Biology subjects

Dertinger, S. D.

Publications and source records attributed to Dertinger, S. D..

4 recordsLinked to original sources

bioRxiv2026

INVESTIGATION OF ETHYLENE OXIDE GENOTOXICITY DOSE-RESPONSE TO INFORM CANCER RISK ASSESSMENT

Ethylene oxide (EtO) is primarily used as an intermediate in the manufacture of chemicals, with a minor use as a sterilant for medical equipment and food products. It is a direct-acting alkylating agent that reacts with cellular macromolecules, including proteins and DNA. EtO has been shown to induce tumors in rodents and humans. DNA reactivity has been the postulated mode of action (MOA) for its carcinogenicity. The current study has investigated the dose response for EtO-induced genetic damage to inform the biological plausibility of a dose-response model for cancer risk assessment. Male and female B6C3F1 mice were exposed to 0, 0.05, 0.1, 0.5, 1, 50, 100, or 200 ppm EtO by whole-body inhalation (6 hours/day for 28 days, 7 days/week). Mutagenicity was assessed by determining the frequency of mutant Pig-a phenotype in reticulocytes (RET) and mature red blood cells (RBC) on Day 28. Cytogenetic damage was evaluated by the erythrocyte micronucleus (MN) test in blood samples collected on Days 5 and 28. EtO is a relatively weak genotoxicant with treatment-related increases in Pig-a and MN frequencies being seen primarily at 200 ppm. The hockey-stick shaped dose response for genetic damage may be conservatively interpreted as being no more than a linear response with a single slope. Thus, a cancer risk assessment dose-response model consisting of a single linear slope throughout the exposure range is biologically plausible and consistent if EtO were acting through a mutagenic MoA for its carcinogenicity.

pharmacology and toxicology↗

bioRxiv2025

Persistent interferon signaling and clonal expansion mark early events in DNA methylation damage-induced liver cancer

N-Nitrosodimethylamine (NDMA), a probable human carcinogen, induces toxic and mutagenic O6-methylguanine lesions that are repaired by the O6-methylguanine methyltransferase (MGMT). To elucidate mechanisms of NDMA-induced liver cancer progression, we performed longitudinal analyses of phenomic, transcriptomic, and phosphoproteomic changes in wild-type and MGMT-deficient mice, observing amplified responses in the deficient genotype. Early molecular rewiring indicative of a DNA damage response was detected by phosphoproteomic and transcriptomic profiling within days post-exposure. Transcriptomic analyses identified a persistent and robust interferon response as the dominant activated pathway. This chronic interferon signaling, which remained unresolved, correlated with extensive clonal expansion, an early hallmark of oncogenesis. Spatial transcriptomics further revealed pathway alterations favoring tumorigenesis within clonally expanded cells. These findings delineate the cascade of molecular events triggered by acute early-life NDMA exposure, culminating in cancer development months later. Our study unveils potential predictive biomarkers and strategies for disease mitigation.

cancer biology↗

bioRxiv2025

Sex and Alkyladenine DNA Glycosylase Expression are Key Susceptibility Factors for NDMA-induced Mutations, Toxicity, and Cancer

N-Nitrosodimethylamine (NDMA) is present in food, water, and drugs and is considered a probable human carcinogen by the International Agency for Research on Cancer. The mechanism of action of NDMA involves the generation of carcinogenic methyl lesions such as 3-methyladenine (3MeA) on DNA bases. Alkyladenine DNA Glycosylase (AAG) removes 3MeA to initiate Base Excision Repair, leaving an intermediary lesion that is subsequently resolved by backbone cleavage, nucleotide insertion, and backbone ligation. The intermediate steps following lesion removal produce potentially toxic and mutagenic single-strand DNA breaks. Here, we explored differences between males and females regarding downstream DNA damage, toxicity, mutations and cancer arising from 3MeA in the livers of WT, Aag-/-, and Aag-overexpressing (AagTg) mice. We found that males were more susceptible to NDMA-induced mutations (WT and Aag-/-) and cancer (all genotypes). In contrast, AagTg females were more prone than males to micronucleus induction. As we showed in our prior analyses where data were pooled for males and females, Aag-/- mice were significantly more susceptible to NDMA-induced mutations and cancer, and AagTg mice displayed significantly greater toxicity. Building on these findings, our analyses of sex-related differences show that Aag deficiency and maleness are both susceptibility factors for NDMA-induced liver cancer, while Aag overexpression drives toxicity, potentially with a greater effect on females. By assessing differences between males and females, this study reveals a deeper mechanistic understanding of the underpinnings for a well-known increased risk of liver cancer in men versus women by demonstrating a higher susceptibility of male mice to both mutations and cancer.

cancer biology↗

bioRxiv2021

Excision of mutagenic replication-blocking lesions suppresses cancer but promotes cytotoxicity and lethality in nitrosamine-exposed mice

N-nitrosodimethylamine (NDMA) is a DNA methylating agent that has been discovered to contaminate water, food and drugs. The alkyladenine glycosylase (AAG) removes methylated bases to initiate the base excision repair (BER) pathway. To understand how gene-environment interactions impact disease susceptibility, we studied Aag-/- and Aag-overexpressing mice that harbor increased levels of either replication-blocking lesions (3-methyladenine, or 3MeA) or strand breaks (BER intermediates), respectively. Remarkably, the disease outcome switched from cancer to lethality simply by changing AAG levels. To understand the underlying basis for this observation, we integrated a suite of molecular, cellular and physiological analyses. We found that unrepaired 3MeA is somewhat toxic but highly mutagenic (promoting cancer), whereas excess strand breaks are poorly mutagenic and highly toxic (suppressing cancer and promoting lethality). We demonstrate that the levels of a single DNA repair protein tips the balance between blocks and breaks, and thus dictates the disease consequences of DNA damage.

cancer biology↗