African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A.

African American (AA) prostate cancer associates with vitamin D3 deficiency, but vitamin D receptor (VDR) genomic actions have not been investigated in this context. We undertook VDR proteogenomic analyses in European American (EA) and AA prostate cell lines and four clinical cohorts. Rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) analyses revealed that nonmalignant AA RC43N prostate cells displayed the greatest dynamic protein content in the VDR complex. Likewise, in AA cells, Assay for Transposase-Accessible Chromatin using sequencing established greater 1α,25(OH)2D3-regulated chromatin accessibility, chromatin immunoprecipitation sequencing revealed significant enhancer-enriched VDR cistrome, and RNA sequencing identified the largest 1α,25(OH)2D3-dependent transcriptome. These VDR functions were significantly corrupted in the isogenic AA RC43T prostate cancer cells, and significantly distinct from EA cell models. We identified reduced expression of the chromatin remodeler, BAZ1A, in three AA prostate cancer cohorts as well as RC43T compared with RC43N. Restored BAZ1A expression significantly increased 1α,25(OH)2D3-regulated VDR-dependent gene expression in RC43T, but not HPr1AR or LNCaP cells. The clinical impact of VDR cistrome-transcriptome relationships were tested in three different clinical prostate cancer cohorts. Strikingly, only in AA patients with prostate cancer, the genes bound by VDR and/or associated with 1α,25(OH)2D3-dependent open chromatin (i) predicted progression from high-grade prostatic intraepithelial neoplasia to prostate cancer; (ii) responded to vitamin D3 supplementation in prostate cancer tumors; (iii) differentially responded to 25(OH)D3 serum levels. Finally, partial correlation analyses established that BAZ1A and components of the VDR complex identified by RIME significantly strengthened the correlation between VDR and target genes in AA prostate cancer only. Therefore, VDR transcriptional control is most potent in AA prostate cells and distorted through a BAZ1A-dependent control of VDR function. Significance: Our study identified that genomic ancestry drives the VDR complex composition, genomic distribution, and transcriptional function, and is disrupted by BAZ1A and illustrates a novel driver for AA prostate cancer.

Early-life AFB1 exposure: DNA methylation and hormone alterations.

Aflatoxins are secondary metabolites of mold that contaminate food and feedstuff. They are found in various food including grains, nuts, milk and eggs. Aflatoxin B1 (AFB1) is the most poisonous and commonly found of the various types of aflatoxins. Exposures to AFB1 start early in life viz. in utero, during breastfeeding, and during weaning through the waning foods which are mainly grain based. Several studies have shown that early-life exposures to various contaminants may have various biological effects. In this chapter, we reviewed the effects of early-life AFB1 exposures on changes in hormone and DNA methylation. In utero AFB1 exposure results in alterations in steroid and growth hormones. Specifically, the exposure results in a reduction in testosterone levels later in life. The exposure also affects the methylation of various genes that are significant in growth, immune, inflammation, and signaling pathways.

Vitamin D: Possible Therapeutic Roles in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a unique type of liver cancer instigated by underlying liver diseases. Pre-clinical evidence suggests that HCC progression, like other cancers, could be aided by vitamin D deficiency. Vitamin D is a lipid-soluble hormone usually obtained through sunlight. Vitamin D elucidates its biological responses by binding the vitamin D receptor; thus, promoting skeletal mineralization, and maintain calcium homeostasis. Other reported Vitamin D functions include specific roles in proliferation, angiogenesis, apoptosis, inflammation, and cell differentiation. This review highlighted studies on vitamin D's functional roles in HCC and discussed the specific therapeutic targets from various in vivo, in vitro and clinical studies over the years. Furthermore, it described recent advancements in vitamin D's anticancer effects and its metabolizing enzymes' roles in HCC development. In summary, the review elucidated specific vitamin D-associated target genes that play critical functions in the inhibition of tumorigenesis through inflammation, oxidative stress, invasion, and apoptosis in HCC progression.

Early Life Exposure to Aflatoxin B1 in Rats: Alterations in Lipids, Hormones, and DNA Methylation among the Offspring.

Aflatoxins are toxic compounds produced by molds of the Aspergillus species that contaminate food primarily in tropical countries. The most toxic aflatoxin, aflatoxin B1 (AFB1), is a major cause of hepatocellular carcinoma (HCC) in these countries. In sub-Saharan Africa, aflatoxin contamination is common, and perinatal AFB1 exposure has been linked to the early onset of HCC. Epigenetic programming, including changes to DNA methylation, is one mechanism by which early life exposures can lead to adult disease. This study aims to elucidate whether perinatal AFB1 exposure alters markers of offspring health including weight, lipid, and hormone profiles as well as epigenetic regulation that may later influence cancer risk. Pregnant rats were exposed to two doses of AFB1 (low 0.5 and high 5 mg/kg) before conception, throughout pregnancy, and while weaning and compared to an unexposed group. Offspring from each group were followed to 3 weeks or 3 months of age, and their blood and liver samples were collected. Body weights and lipids were assessed at 3 weeks and 3 months while reproductive, gonadotropic, and thyroid hormones were assessed at 3 months. Prenatal AFB1 (high dose) exposure resulted in significant 16.3%, 31.6%, and 7.5% decreases in weight of the offspring at birth, 3 weeks, and 3 months, respectively. Both doses of exposure altered lipid and hormone profiles. Pyrosequencing was used to quantify percent DNA methylation at tumor suppressor gene Tp53 and growth-regulator H19 in DNA from liver and blood. Results were compared between the control and AFB1 exposure groups in 3-week liver samples and 3-week and 3-month blood samples. Relative to controls, Tp53 DNA methylation in both low- and high-dose exposed rats was significantly decreased in liver samples and increased in the blood (p < 0.05 in linear mixed models). H19 methylation was higher in the liver from low- and high-exposed rats and decreased in 3-month blood samples from the high exposure group (p < 0.05). Further research is warranted to determine whether such hormone, lipid, and epigenetic alterations from AFB1 exposure early in life play a role in the development of early-onset HCC.

