Gang Chen

Fetal alcohol spectrum disorder (FASD) is a significant public health issue that affects children. It results from ethanol exposure during pregnancy, leading to considerable physical, neurodevelopmental, behavioral, and cognitive deficits. The exact mechanism is not well understood. Recently, considerable attention has been focused on the influence of gut microbiome on brain development through the gut–brain axis. Changes in the gut microbiome resulting from ethanol exposure may contribute to the pathology of FASD, potentially involving neuroinflammation. This literature review summarizes the existing research and primary animal studies on the impact of early ethanol exposure on the gut microbiome, neuroinflammation, brain development, and behavioral consequences. The evidence suggests that early ethanol exposure alters the gut microbiome, which may induce neuroinflammation, brain damage, and cognitive impairment. However, a clear causal relationship among these factors remains to be fully elucidated.

Background Alcohol exposure increases the risk of breast cancer. Alcohol consumption by adolescents is a serious social and public health issue. This study investigated the impact of adolescent alcohol consumption on mammary tumorigenesis and progression and compared it to that of adult alcohol exposure in animal models. Methods Female adolescent (5 weeks) and adult (8 weeks) MMTV-Wnt1 mice were exposed to alcohol either chronically or acutely. For chronic alcohol exposure, animals were fed a liquid diet containing 6.7% ethanol for 23 weeks. For acute exposure, animals were treated with ethanol (2.5 g/kg, 25% w/v) via intraperitoneal (IP) injection for 15 days. Results In control animals, the tumor latency was 18.5 to 22 weeks. Both chronic and acute alcohol exposure in adolescent mice significantly shortened the tumor latency to 9.5 and 8.4 weeks, respectively. However, adult-initiated alcohol exposure had little effect on the tumor latency. Both adolescent- and adult-initiated alcohol exposure significantly increased lung metastasis. Adolescent-initiated alcohol exposure but not adult-initiated alcohol exposure increased the breast cancer stem cell population. Adolescent-initiated alcohol exposure significantly altered the proliferation of mammary epithelial cells, ductal growth, and the formation of terminal end buds in the mammary glands. Adolescent-initiated alcohol exposure but not adult-initiated alcohol exposure increased estradiol levels in the blood. Acute adolescent alcohol exposure also significantly increased blood progesterone levels. Furthermore, adolescent-initiated alcohol exposure activated PAK1 and p38γ MAPK, critical regulators of mammary tumorigenesis and aggressiveness, respectively, while adult-initiated alcohol exposure activated only p38γ MAPK. In addition, both adolescent and adult alcohol exposure significantly decreased the levels of a prognostic marker miR200b. Conclusions Adolescent-initiated alcohol exposure enhanced both tumorigenesis and aggressiveness of mammary tumors, while adult-initiated alcohol exposure mainly promoted tumor metastasis. Thus, adolescent mice were more sensitive than adult mice in response to alcohol-induced tumor promotion.

Alcohol consumption in women enhances breast cancer incidence and ethanol is the main causal factor. Compromised host immunity through immunosuppression facilitates the development of many types of cancer, including breast cancer. Immune cells in breast tissues, particularly tumor-infiltrating CD8 cytotoxic T cells, play a critical role in the host anti-tumor immunity against breast tumorigenesis. These cytotoxic T cells are the major immune cells to carry out anti-tumor immunity through their cytotoxic effector function, which can be regulated by immune checkpoint pathways. The PD-1/PD-L1 pathway (the interaction between programmed death-1, PD-1, and its ligand, programmed death-ligand 1, PD-L1) is the best characterized one. However, the effects of ethanol exposure on T cell anti-tumor immunity and how that may contribute to ethanol-enhanced mammary tumorigenicity remain unknown. FVB.Cg-Tg(Wnt1)1Hev/J transgenic mice develop spontaneous mammary tumors starting around the age of 2-3 months and have been a widely-used mouse model for breast cancer research. Using this mouse model, the current study determined the effects of ethanol on the PD-L1/PD-1 pathway and how that may contribute to mammary tumorigenesis. The results indicated that ethanol exposure enhanced mammary tumor formation accompanied with an up-regulation of PD-1/PD-L1 pathway (increased PD-L1 levels in tumor tissue cells and the amount of PD-1-expressing tumor-infiltrating CD8 T cells) and inhibited T cell anti-tumor function, while inhibition of PD-1/PD-L1 restored T cell anti-tumor effector function and mitigated ethanol-enhanced tumorigenesis.

Background Alcohol consumption during pregnancy may damage the developing central nervous system of the fetus and lead to brain structural and functional deficits in the children, known as Fetal Alcohol Spectrum Disorders. The underlying mechanisms have not been fully elucidated. Previously using a third trimester‐equivalent mouse model, ethanol‐induced behavioral deficits (including spatial learning and memory dysfunction) in the mice were detected on postnatal day (PD) 35. The hippocampal formation is critically involved in spatial learning/memory and contains two major neuron populations: the pyramidal cells in the hippocampus proper and the dentate gyrus granule cells (DGGCs) in the dentate gyrus (DG). In rodents, while the pyramidal cells are almost exclusively generated prenatally, the dentate gyrus granule neurons are majorly generated during the first two weeks postnatally, which coincides with the period of ethanol exposure in our mouse model. Therefore, in the current study the effects of ethanol exposure on the development of the dentate gyrus granule cells were examined. Methods C57BL/6 mice were treated with 4 g/kg of ethanol by intubation on PD 4‐10 to mimic alcohol exposure to the fetus during the third trimester in humans, and the development of dentate gyrus granule cells was examined by immunohistochemistry and quantified on PD 35. Results Ethanol exposure does not affect the number of total or newly generated DGGCs, but reduces the number of mature DGGCs on PD 35 in both male and female mice. The ratio of immature DGGCs over total DGGCs was increased, and the ratio of mature DGGCs over total DGGCs was decreased by ethanol exposure. In addition, no sex‐dependent effects of ethanol treatment were detected. Conclusion Our data indicates that ethanol exposure in mice during PD 4‐10 does not affect the generation/proliferation but inhibits the differentiation of the DGGCs on PD 35.

Background: Fetal ethanol (EtOH) exposure can damage the developing central nervous system and lead to cognitive and behavioral deficits, known as fetal alcohol spectrum disorders (FASD). EtOH exposure to mouse pups during early neonatal development was used as a model of EtOH exposure that overlaps the human third‐trimester “brain growth spurt”—a model that has been widely used to study FASD in rats.Methods: C57BL/6 male and female mice were exposed to EtOH (4 g/kg/d) on postnatal days (PD) 4 to 10 by oral intubation. Intubated and nontreated controls were also included. Behavioral testing of the offspring, including open field, elevated plus maze, and Morris water maze, was performed on PD 20 to 45.Results: EtOH exposure during PD 4 to 10 resulted in hyperactivity and deficits in learning and memory in young mice with no apparent sex differences.Conclusions: Based on these data, this neonatal intubation mouse model may be useful for future mechanistic and genetic studies of FASD and for screening of novel therapeutic agents.

M2 polarization of macrophages facilitates arsenic-induced cell transformation of lung epithelial cells