Strain and sex effects on blood accumulation of lead, chromium, and cadmium in strains from the Collaborative Cross mouse population

Abstract

Lead (Pb), chromium (Cr), and cadmium (Cd) are heavy metals that contaminate sites throughout North America. Historically, toxicological effects of Pb, Cr, or Cd compounds have been investigated in a hybrid mouse strain, B6C3F1. However, humans have more genetic diversity and population variability in response to toxicants than is represented in this homogeneous mouse model, which leaves genetic effects on dose response uncertain. Use of the Collaborative Cross (CC) addresses the problem of limited genetic diversity inherent in models like B6C3F1. In previous work, blood Pb levels in panel of female CC lines exposed to high-dose (0.1%) lead acetate showed a strain dependent response. Four strains from the original study with varying Pb blood levels after exposure were selected to determine if strain and sex dependence was exhibited in a two-week acute exposure to Pb, but also to Cr or Cd exposure. To investigate genetic background influence on metal deposition, five animals of each sex from each strain were placed on an American diet for one week prior to dosing high- (0.1%) or low- (0.01%) dose Pb acetate, high- (0.1%) or low- (0.01%) sodium dichromate, or high- (0.1%) or low- (0.01%) cadmium chloride via drinking water ad libitum for 14-days, matching the standard short-term exposure of the National Toxicology Program. Body composition was measured before the start of dosing and prior to necropsy using EcoMRI. Blood Pb at necropsy from this study suggests the strain dependent trends observed in previous exposures is conserved for acute Pb exposure but with different trends for Cr and Cd indicating that even a small panel of strains will not suffice for estimating variation across all toxicants.