Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N -methyl- N -nitrosourea

Abstract

Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently. A hormetic-style dose-response following a 24h exposure to the alkylating agent N-methyl-N-nitrosourea (MNU) was observed in a previous study for HPRT mutagenesis in the human lymphoblastoid cell line AHH-1. A second recent study demonstrated a J-shaped dose-response for the induction of micronuclei by MNU in a 24h treatment in a similar test system. Following mechanistic investigations, it was hypothesized that p53 may be responsible for the observed hormetic phenomenon. As genotoxic carcinogens are a major causative factor of many cancers, consideration of hormesis in carcinogenesis could be important in safety assessment. The data examined here offer possible insights into hormesis, including its estimated prevalence, underlying mechanisms and lack of generalizability.

An experimental pig model with outer retinal degeneration induced by temporary intravitreal loading of N-methyl-N-nitrosourea during vitrectomy

“…Zulliger et al showed retinal changes to be MNU concentrationdependent, a relationship that was most obvious with the ONL 43 . Other reports showed a dose-dependent response over the threshold dose as a carcinogen 44,45 .…”

A test battery for assessing the ecotoxic effects of textile dyes

“…Opposite biological effects of a stressor at low and high doses, showing a biphasic dose-response relationship (inverted U-or J-shaped curves), may represent hormesis [70]. Hormetic dose-response in Genetic Toxicology is usually reported as J-shaped curves, wherein mutation rates at low doses are less than the spontaneous level, whereas high doses display mutagenicity [71,72].…”

“…DB38 has also been investigated by the present research group regarding its capacity for inducing DNA damage in humans. Genotoxicity was not verified for DB38 when assessed by the in vitro Comet assay with dermal human fibroblast (primary cells) [72], studying the hormetic genotoxic response of N-methyl-N-nitrosourea (MNU) in two human lymphoblastoid cell lines (TK6 and NH32), showed that hormesis is unlikely to be generalized across different cell types, due to differences in the cell cycle control (e.g. p53 functional status) and in the DNA repair capacities.…”

Exposure to Low Levels of Radiofrequency Electromagnetic Fields Emitted from Cell-phones as a Promising Treatment of Alzheimer’s Disease: A Scoping Review Study

“…On the other hand, a cumulative body of evidence shows that living organisms exposed to different carcinogens at a specific window of doses may demonstrate hormetically or Jshaped dose-response relationships [14][15][16]. According to J-shaped models, the biological effects of low doses of a stressor may show beneficial or stimulatory effects.…”