Increasing the utility of epidemiologic studies as key evidence in chemical risk assessment.

The Society of Toxicology 2024 meeting assembled risk assessors, epidemiologists, and toxicologists to discuss the utility of integrating epidemiologic data into the derivation of reference values. Advantages of the use of epidemiologic evidence include (i) human relevance; (ii) increased likelihood that exposure levels are relevant to risk assessment; and (iii) incorporation of uncertainties attributed to co-exposures or other population-based considerations. The workshop panelists discussed the challenges of incorporating epidemiologic evidence due to uncertain exposure measurements, confounding, heterogeneity, and inherent study design limitations.

Do shale oil and gas production activities impact ambient air quality? A comprehensive study of 12Â years of chemical concentrations and well production data from the Barnett Shale region of Texas.

Starting around 2008, there was rapid expansion of oil and natural gas (ONG) production into more heavily populated areas within the Dallas-Fort Worth metroplex in the Barnett Shale region of Texas. This colocation raised concerns regarding the effect of ONG activities on chemical levels in the air. In the current study, we examined the potential impacts of ONG activity on the types and concentrations of chemicals in ambient air in the Barnett Shale.

DNA polymerase zeta contributes to heterochromatin replication to prevent genome instability.

The DNA polymerase zeta (Polζ) plays a critical role in bypassing DNA damage. REV3L, the catalytic subunit of Polζ, is also essential in mouse embryonic development and cell proliferation for reasons that remain incompletely understood. In this study, we reveal that REV3L protein interacts with heterochromatin components including repressive histone marks and localizes in pericentromeric regions through direct interaction with HP1 dimer.

Comparing apples to oranges: Interpreting ozone concentrations from observational studies in the context of the United States ozone regulatory standard.

In 2015, the United States Environmental Protection Agency (US EPA) set the ozone National Ambient Air Quality Standards (NAAQS) at 0.070 parts per million (ppm), for an annual 4th highest daily 8-hour (h) maximum average concentration, averaged over three years, with compliance based on the monitor with the highest concentrations. Numerous epidemiological studies have evaluated associations between ozone and health effects, but how the ozone concentrations derived from those studies can be compared to the ozone NAAQS is not clear, because of the complexity of the standard.

What Are the Net Benefits of Reducing the Ozone Standard to 65 ppb? An Alternative Analysis.

In October 2015, the United States Environmental Protection Agency (EPA) lowered the level of the ozone National Ambient Air Quality Standard (NAAQS) from 0.075 ppm to 0.070 ppm (annual 4th highest daily maximum 8-h concentration, averaged over three years).

DNA polymerase ζ deficiency causes impaired wound healing and stress-induced skin pigmentation.

DNA polymerase ζ (pol ζ) is a specialized enzyme important for DNA damage tolerance, facilitating synthesis past lesions caused by radiation or chemical damage. Here we report that disruption of (encoding the catalytic subunit of pol ζ) in mouse epidermis leads to a defect in proliferation that impairs cutaneous wound healing. A striking increase in epidermal skin pigmentation accompanied both wound healing and UV irradiation in these mice.

DNA polymerase ζ limits chromosomal damage and promotes cell survival following aflatoxin exposure.

Routine dietary consumption of foods that contain aflatoxins is the second leading cause of environmental carcinogenesis worldwide. Aflatoxin-driven mutagenesis is initiated through metabolic activation of aflatoxin B (AFB) to its epoxide form that reacts with N7 guanine in DNA. The resulting AFB-N7-dG adduct undergoes either spontaneous depurination or imidazole-ring opening yielding formamidopyrimidine AFB (AFB-Fapy-dG).

DNA polymerase ι functions in the generation of tandem mutations during somatic hypermutation of antibody genes.

DNA polymerase ι (Pol ι) is an attractive candidate for somatic hypermutation in antibody genes because of its low fidelity. To identify a role for Pol ι, we analyzed mutations in two strains of mice with deficiencies in the enzyme: 129 mice with negligible expression of truncated Pol ι, and knock-in mice that express full-length Pol ι that is catalytically inactive. Both strains had normal frequencies and spectra of mutations in the variable region, indicating that loss of Pol ι did not change overall mutagenesis.

