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Both obesity and arsenic exposure are global public health problems that are associated with increased risk of renal disease. The effect of whole-life exposure to environmentally relevant levels of arsenic within dietary high fat diet on renal pathogenesis were examined. In this study, C57BL/6 J mice were parentally exposed to 100 ppb arsenic before conception. After weaning, both male and female offspring were maintained on 100 ppb arsenic and fed either a normal (LFD) or high fat diet (HFD). At 10 and 24 weeks of age, the offspring were sacrificed and kidneys collected. Exposure to arsenic led to an increase body-weight in LFD diet-fed female but not male mice. This response was not observed in HFD-fed female mice; however male mice showed significant increases in body weight in both As- and non-treated animals. Histological analysis shows that arsenic exposure significantly increases HFD-induced glomerular area expansion, mesangial matrix accumulation and fibrosis compared to LFD control animals. HFD alone increases renal inflammation and fibrosis; reflected by increases in IL-1β, ICAM-1 and fibronectin levels. Arsenic exposure significantly increases HFD-induced inflammatory and oxidative stress responses. In general, male mice have more severe responses than female mice to HFD or arsenic treatment. These results demonstrate that arsenic exposure causes sex-dependent alterations in HFD-induced kidney damage., (Copyright © 2019. Published by Elsevier B.V.)