment. It was concluded that the increased MIE frequencies induced by both AZD2906 and prednisolone are a consequence of their pharmacological effects on the bone marrow, either by directly inducing erythropoiesis or by some other unknown effect on cellular function, and do not indicate potential genotoxicity. This conclusion is supported by the lack of carcinogenic risk in man demonstrated by decades of clinical use of prednisolone and other GR agonists.

DNA damage in peripheral blood lymphocytes of severely ill COVID-19 patients in relation to inflammatory markers and parameters of hemostasis

“…Thus, the administration of some antibiotics (fluoroquinolone and macrolides), corticosteroids, anticoagulant, and antiviral agents has been shown to increase the level of DNA damage in COVID-19 patients. This is in line with the available literature data about genotoxic effects of certain medications like erythromycin and/or lincomycin [ 55 ], metronidazole and dimetridazole [ 56 ], and glucocorticoid receptor agonists [ 57 ]. Likewice, our results correspond to previously conducted studies related to genotoxic potential of oral anticoagulant [ 58 ] and antiviral [ 59 ] therapy.…”

Three dimensional and microphysiological bone marrow models detect in vivo positive compounds

“…The animal data for prednisolone used for comparison to in vitro data in the current study were previously obtained in accordance with ARRIVE guidelines as described in Hayes et al 3 .…”

“…The animal data for AZ12785452 used for comparison to in vitro data in the current study were previously obtained in accordance with ARRIVE guidelines using the study design outlined in Hayes et al 3 except that animals were killed by administration of isoflurane followed by severance of major blood vessels.…”

“…Despite this, a number of compounds are negative in vitro but positive in vivo 2 , such as the glucocorticoid receptor agonists, prednisolone and dexamethasone. These are not truly genotoxic or carcinogenic, as evidenced by the lack of carcinogenic risk in humans following decades of clinical use 3 , 4 , but are the result of pharmacological effects on the BM leading to an increase in MN in vivo 3 . This is further supported by observations where post-dexamethasone treatment there was increase in erythropoiesis in haematopoietic cells from mouse foetal livers in vitro 5 , and in a mouse model with Diamond-Blackfan Anaemia (DBA), which have depleted erythroid progenitors, glucocorticoid treatment reversed the effect leading to an increase in erythrocytes 6 .…”

Does bleeding induce micronuclei via erythropoietin in Han-Wistar rats?

“…There is now evidence that not all in vivo positive results are due to genotoxicity, and sustained changes in core body temperature, increased erythropoiesis, or decreased protein synthesis induced by test agents have all been shown to increase the frequency of micronucleated immature erythrocytes (MIEs). 6 More recently it has also been shown that increased MIE numbers in rat bone marrow can be a consequence of the pharmacological action of glucocorticoid receptor agonists 7 and long-acting β-2 agonism. 8 It is important to understand whether or not increases in MIE are due to geno-toxicity because, in the absence of a plausible non-genotoxic mechanism, a positive micronucleus test result is taken to indicate potential rodent carcinogenicity by regulators.…”