The Polymerase Activity of Mammalian DNA Pol ζ Is Specifically Required for Cell and Embryonic Viability.

DNA polymerase ζ (pol ζ) is exceptionally important for maintaining genome stability. Inactivation of the Rev3l gene encoding the polymerase catalytic subunit causes a high frequency of chromosomal breaks, followed by lethality in mouse embryos and in primary cells. Yet it is not known whether the DNA polymerase activity of pol ζ is specifically essential, as the large REV3L protein also serves as a multiprotein scaffold for translesion DNA synthesis via multiple conserved structural domains.

REV7 is essential for DNA damage tolerance via two REV3L binding sites in mammalian DNA polymerase ζ.

DNA polymerase zeta (pol ζ) is exceptionally important for controlling mutagenesis and genetic instability. REV3L comprises the catalytic subunit, while REV7 (MAD2L2) is considered an accessory subunit. However, it has not been established that the role of REV7 in DNA damage tolerance is necessarily connected with mammalian pol ζ, and there is accumulating evidence that REV7 and REV3L have independent functions.

Dual role for mammalian DNA polymerase ζ in maintaining genome stability and proliferative responses.

DNA polymerase ζ (polζ) is critical for bypass of DNA damage and the associated mutagenesis, but also has unique functions in mammals. It is required for embryonic development and for viability of hematopoietic cells, but, paradoxically, skin epithelia appear to survive polζ deletion. We wished to determine whether polζ functions in a tissue-specific manner and how polζ status influences skin tumorigenesis.

DNA polymerase zeta is required for proliferation of normal mammalian cells.

Unique among translesion synthesis (TLS) DNA polymerases, pol ζ is essential during embryogenesis. To determine whether pol ζ is necessary for proliferation of normal cells, primary mouse fibroblasts were established in which Rev3L could be conditionally inactivated by Cre recombinase. Cells were grown in 2% O(2) to prevent oxidative stress-induced senescence.

DNA polymerases and cancer.

There are 15 different DNA polymerases encoded in mammalian genomes, which are specialized for replication, repair or the tolerance of DNA damage. New evidence is emerging for lesion-specific and tissue-specific functions of DNA polymerases. Many point mutations that occur in cancer cells arise from the error-generating activities of DNA polymerases.

Human HMGB1 directly facilitates interactions between nucleotide excision repair proteins on triplex-directed psoralen interstrand crosslinks.

Psoralen is a chemotherapeutic agent that acts by producing DNA interstrand crosslinks (ICLs), which are especially cytotoxic and mutagenic because their complex chemical nature makes them difficult to repair. Proteins from multiple repair pathways, including nucleotide excision repair (NER), are involved in their removal in mammalian cells, but the exact nature of their repair is poorly understood. We have shown previously that HMGB1, a protein involved in chromatin structure, transcriptional regulation, and inflammation, can bind cooperatively to triplex-directed psoralen ICLs with RPA, and that mammalian cells lacking HMGB1 are hypersensitive to psoralen ICLs.

HMGB1: the jack-of-all-trades protein is a master DNA repair mechanic.

The high mobility group protein B1 (HMGB1) is a highly abundant protein with roles in several cellular processes, including chromatin structure and transcriptional regulation, as well as an extracellular role in inflammation. HMGB1's most thoroughly defined function is as a protein capable of binding specifically to distorted and damaged DNA, and its ability to induce further bending in the DNA once it is bound. This characteristic in part mediates its function in chromatin structure (binding to the linker region of nucleosomal DNA and increasing the instability of the nucleosome structure) as well as transcription (bending promoter DNA to enhance the interaction of transcription factors), but the functional consequences of HMGB1's binding to damaged DNA is still an area of active investigation.

High mobility group protein B1 enhances DNA repair and chromatin modification after DNA damage.

High mobility group protein B1 (HMGB1) is a multifunctional protein with roles in chromatin structure, transcriptional regulation, V(D)J recombination, and inflammation. HMGB1 also binds to and bends damaged DNA, but the biological consequence of this interaction is not clearly understood. We have shown previously that HMGB1 binds cooperatively with nucleotide excision repair damage recognition proteins to triplex-directed psoralen DNA interstrand cross-links (ICLs).