Kathy S. Xue

Mitigation of Oxidative Damage by Green Tea Polyphenols and Tai Chi Exercise in Postmenopausal Women with Osteopenia

Background Osteoporosis is a degenerative bone disease predominantly in postmenopausal women. Green tea polyphenols (GTP) and Tai Chi (TC) have been shown to be beneficial on human bone health. This study examined the efficacy of GTP and TC on mitigation of oxidative damage in postmenopausal women with osteopenia. Methods A 6-month randomized and placebo-controlled clinical trial was conducted in 171 postmenopausal women with osteopenia, who were recruited from Lubbock County, Texas. These participants were treated with placebo, GTP (500 mg daily), placebo + TC (60-minute group exercise, 3 times/week), or GTP (500 mg daily) + TC (60-minute group exercise, 3 times/week), respectively. Their blood and urine samples were collected at the baseline, 1-, 3- and 6-months during intervention for assessing levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), an oxidative DNA damage biomarker, and concentrations of serum and urine GTP components. Results The elevated concentrations of serum and urinary GTP components demonstrated a good adherence for the trial. A significant reduction of urinary 8-OHdG concentrations was found in all three treated groups during 3-month (P<0.001) and 6-month (P<0.001) intervention, as compared to the placebo group. The significant time- and dose-effects on mitigation of the oxidative damage biomarker were also found for GTP, TC, and GTP+TC intervened groups. Conclusion Our study demonstrated that GTP and TC interventions were effective strategies of reducing the levels of oxidative stress, a putative mechanism for osteoporosis in postmenopausal women, and more importantly, working in an additive manner, which holds the potential as alternative tools to improve bone health in this population. Trial Registration ClinicalTrials.gov NCT00625391

Calcium montmorillonite clay reduces AFB1 and FB1 biomarkers in rats exposed to single and co‐exposures of aflatoxin and fumonisin

Aflatoxins (AFs) and fumonisins (FBs) can co‐contaminate foodstuffs and have been associated with hepatocellular and esophageal carcinomas in humans at high risk for exposure. One strategy to reduce exposure (and toxicity) from contaminated foodstuffs is the dietary inclusion of a montmorillonite clay (UPSN) that binds AFs and FBs in the gastrointestinal tract. In this study, the binding capacity of UPSN was evaluated for AFB1, FB1 and a combination thereof in Fischer 344 rats. Rats were pre‐treated with different dietary levels of UPSN (0.25% or 2%) for 1 week. Rats were gavaged with a single dose of either 0.125 mg AFB1 or 25 mg FB1 per kg body weight and a combination thereof in the presence and absence of an aqueous solution of UPSN. The kinetics of mycotoxin excretion were monitored by analyzing serum AFB1‐albumin, urinary AF (AFM1) and FB1 biomarkers over a period of 72 h. UPSN decreased AFM1 excretion by 88–97%, indicating highly effective binding. FB1 excretion was reduced, to a lesser extent, ranging from 45% to 85%. When in combination, both AFB1 and FB1 binding occurred, but capacity was decreased by almost half. In the absence of UPSN, the combined AFB1 and FB1 treatment decreased the urinary biomarkers by 67% and 45% respectively, but increased levels of AFB1‐albumin, presumably by modulating its cytochrome metabolism. UPSN significantly reduced bioavailability of both AFB1 and FB1 when in combination; suggesting that it can be utilized to reduce levels below their respective thresholds for affecting adverse biological effects. Copyright

Biological detoxification of zearalenone by Aspergillus niger strain FS10.

Zearalenone (ZEN) contamination of corn and cereal products is a serious health hazard throughout the world and its elimination by microbial methods is now being widely examined. In this study, an Aspergillus niger strain, FS10, isolated from Chinese fermented soybean, was shown to reduce levels of ZEN in corn steep liquor (CSL). Spores, mycelium and culture filtrate of the strain FS10 were tested for their ability to remove ZEN. The results indicated that strain FS10 could remove 89.56% of ZEN from potato dextrose broth (PDB) medium. Mycelium and culture filtrate decreased the ZEN content by 43.10% and 68.16%, respectively. The contaminated corn steep liquor initially contained ZEN 29 μg/ml, 60.01% of which could be removed by strain FS10. To demonstrate the loss of toxicity in vivo, the culture filtrate incubated with the contaminated corn steep liquor for 48 h was administered to rats. The results indicated that the contaminated corn steep liquor severely damaged liver and kidney tissue. Rats administered with contaminated corn steep liquor treated with the strain FS10 culture filtrate showed significantly less severe liver and kidney damage, and organ index values were comparable to the non-ZEN-exposed control (p<0.05). Our study suggests an effective approach to reduce the hazards of ZEN in corn steep liquor.

