Previously this laboratory characterized Slc39a8-encoded ZIP8 as a Zn2+/(HCO3 –)2 symporter; yet, the overall physiological importance of ZIP8 at the whole-organism level remains unclear. Herein we describe the phenotype of the hypomorphic Slc39a8(neo/neo) mouse which has retained the neomycin-resistance gene in intron 3, hence causing significantly decreased ZIP8 mRNA and protein levels in embryo, fetus, placenta, yolk sac, and several tissues of neonates. The Slc39a8(neo) allele is associated with diminished zinc and iron uptake in mouse fetal fibroblast and liver-derived cultures; consequently, Slc39a8(neo/neo) newborns exhibit diminished zinc and iron levels in several tissues. Slc39a8(neo/neo) homozygotes from gestational day(GD)-11.5 onward are pale, growth-stunted, and die between GD18.5 and 48 h postnatally. Defects include: severely hypoplastic spleen; hypoplasia of liver, kidney, lung, and lower limbs. Histologically, Slc39a8(neo/neo) neonates show decreased numbers of hematopoietic islands in yolk sac and liver. Low hemoglobin, hematocrit, red cell count, serum iron, and total iron-binding capacity confirmed severe anemia. Flow cytometry of fetal liver cells revealed the erythroid series strikingly affected in the hypomorph. Zinc-dependent 5-aminolevulinic acid dehydratase, required for heme synthesis, was not different between Slc39a8(+/+) and Slc39a8(neo/neo) offspring. To demonstrate further that the mouse phenotype is due to ZIP8 deficiency, we bred Slc39a8(+/neo) with BAC-transgenic BTZIP8-3 line (carrying three extra copies of the Slc39a8 allele); this cross generated viable Slc39a8(neo/neo)_BTZIP8-3(+/+) pups showing none of the above-mentioned congenital defects–proving Slc39a8(neo/neo) causes the described phenotype. Our study demonstrates that ZIP8-mediated zinc transport plays an unappreciated critical role during in utero and neonatal growth, organ morphogenesis, and hematopoiesis.

Resistance to chemotherapy is a major obstacle for successful treatment of breast cancer patients. Given that prolactin (PRL) acts as an anti-apoptotic/survival factor in the breast, we postulated that it antagonizes cytotoxicity by chemotherapeutic drugs. Treatment of breast cancer cells with PRL caused variable resistance to taxol, vinblastine, doxorubicin and cisplatin. PRL prevented cisplatin-induced G(2)/M cell cycle arrest and apoptosis. In the presence of PRL, significantly less cisplatin was bound to DNA, as determined by mass spectroscopy, and little DNA damage was seen by gamma-H2AX staining. PRL dramatically increased the activity of glutathione-S-transferase (GST), which sequesters cisplatin in the cytoplasm; this increase was abrogated by Jak and mitogen-activated protein kinase inhibitors. PRL upregulated the expression of the GSTmu, but not the pi, isozyme. A GST inhibitor abrogated antagonism of cisplatin cytotoxicity by PRL. In conclusion, PRL confers resistance against cisplatin by activating a detoxification enzyme, thereby reducing drug entry into the nucleus. These data provide a rational explanation for the ineffectiveness of cisplatin in breast cancer, which is characterized by high expression of both PRL and its receptor. Suppression of PRL production or blockade of its actions should benefit patients undergoing chemotherapy by allowing for lower drug doses and expanded drug options.

Association of urinary arsenic concentration with incident diabetes was examined in American Indians from Arizona who have a high prevalence of type 2 diabetes and were screened for diabetes between 1982 and 2007. The population resides where drinking water contains arsenic at concentrations above federally recommended limits. A total of 150 nondiabetic subjects aged ≥25 years who subsequently developed type 2 diabetes were matched by year of examination and sex to 150 controls who remained nondiabetic for ≥10 years. Total urinary arsenic concentration, adjusted for urinary creatinine level, ranged from 6.6 µg/L to 123.1 µg/L, and inorganic arsenic concentration ranged from 0.1 µg/L to 36.0 µg/L. In logistic regression models adjusted for age, sex, body mass index, and urinary creatinine level, the odds ratios for incident diabetes were 1.11 (95% confidence interval (CI): 0.79, 1.57) and 1.16 (95% CI: 0.89, 1.53) for a 2-fold increase in total arsenic and inorganic arsenic, respectively. Categorical analyses suggested a positive relationship between quartiles of inorganic arsenic and incident diabetes (P = 0.056); post-hoc comparison of quartiles 2-4 with quartile 1 revealed 2-fold higher odds of diabetes in the upper quartiles (OR = 2.14, 95% CI: 1.19, 3.85). Modestly elevated exposure to inorganic arsenic may predict type 2 diabetes in American Indians. Larger studies that include measures of speciated arsenic are required for confirmation.

Resistance to chemotherapy is a major problem facing breast cancer patients. Cisplatin, a highly effective DNA-damaging drug, has shown only little success in breast cancer treatment. We are reporting that low nanomolar doses of bisphenol A (BPA) or estradiol antagonize cisplatin cytotoxicity in breast cancer cells, with their effects not mediated via classical estrogen receptors. Although both compounds increase the expression of Bcl-2, a Bcl-2 inhibitor completely blocked the protective effects of BPA while only partially affecting those of estradiol. Blockade of BPA and E2 actions should sensitize ER-negative breast tumors to anti-cancer drugs and allow for the inclusion of cisplatin in treatment regimens.

Soybean (Glycine Max) plants were grown in soil supplemented with sodium selenite. A comprehensive selenium profile, including total selenium concentration, distribution of high molecular weight selenium and characterization of low molecular weight selenium compounds, is reported for each plant compartment: bean, pod, leaf and root of the Se-enriched soybean plants. Two chromatographic techniques, coupled with inductively coupled plasma mass spectrometry (ICPMS) for specific selenium detection, were employed in this work to analyze extract solutions from the plant compartments. Size-exclusion chromatography revealed that the bean compartment, well-known for its strong ability to make proteins, produced high amounts (82% of total Se) of high molecular weight selenospecies, which may offer additional nutritional value and suggest high potential for studying proteins containing selenium in plants. The pod, leaf and root compartments primarily accumulate low molecular weight selenium species. For each compartment, low molecular weight selenium species (lower than 5 kDa) were characterized by ion-pairing reversed phase HPLC-ICPMS and confirmed by electrospray ionization ion trap mass spectrometry (ESI-ITMS). Selenomethionine and selenocystine are the predominant low molecular weight selenium compounds found in the bean, while inorganic selenium was the major species detected in other plant compartments.