Biology subjects

Kahana, A.

Publications and source records attributed to Kahana, A..

4 recordsLinked to original sources

bioRxiv2021

Identifying the Link Between Chemical Exposures and Breast Cancer in African American Women via ToxCast High Throughput Screening Data

Among women, breast cancer is the most prevalent form of cancer worldwide and has the second highest mortality rate of any cancer in the United States. The breast cancer related death rate is 40% higher in African American women compared to European American women. The incidence of triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which there is no targeted therapy, is approximately three times higher in non-Hispanic Black women (NHBW) compared to non-Hispanic White women (NHWW). The drivers of these differences in breast cancer incidence and mortality are still poorly understood, and likely lie in an interaction between genetic and environmental factors. Here, we aimed to identify chemical exposures which may play a role in breast cancer disparities. Using chemical biomonitoring data from the National Health and Nutrition Examination Survey (NHANES) and biological activity data from the EPAs ToxCast program, we assessed the toxicological profiles of chemicals with higher biomarker concentrations in US NHBW. We conducted a literature search to identify a gene set of breast cancer targets included in ToxCast to analyze the response of prioritized chemicals in these assays. Forty-three chemical biomarkers are significantly higher in NHBW. Investigation of these chemicals in ToxCast resulted in a total of 32,683 assays for analysis, 5,172 of which contained nonzero values for the concentration at which the dose-response fitted model reaches the cutoff considered "active" and the scaled top value of dose response curve. Of these chemicals BPA, PFOS, and thiram are most comprehensively assayed. 2,5-dichlorophenol, 1,4-dichlorobenzene, and methyl and propyl parabens had higher biomarker concentrations in NHBW and moderate testing and activity in ToxCast. The distribution of active concentrations for these chemicals in ToxCast assays are comparable to biomarker concentrations in NHBW. Through this integrated analysis, we have identified that multiple chemicals, including thiram, propylparaben, and p,p DDE, with disproportionate exposures in NHBW, have breast cancer associated biological activity at human exposure relevant doses.

pharmacology and toxicology↗

bioRxiv2020

Polyamines Mediate Folding of Primordial Hyper-Acidic Helical Proteins

Polyamines are known to mediate diverse biological processes, and specifically to bind and stabilize compact conformations of nucleic acids, acting as chemical chaperones that promote folding by offsetting the repulsive negative charges of the phosphodiester backbone. However, whether and how polyamines modulate the structure and function of proteins remains unclear. Further, early proteins are thought to have been highly acidic, like nucleic acids, due to a scarcity of basic amino acids in the prebiotic context. Perhaps polyamines, the abiotic synthesis of which is simple, could have served as chemical chaperones for such primordial proteins? We replaced all lysines of an ancestral 60-residue helix-bundle protein to glutamate, resulting in a disordered protein with 21 glutamates in total. Polyamines efficiently induce folding of this hyper-acidic protein at sub-millimolar concentrations, and their potency scaled with the number of amine groups. Compared to cations, polyamines were several orders of magnitude more potent than Na+, while Mg2+ and Ca2+ had an effect similar to a di-amine, inducing folding at approximately seawater concentrations. We propose that (i) polyamines and dications may have had a role in promoting folding of early proteins devoid of basic residues, and that (ii) coil-helix transitions could be the basis of polyamine regulation in contemporary proteins.

evolutionary biology↗

bioRxiv2020

Midkine-a functions as a universal regulator of proliferation during epimorphic regeneration in adult zebrafish

Zebrafish have the ability to regenerate damaged cells and tissues by activating quiescent stem and progenitor cells or reprogramming differentiated cells into regeneration-competent precursors. Proliferation among the cells that will functionally restore injured tissues is a fundamental biological process underlying regeneration. Midkine-a is a cytokine growth factor, whose expression is strongly induced by injury in a variety of tissues across a range of vertebrate classes. Using a zebrafish Midkine-a loss of function mutant, we evaluated regeneration of caudal fin, extraocular muscle and retinal neurons to investigate the function of Midkine-a during epimorphic regeneration. In wildtype zebrafish, injury among these tissues induces robust proliferation and rapid regeneration. In Midkine-a mutants, the initial proliferation in each of these tissues is significantly diminished or absent. Regeneration of the caudal fin and extraocular muscle is delayed; regeneration of the retina is nearly completely absent. These data demonstrate that Midkine-a is universally required in the signaling pathways that convert tissue injury into the initial burst of cell proliferation. Further, these data highlight differences in the molecular mechanisms that regulate epimorphic regeneration in zebrafish.

developmental biology↗

bioRxiv2019

A comprehensive analysis of racial disparities in chemical biomarker concentrations in United States women, 1999-2014

BackgroundStark racial disparities in disease incidence among American women remains a persistent public health challenge. These disparities likely result from complex interactions between genetic, social, lifestyle, and environmental risk factors. The influence of environmental risk factors, such as chemical exposure, however, may be substantial and is poorly understood.\n\nObjectivesWe quantitatively evaluated chemical-exposure disparities by race/ethnicity and age in United States (US) women by using biomarker data for 143 chemicals from the National Health and Nutrition Examination Survey (NHANES) 1999-2014.\n\nMethodsWe applied a series of survey-weighted, generalized linear models using data from the entire NHANES women population and age-group stratified subpopulations. The outcome was chemical biomarker concentration and the main predictor was race/ethnicity with adjustment for age, socioeconomic status, smoking habits, and NHANES cycle.\n\nResultsThe highest disparities across non-Hispanic Black, Mexican American, Other Hispanic, and other race/multiracial women were observed for pesticides and their metabolites, including 2,5-dichlorophenol, o,p-DDE, beta-hexachlorocyclohexane, and 2,4-dichlorophenol, along with personal care and consumer product compounds. The latter included parabens, monoethyl phthalate, and several metals, such as mercury and arsenic. Moreover, for Mexican American, Other Hispanic, and non-Hispanic black women, there were several exposure disparities that persisted across age groups, such as higher 2,4- and 2,5-dichlorophenol concentrations. Exposure differences for methyl and propyl parabens, however, were the starkest between non-Hispanic black and non-Hispanic white children with average differences exceeding 4 folds.\n\nDiscussionsWe systematically evaluated differences in chemical exposures across women of various race/ethnic groups and across age groups. Our findings could help inform chemical prioritization in designing epidemiological and toxicological studies. In addition, they could help guide public health interventions to reduce environmental and health disparities across populations.

bioinformatics↗