Sequential dietary exposure to aflatoxin B1 and fumonisin B1 in F344 rats increases liver preneoplastic changes indicative of a synergistic interaction

Dietary co-exposure to aflatoxin B1 (AFB1) and fumonisin B1 (FB1) and their interaction on hepatocellular carcinogenesis is of particular concern in toxicology and public health. In this study we evaluated the liver preneoplastic effects of single and sequential dietary exposure to AFB1 and FB1 in the F344 rat carcinogenesis model. Serum biochemical alterations, liver histopathological changes, and the formation of liver glutathione S transferase positive (GST-P+) foci were the major outcome parameters examined. Compared to the AFB1-only treatment, the FB1-only treatment induced less dysplasia, and more apoptosis and mitoses. Sequential AFB1 and FB1 treatment lead to increased numbers of dysplasia, apoptosis and foci of altered hepatocytes, as compared to either mycotoxin treatment alone. More importantly, sequential exposure to AFB1 and FB1 synergistically increased the numbers of liver GTP-P+ foci by approximately 7.3-and 12.9-fold and increased the mean sizes of GST-P+ foci by 6- and 7.5-fold, respectively, as compared to AFB1- or FB1-only treatment groups. In addition, liver ALT and AST levels were significantly increased after sequential treatment as compared to single treatment groups. The results demonstrate the interactive effect of dietary AFB1 and FB1 in inducing liver GST-P+ foci formation and provide information to model future intervention studies.

Multi-Toxic Endpoints of the Foodborne Mycotoxins in Nematode Caenorhabditis elegans

Aflatoxins B1 (AFB1), deoxynivalenol (DON), fumonisin B1 (FB1), T-2 toxin (T-2), and zearalenone (ZEA) are the major foodborne mycotoxins of public health concerns. In the present study, the multiple toxic endpoints of these naturally-occurring mycotoxins were evaluated in Caenorhabditis elegans model for their lethality, toxic effects on growth and reproduction, as well as influence on lifespan. We found that the lethality endpoint was more sensitive for T-2 toxicity with the EC50 at 1.38 mg/L, the growth endpoint was relatively sensitive for AFB1 toxic effects, and the reproduction endpoint was more sensitive for toxicities of AFB1, FB1, and ZEA. Moreover, the lifespan endpoint was sensitive to toxic effects of all five tested mycotoxins. Data obtained from this study may serve as an important contribution to knowledge on assessment of mycotoxin toxic effects, especially for assessing developmental and reproductive toxic effects, using the C. elegans model.

Intervention trial with calcium montmorillonite clay in a south Texas population exposed to aflatoxin

ABSTRACT South Texas currently has the highest incidence of hepatocellular carcinoma (HCC) in the United States, a disease that disproportionately affects Latino populations in the region. Aflatoxin B1 (AFB1) is a potent liver carcinogen that has been shown to be present in a variety of foods in the United States, including corn and corn products. Importantly, it is a dietary risk factor contributing to a higher incidence of HCC in populations frequently consuming AFB1-contaminated diets. In a randomised double-blind placebo controlled trial, we evaluated the effects of a 3-month administration of ACCS100 (refined calcium montmorillonite clay) on serum AFB1–lysine adduct (AFB-Lys) level and serum biochemistry in 234 healthy men and women residing in Bexar and Medina counties, Texas. Participants recruited from 2012 to 2014 received either a placebo, 1.5 g or 3 g ACCS100 each day for 3 months, and no treatment during the fourth month. Adverse event rates were similar across treatment groups and no significant differences were observed for serum biochemistry and haematology parameters. Differences in levels of AFB-Lys at 1, 3 and 4 months were compared between placebo and active treatment groups. Although serum AFB-Lys levels were decreased by month 3 for both treatment groups, the low dose was the only treatment that was significant (p = 0.0005). In conclusion, the observed effect in the low-dose treatment group suggests that the use of ACCS100 may be a viable strategy to reduce dietary AFB1 bioavailability during aflatoxin outbreaks and potentially in populations chronically exposed to this carcinogen.

Mitigation of Fumonisin Biomarkers by Green Tea Polyphenols in a High-Risk Population of Hepatocellular Carcinoma

Green tea polyphenols (GTP) are highly effective in inhibiting a variety of tumorigenic effects induced by carcinogens. In this study we assessed GTP mitigation on biomarkers of fumonisin B1 (FB1), a class 2B carcinogen, in blood and urine samples collected from an intervention trial. A total of 124 exposed people were recruited and randomly assigned to low-dose (GTP 500 mg, n = 42), high-dose (GTP 1,000 mg, n = 41) or placebo (n = 41) for 3 months. After one-month of intervention, urinary FB1 was significantly decreased in high-dose group compared to that of placebo group (p = 0.045), with reduction rates of 18.95% in the low-dose group and 33.62% in the high-dose group. After three-month intervention, urinary FB1 showed significant decrease in both low-dose (p = 0.016) and the high-dose (p = 0.0005) groups compared to that of both placebo group and baseline levels, with reduction rates of 40.18% in the low-dose group and 52.6% in the high-dose group. GTP treatment also significantly reduced urinary excretion of sphinganine (Sa), sphingosine (So), and Sa/So ratio, but had no effect on serum Sa, So, and Sa/So ratio. Analysis with mixed-effect model revealed significant interactions between time and treatment effects of GTP on both urinary free FB1 levels and Sa/So ratios.

