Maternal intake of high n-6 polyunsaturated fatty acid diet during pregnancy causes transgenerational increase in mammary cancer risk in mice.

BACKGROUND: Maternal and paternal high-fat (HF) diet intake before and/or during pregnancy increases mammary cancer risk in several preclinical models. We studied if maternal consumption of a HF diet that began at a time when the fetal primordial germ cells travel to the genital ridge and start differentiating into germ cells would result in a transgenerational inheritance of increased mammary cancer risk. METHODS: Pregnant C57BL/6NTac mouse dams were fed either a control AIN93G or isocaloric HF diet composed of corn oil high in n-6 polyunsaturated fatty acids between gestational days 10 and 20. Offspring in subsequent F1-F3 generations were fed only the control diet. RESULTS: Mammary tumor incidence induced by 7,12-dimethylbenz[a]anthracene was significantly higher in F1 (p < 0.016) and F3 generation offspring of HF diet-fed dams (p < 0.040) than in the control offspring. Further, tumor latency was significantly shorter (p < 0.028) and burden higher (p < 0.027) in F1 generation HF offspring, and similar trends were seen in F3 generation HF offspring. RNA sequencing was done on normal mammary glands to identify signaling differences that may predispose to increased breast cancer risk by maternal HF intake. Analysis revealed 1587 and 4423 differentially expressed genes between HF and control offspring in F1 and F3 generations, respectively, of which 48 genes were similarly altered in both generations. Quantitative real-time polymerase chain reaction analysis validated 13 chosen up- and downregulated genes in F3 HF offspring, but only downregulated genes in F1 HF offspring. Ingenuity Pathway Analysis identified upregulation of Notch signaling as a key alteration in HF offspring. Further, knowledge-fused differential dependency network analysis identified ten node genes that in the HF offspring were uniquely connected to genes linked to increased cancer risk (ANKEF1, IGFBP6, SEMA5B), increased resistance to cancer treatments (SLC26A3), poor prognosis (ID4, JAM3, TBX2), and impaired anticancer immunity (EGR3, ZBP1). CONCLUSIONS: We conclude that maternal HF diet intake during pregnancy induces a transgenerational increase in offspring mammary cancer risk in mice. The mechanisms of inheritance in the F3 generation may be different from the F1 generation because significantly more changes were seen in the transcriptome.

Oxygen saturation monitoring using resonance Raman spectroscopy.

BACKGROUND: The knowledge of hemoglobin oxygen saturation (SO2) and tissue oxygenation is critical to identify the presence of shock and therapeutic options. The resonance vibrational enhancement of hemoglobin allows measurement of oxy- and deoxy species of hemoglobin and resonance Raman spectroscopy (RRS-StO2) has been successfully used to measure aggregate microvascular oxygenation. We tested the hypothesis that noninvasive oxygen saturation measured by RRS-StO2 could serve as surrogate of systemic central venous SO2. METHODS: In anesthetized rats, measurements of RRS-StO2 made in oral mucosa, skin, muscle, and liver were compared with measurements of central venous SO2 using traditional multi-wavelength oximetry. Various oxygenation levels were obtained using a stepwise hemorrhage while over 100 paired blood samples and Raman-based measurements were performed. The relationships between RRS-StO2 and clinically important systemic blood parameters were also evaluated. RRS-StO2 measurements were made in 3-mm diameter tissue areas using a microvascular oximeter and a handheld probe. RESULTS: Significant correlations were found between venous SO2 and RRS-StO2 measurements made in the oral mucosa (r = 0.913, P < 0.001), skin (r = 0.499, P < 0.01), and liver (r = 0.611, P < 0.05). The mean difference between sublingual RRS-StO2 and blood sample SO2 values was 5.4 ± 1.6%. Sublingual RRS-StO2 also correlated with lactate (r = 0.909, P < 0.01), potassium (r = 0.757, P < 0.01), and pH (r = 0.703, P < 0.05). CONCLUSIONS: Raman-based oxygen saturation is a promising technique for the noninvasive evaluation of oxygenation in skin, thin tissues, and solid organs. Under certain conditions, sublingual RRS-StO2 measurements correlate with central venous SO2.

Associations between lean mass and leptin in men with chronic spinal cord injury: Results from the FRASCI-muscle study.

Leptin is an adipo-myokine that regulates appetite and energy expenditure by a neuroendocrine feedback loop. Leptin levels are positively correlated with BMI in the spinal cord injury population and leptin levels are greater in individuals with spinal cord injury compared to uninjured controls. Leptin is produced in multiple tissues, including fat, bone, and skeletal muscle and is a putative biomarker of sedentary behavior in older adults. We assessed body composition leptin, adiponectin, and IL-6 levels in 205 men with chronic spinal cord injury. We found no association between age, injury duration, injury level, injury completeness, or walking status and leptin. There was a significant positive association between lean mass and leptin in men with SCI that was independent of fat. Adjusting for body composition, leptin levels were positively associated with IL-6 and negatively associated with adiponectin levels. When considering men with SCI and sarcopenic obesity, only fat mass remained positively associated with leptin. We found no association between IL-6, adiponectin, or lean mass and leptin in the sarcopenic obesity group. Our findings suggest that lean mass is an under recognized, but substantial, source of circulating leptin. Furthermore, SCI-related sarcopenic obesity may result in dysregulated adipo-myokine metabolism with local and systemic physiologic effects.

Paternal overweight is associated with increased breast cancer risk in daughters in a mouse model.

While many studies have shown that maternal weight and nutrition in pregnancy affects offspring's breast cancer risk, no studies have investigated the impact of paternal body weight on daughters' risk of this disease. Here, we show that diet-induced paternal overweight around the time of conception can epigenetically reprogram father's germ-line and modulate their daughters' birth weight and likelihood of developing breast cancer, using a mouse model. Increased body weight was associated with changes in the miRNA expression profile in paternal sperm. Daughters of overweight fathers had higher rates of carcinogen-induced mammary tumors which were associated with delayed mammary gland development and alterations in mammary miRNA expression. The hypoxia signaling pathway, targeted by miRNAs down-regulated in daughters of overweight fathers, was activated in their mammary tissues and tumors. This study provides evidence that paternal peri-conceptional body weight may affect daughters' mammary development and breast cancer risk and warrants further studies in other animal models and humans.

Perfluorocarbon emulsion improves oxygen transport of normal and sickle cell human blood in vitro.

Perfluorocarbons (PFC) are compounds with high gas solubility that could help deliver O2 to tissues and have been suggested as adjunct therapy to ischemia. Using a newly designed in vitro system, we tested the hypothesis that a third generation PFC emulsion (Oxycyte) increased O2 transport of blood by measuring changes in O2 extraction ratio. The system included a computer-controlled pump and blood-gas exchange chambers to oxygenate and deoxygenate the blood from nine sickle cell disease (SCD) patients and five healthy donors. The flowing blood reached various levels of hemoglobin O2 saturation and O2 partial pressures (PO2), measured using a CO-oximeter and a blood gas analyzer. The mixtures were kept at physiological blood pressure and temperature, constant flow, normobaric conditions, and FiO2 = 0.30. After adding PFC, the measurements suggested an increase in the transport of O2 and CO. Addition of PFC resulted in larger PO2 difference from 15 ± 2 mmHg to 23 ± 2 mmHg. Using normal blood and blood from SCD patients, the average O2 extraction ratio (O2ER) after PFC was significantly higher than baseline. Addition of saline did not cause statistically significant changes. The data suggest increased (facilitated) O2 transport by this PFC emulsion in both normal and SCD blood.