Alcohol consumption suppresses mammary tumor metastasis in a syngeneic tumor transplantation model.

Epidemiological studies indicate a positive correlation between alcohol consumption and the risk of developing breast cancer. However, little is known about whether alcohol consumption affects breast cancer metastasis. Considering that the primary cause of death in breast cancer patients is due to metastasis, further insight into whether alcohol consumption influences disease progression and survival is needed. We tested the effect of alcohol consumption on breast cancer metastasis using the 4T1.2 syngeneic mammary tumor model in Balb/c mice. The treatment groups included a High-consuming group (18 % w/v alcohol in drinking water), a Moderate-consuming group (5 % w/v), a Low-consuming group (1 % w/v), and a Water-drinking control group. 4T1.2 mammary tumor cells were injected orthotopically into the mammary fat pad. Metastases were enumerated in lungs and in distant mammary glands 4 weeks after injection. Consumption of High alcohol protected against metastasis, as High-consuming mice typically had 65-75 % fewer metastases compared to Water-drinking controls. A suggestive reduction in tumor spread was observed in the Moderate-drinking group, although the effects did not reach statistical significance. Consumption of the Low alcohol dose did not affect metastasis. CXCR4 expression in the primary tumors was significantly reduced by High alcohol consumption; however, expression of this chemokine receptor in the primary tumor did not correlate with metastatic potential. Additional studies were conducted to test for possible direct effects of 0.3 % w/v ethanol on tumor cell proliferation, migration, invasion, and colony formation of 4T1.2 cells in vitro. Our results indicate that, for this murine model, alcohol consumption does not exacerbate tumor metastasis, and that High alcohol consumption reduces tumor spread.

Mechanistic exploration of AhR-mediated host protection against Streptococcus pneumoniae infection.

Streptococcus pneumoniae is a primary cause of invasive bacterial infection and pneumonia and is one of the leading causes of death worldwide. In prior studies we showed that pre-treating mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent agonist of the aryl hydrocarbon receptor (AhR), protects against S. pneumoniae-induced mortality and reduces pulmonary bacterial burden. The current studies were conducted to help elucidate the mechanism for this protective effect, and to characterize the response in the lung during the first 10h following infection. C57Bl/6 mice were treated with TCDD one day prior to intranasal infection with serotype 3 S. pneumoniae. Monitoring of bacteria in the lung airways revealed that bacterial growth was inhibited in the TCDD-treated animals within 10h of infection. To address the mechanism of this rapid protective response, macrophages, neutrophils, and invariant Natural Killer T (iNKT) cells were quantified, and levels of natural antibodies produced by B-1 B cells were evaluated. Functional assays addressed whether AhR activation reduced the capacity of lung epithelial cells to bind bacteria, and whether TCDD treatment enhanced production of antimicrobial agents in the lung or blood. None of the hypothesized mechanisms was able to explain the protective effect. Finally, the exposure paradigm was manipulated to test whether administration of TCDD after instillation of the bacteria was also protective. Results showed that TCDD must be administered in advance of exposure to bacteria, suggesting that the lung environment is rendered inhospitable to the pathogens.

Methamphetamine enhances memory of operantly conditioned respiratory behavior in the snail Lymnaea stagnalis.

Amphetamines have been used as cognitive enhancers to promote learning and memory. Amphetamines are also drugs of abuse that may promote the initiation of strong memories that ultimately lead to addiction. To understand how methamphetamine (Meth) may be augmenting learning and memory, we chose a relatively simple system, the pond snail, Lymnaea stagnalis. We studied the effects of Meth exposure on the long-term memory (LTM), extinction and reinstatement of operantly conditioned aerial respiratory behavior in Lymnaea. We first determined doses of Meth that would acutely alter respiratory behavior. Next, we measured the impact of training snails in Meth solution or water (control group) using a training procedure that produces LTM (>6 h) in control conditions. Meth exposure impaired the expression of LTM 21 h after two training sessions, but this appeared to be a context-dependent effect only. However, snails exposed to 3.3 mumol l(-1) Meth during training had a decreased rate of extinction of the operantly conditioned memory. We then tested whether this decreased ability of snails to extinguish memory was due to enhanced LTM or impaired extinction of that memory. Snails were operantly conditioned in water and exposed to Meth 16 h after their last trial but 4-5 h prior to extinction. Meth produced an increase rather than a decrease in extinction rate. Thus, Meth impaired extinction only when snails were exposed to Meth during training. Last, we tested the effect of Meth on the ability to form LTM using a single training procedure that is suboptimal for LTM formation. Control snails did not demonstrate LTM, as expected, but pre-exposure of snails to 3.3 micromol l(-1) Meth 24 h prior to the single training session produced LTM 24 h later, indicating that Meth pre-exposure primed snails for LTM formation. Taken together, our studies suggest that LTM is strengthened by Meth such that extinction training is less effective. Lymnaea provides a simple and useful model system to dissect the cellular and/or molecular mechanisms of how Meth may initiate the formation of stronger memories.