Sex differences in improved efficacy of doxorubicin chemotherapy in Cbr1+/- mice.

The anthracycline chemotherapeutic agent doxorubicin is converted by the enzyme carbonyl reductase 1 (CBR1) into its cardiotoxic metabolite doxorubicinol. Cbr1+/- mice have been shown to be protected from doxorubicin-induced cardiotoxicity, and the inhibition of CBR1 activity may be a useful means of ameliorating the side effects of doxorubicin in patients undergoing chemotherapy. Because reduced conversion to doxorubicinol increases circulating levels of the more effective parent drug doxorubicin, it was hypothesized that therapeutic efficacy against tumors might also be enhanced. Cbr1+/- mice were bred to mice transgenic for the polyomavirus middle T antigen (PyVT) to create offspring with palpable mammary tumors. Latency to initial tumor formation was similar in Cbr1+/- and Cbr1+/+ animals. Tumor regression was improved in Cbr1+/- animals, but only in male mice. Western blotting showed a marked sex difference in protein levels, with a much higher expression of Cbr1 in the female kidney and liver. Thus, the combined effects of a naturally low expression and the heterozygous Cbr1 null allele seem to have enhanced tumor regression in Cbr1+/- males. Future efforts to design a clinical CBR1 inhibitor to protect patients from the cardiac side effects of doxorubicin treatment should evaluate the effect of sex on anticancer efficacy.

Thermodynamics Affecting Glacier-Released 4-Nonylphenol Deposition in Alaska, USA.

Glaciers have recently been recognized as a secondary source of organic pollutants. As glacier melt rates increase, downstream ecosystems are at increasing risk of exposure to these pollutants. Nonylphenols (NPs) are well-documented anthropogenic persistent pollutants whose environmental prevalence and ecotoxicity make them of immediate concern to the health of humans and wildlife populations. As glacier melt increases, transport of NPs to downstream environments will also increase. Snow, ice, meltwater, and till for five glaciers in the Chugach National Forest and Kenai Fjords National Park, Alaska, USA, were investigated for the presence of 4-nonylphenol (4NP). Average concentrations for snow, ice, meltwater, and glacial till were 0.77 ± .017 µg/L snow water, 0.75 ± .006 µg/L, 0.26 ± .053 µg/L, and 0.016 ± .004 µg/g, respectively. All samples showed the presence of 4NP. Deposition of 4NP downstream from glaciers will depend more on the ionic strength of the water than organic carbon to drive partitioning and deposition. Laboratory studies of partition coefficients showed that ionic strength contributed 59% of the driving force behind partitioning, while organic carbon contributed 36%. Evidence was found for interaction between organic carbon and the aqueous phase. The 4NP Setschenow constants (Ks ) were determined for particle types with varying percentages of organic carbon. Values of Ks increased with the percentage of organic carbon. These relationships will shape further studies of 4NP deposition into the environment downstream of glacier outflow. Environ Toxicol Chem 2022;41:1623-1636. © The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.