Aflatoxin B1-Induced Developmental and DNA Damage in Caenorhabditis elegans

Aflatoxin B1 (AFB1) is a ubiquitous mycotoxin produced by toxicogenic Aspergillus species. AFB1 has been reported to cause serious adverse health effects, such as cancers and abnormal development and reproduction, in animals and humans. AFB1 is also a potent genotoxic mutagen that causes DNA damage in vitro and in vivo. However, the link between DNA damage and abnormal development and reproduction is unclear. To address this issue, we examined the DNA damage, germline apoptosis, growth, and reproductive toxicity following exposure to AFB1, using Caenorhabditis elegans as a study model. Results found that AFB1 induced DNA damage and germline apoptosis, and significantly inhibited growth and reproduction of the nematodes in a concentration-dependent manner. Exposure to AFB1 inhibited growth or reproduction more potently in the DNA repair-deficient xpa-1 nematodes than the wild-type N2 strain. According to the relative expression level of pathway-related genes measured by real-time PCR, the DNA damage response (DDR) pathway was found to be associated with AFB1-induced germline apoptosis, which further played an essential role in the dysfunction of growth and reproduction in C. elegans.

Maternal aflatoxin exposure during pregnancy and adverse birth outcomes in Uganda

Abstract Aflatoxins are toxic metabolites of Aspergillus moulds and are widespread in the food supply, particularly in low‐ and middle‐income countries. Both in utero and infant exposure to aflatoxin B1 (AFB1) have been linked to poor child growth and development. The objective of this prospective cohort study was to investigate the association between maternal aflatoxin exposure during pregnancy and adverse birth outcomes, primarily lower birth weight, in a sample of 220 mother–infant pairs in Mukono district, Uganda. Maternal aflatoxin exposure was assessed by measuring the serum concentration of AFB1‐lysine (AFB‐Lys) adduct at 17.8 ± 3.5 (mean ± SD)‐week gestation using high‐performance liquid chromatography. Anthropometry and birth outcome characteristics were obtained within 48 hr of delivery. Associations between maternal aflatoxin exposure and birth outcomes were assessed using multivariable linear regression models adjusted for confounding factors. Median maternal AFB‐Lys level was 5.83 pg/mg albumin (range: 0.71–95.60 pg/mg albumin, interquartile range: 3.53–9.62 pg/mg albumin). In adjusted linear regression models, elevations in maternal AFB‐Lys levels were significantly associated with lower weight (adj‐β: 0.07; 95% CI: −0.13, −0.003; p = 0.040), lower weight‐for‐age z‐score (adj‐β: −0.16; 95% CI: −0.30, −0.01; p = 0.037), smaller head circumference (adj‐β: −0.26; 95% CI: −0.49, −0.02; p = 0.035), and lower head circumference‐for‐age z‐score (adj‐β: −0.23; 95% CI: −0.43, −0.03; p = 0.023) in infants at birth. Overall, our data suggest an association between maternal aflatoxin exposure during pregnancy and adverse birth outcomes, particularly lower birth weight and smaller head circumference, but further research is warranted.

Modulation of pre-neoplastic biomarkers induced by sequential aflatoxin B 1 and fumonisin B 1 exposure in F344 rats treated with UPSN clay

Populations consuming aflatoxin (AF) and fumonisin (FN)-contaminated foods may be at increased risk for hepatocellular carcinoma (HCC) and developmental disorders; consequently, development of intervention strategies to reduce AF/FN-induced liver disease and adverse health effects in humans could be very useful. Calcium montmorillonite clay (NovaSil) has been shown to absorb AF in vitro, in multiple animal models, as well as in human studies. In the present study, we aimed to evaluate whether uniform particle size NovaSil (UPSN) possessed an ability to modulate the co-carcinogenic potentials of aflatoxin B1 (AFB1) and fumonisin B1 (FB1) in F344 rats. Sequential treatment of FB1 following AFB1 synergistically induces preneoplastic alterations as well as liver damage, indicating that AFB1 acts as an initiator while FB1 as a promoter in the carcinogenesis model, confirming findings from previous studies. The enterosorbent agent UPSN clay at dose of up to 0.5% in diet was shown to be effective in modulating the toxicity and carcinogenicity of co-exposure to AFB1 and FB1, as demonstrated by significant reduction in number and size of hepatic GST-P+ foci, in alterations indicative of liver toxicity, and in levels of AFB1 and FB1 biomarkers.