Refining risk estimates for lead in drinking water based on the impact of genetics and diet on blood lead levels using the Collaborative Cross mouse population.

Blood lead (Pb) level (BLL) is a commonly used biomarker to evaluate associations with health effects. However, interventions to reduce the adverse effects of Pb require relating BLL to external exposure. Moreover, risk mitigation actions need to ensure protection of more susceptible individuals with a greater tendency to accumulate Pb. Because little data is available to quantify inter-individual variability in biokinetics of Pb, we investigated the influence of genetics and diet on BLL in the genetically diverse Collaborative Cross (CC) mouse population. Adult female mice from 49 CC strains received either a standard mouse chow or a chow mimicking the American diet while being provided water ad libitum with 1000 ppm Pb for 4 weeks. In both arms of the study, inter-strain variability was observed; however, in American diet-fed animals, the BLL was greater and more variable. Importantly, the degree of variation in BLL among strains on the American diet was greater (2.3) than the default variability estimate (1.6) used in setting the regulatory standards. Genetic analysis identified suggestive diet-associated haplotypes that were associated with variation in BLL, largely contributed by the PWK/PhJ strain. This study quantified the variation in BLL that is due to genetic background, diet, and their interactions, and observed that it may be greater than that assumed for current regulatory standards for Pb in drinking water. Moreover, this work highlights the need of characterizing inter-individual variation in BLL to ensure adequate public health interventions aimed at reducing human health risks from Pb.

A molecular subtype of colorectal cancers initiates independently of epidermal growth factor receptor and has an accelerated growth rate mediated by IL10-dependent anergy.

Although epidermal growth factor receptor (EGFR)-targeted therapies are approved for colorectal cancer (CRC) treatment, only 15% of CRC patients respond to EGFR inhibition. Here, we show that colorectal cancers (CRC) can initiate and grow faster through an EGFR-independent mechanism, irrespective of the presence of EGFR, in two different mouse models using tissue-specific ablation of Egfr. The growth benefit in the absence of EGFR is also independent of Kras status. An EGFR-independent gene expression signature, also observed in human CRCs, revealed that anergy-inducing genes are overexpressed in EGFR-independent polyps, suggesting increased infiltration of anergic lymphocytes promotes an accelerated growth rate that is partially caused by escape from cell-mediated immune responses. Many genes in the EGFR-independent gene expression signature are downstream targets of interleukin 10 receptor alpha (IL10RA). We further show that IL10 is detectable in serum from mice with EGFR-independent colon polyps. Using organoids in vitro and Src ablation in vivo, we show that IL10 contributes to growth of EGFR-independent CRCs, potentially mediated by the well-documented role of SRC in IL10 signaling. Based on these data, we show that the combination of an EGFR inhibitor with an anti-IL10 neutralizing antibody results in decreased cell proliferation in organoids and in decreased polyp size in pre-clinical models harboring EGFR-independent CRCs, providing a new therapeutic intervention for CRCs resistant to EGFR inhibitor therapies.