Contents lists available at ScienceDirect Environmental Research journal homepage: www.elsevier.com/locate/envres Inorganic arsenic methylation capacity and breast cancer by immunohistochemical subtypes in northern Mexican women Lizbeth López-Carrillo a , Brenda Gamboa-Loira a , A. Jay Gandolfi b , Mariano E. Cebrián c,* a Instituto Nacional de Salud Pública, Av. Universidad 655, Col. Santa María Ahuacatitlán, C.P, 62100, Cuernavaca, Morelos, Mexico b Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA c Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN, Ave. Instituto Politécnico Nacional 2508, Ciudad de México, Mexico ARTICLE INFO Keywords: Breast cancer Hormonal receptor HER2 Triple negative Inorganic arsenic ABSTRACT Background: Previously we reported that inorganic arsenic (iAs) methylation capacity was associated with breast cancer (BC). BC risk factors may vary according to immunohistochemical subtype. Here we explored the re- lationships between the capacity to methylate iAs and the risk of BC by subtype. Methods: A population-based case-control study was performed in northern Mexico. Patients with available information about BC subtypes (n = 499) were age-matched with healthy controls. Sociodemographic, re- productive, and lifestyle characteristics were obtained. Tumor marker information was obtained from medical records. Cases were classified as HR+ [estrogen receptor (ER+) and/or progesterone (PR+), and human epi- dermal growth factor receptor 2 (HER2-)], HER2+, or triple negative (TN). Urinary arsenic species were de- termined by high performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC- ICP-MS), and methylation capacity parameters calculated. Conditional logistic regression models were used to estimate BC risk by subtypes. Results: Urinary total arsenic varied from 0.60 to 303.29 μg/L. A significant positive association was found between % monomethylarsonic acid (%MMA) and HR + BC: one percent increase resulted in OR %MMA con- tinuous = 2.73, 95% CI: 1.48, 5.05), and this association remained even when %iAs or % dimethylarsinic acid (% DMA) were added to the models with %MMA. MMA/iAs was positively associated with HR + BC (OR MMA/iAs continuous = 2.03, 95% CI: 1.33–3.10). A significant negative association was observed between DMA/MMA and HR + BC (OR DMA/MMA continuous = 0.43, 95% CI: 0.26, 0.71). MMA/iAs was positively associated with TN BC (OR MMA/iAs continuous = 4.05; 95% CI: 1.63, 10.04). Conclusion: Altered iAs methylation capacity resulting in higher %MMA was associated with HR+ and TN BC but not with HER2+. MMA is the iAs metabolite more likely to be related to BC. Further research is needed to confirm these results and elucidate the underlying biological mechanisms. 1. Introduction Inorganic arsenic (iAs) was classified as a type I carcinogen for skin, lung, and bladder (International Agency for Research on Cancer, 2012). However, the relationships between arsenic exposure and breast cancer (BC), the leading cause of malignant tumors among women worldwide, has not yet been elucidated. Inorganic arsenic is a natural water con- taminant whose maximum contaminant level is 10 μg/L (World Health Organization, 2010). Scarce and inconsistent information is available regarding arsenic exposure via drinking water and BC: an ecological study in Argentina found no association between BC cases reported to a local cancer registry and arsenic levels in ground water (ND - 330 μg/L) (Aballay et al., 2012). In American Indians, García-Esquinas et al. (2013) reported that low to moderate exposure to iAs levels in drinking water (less than 10–61 μg/L) leading to 10.4 (6.12–18.4 μg/L) in urine was prospectively associated with increased mortality from cancer in several organs but not from BC. Interestingly, Smith et al. (2014) re- ported a major reduction in BC soon after high exposure to iAs in drinking water commenced in northern Chile, but once a removal plant was installed, BC mortality started to increase back to rates close to that of the unexposed comparison population. However, Wadhwa et al. (2015) reported in Pakistani female BC patients that arsenic levels in https://doi.org/10.1016/j.envres.2020.109361 Received 15 October 2019; Received in revised form 6 March 2020; Accepted 7 March 2020 * Corresponding author. Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del IPN, Ave. Instituto Politécnico Nacional # 2508, Mexico City, 07360, Mexico. E-mail addresses: lizbeth@insp.mx (L. López-Carrillo), blgl.bio@gmail.com (B. Gamboa-Loira), gandolfi@pharmacy.arizona.edu (A.J. Gandolfi), mcebrian@cinvestav.mx (M.E. Cebrián). Environmental Research 184 (2020) 109361 Available online 16 March 2020 0013-9351/ © 2020 Published by Elsevier Inc. T