Bisphenol A in Africa: A review of environmental and biological levels.

Bisphenol A (BPA) is a synthetic ubiquitous environmental toxicant present in many industrial and consumer products. BPA is recognized as an endocrine-disrupting chemical (EDC), and its mechanisms of perturbation of the physiological process include interference with hormone pathways and epigenetic modifications. An increase in industrial productions and food packaging across Africa has resulted in increased utilization of BPA-containing products with a concomitant increase in environmental bioaccumulation and human exposure. In order to assess the extent of this bioaccumulation, we identified, collated, and summarized the levels of BPA that have been reported across Africa. To achieve this aim, we performed a systematic search of four indexing databases to identify articles and extracted the necessary data from the selected articles. Of the 42 publications we retrieved, 42% were on water samples, 22% on food, 20% on human biological fluids, 10% on sediments, soils, and sludge and 6% on consumer and personal care products (PCPs). The highest level of BPA reported in literature across Africa was 251 ng/mL, 384.8 ng/mL, 937.49 ng/g, 208.55 ng/mL, 3,590 µg/g, and 154,820 µg/g for water, wastewater, food, biological fluids, consumer and PCPs, and semisolids, respectively. This review presented a comparative perspective of these levels relative to regulatory limits and levels reported from other continents. Finally, this review highlighted critical needs for the regulation of BPA across Africa in order to stem its environmental and toxicological impact. We hope that this review will stimulate further research in understanding the impact of BPA on health outcomes and wellbeing across Africa.

Annona senegalensis extract demonstrates anticancer properties in N-diethylnitrosamine-induced hepatocellular carcinoma in male Wistar rats.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common and leading cancer around the globe. This study investigated the anticancer properties of extract of Annona senegalensis in N-diethylnitrosamine (DEN) - induced hepatocellular carcinoma in male Wistar rats. METHODS: Rats were simultaneously induced with a combination of 100 mg/kg b.wt of DEN and 0.5 mL/kg of carbon tetrachloride (CCl4) intraperitoneally once a week for three weeks in a row. Thereafter, animals were treated with 100 mg/kg and 200 mg/kg b.wt of A. senegalensis extract daily for 21days. Analysis using gas chromatography-mass spectrometry (GC-MS) was carried out to discover the phytoconstituents contained in the n-hexane extract of A. senegelensis. The levels of liver function parameters and antioxidant enzyme activities were determined via spectrophotometric analysis. Reverse transcriptase-polymerase chain reaction technique was used to assess the gene expression patterns of BCL-2, P53, P21, IL-6, FNTA, VEGF, HIF, AFP, XIAP, and EGFR mRNAs. RESULTS: Treatment of DEN-induced hepatocellular carcinoma Wistar rats with the extract caused significant (p < 0.05) decrease in the activities of ALT and AST. It also resulted in a reduction of the concentration of MDA and a significant increase (p < 0.05) in SOD and GSH activities. IL-6, BCL-2, VEGF, EGFR, XIAP, FNTA, and P21 mRNAs expressions were significantly (p < 0.05) downregulated after treatment. Histopathological analysis revealed that the extract improved the liver architecture. CONCLUSION: A. senegelensis n-hexane extract demonstrates its anticancer properties by improving the liver architecture, increasing the antioxidant defense systems, downregulating the pro-inflammatory, anti-apoptotic, angiogenic, alpha-fetoprotein and farnesyl transferase mRNAs expression and hitherto up-regulate the expression of tumor suppressor (P21 and P53) mRNAs.

Anti-inflammatory and antioxidant activities of fractions and compound from Ricinodendron heudelotii (Baill.).

Medicinal plants have been documented over the years to play vital role in promoting human health. The study evaluated the anti-inflammatory and anti-oxidant activities of different fractions and isolated compound from Ricinodendron heudelotii leaves. The leaves of Ricinodendron heudelotii were extracted with ethanol and further partitioned sequentially using petroleum ether, ethylacetate and butanol. Bioassay-guided fractionation of the ethylacetate fraction was done using repeated column chromatographic technique while the structural elucidation of pure compound was carried out using mass spectra, 13C and 1H NMR analyses. Antioxidant potential of the fractions and isolated compound were evaluated with 2,2-Azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assays and anti-inflammatory effect of fractions was measured by their inhibitory potency on nitric oxide (NO). Corilagin, an amorphous tannin was isolated and structurally elucidated. Corilagin showed scavenging effect against ABTS and DPPH radicals which vary in a dose dependent manner. It also showed an antioxidant potential with IC50 value of 0.003 mg/mL comparable to vitamin C 0.001 mg/mL) used as standard. The butanol and ethylacetate fractions exhibited significant (p < 0.05) NO inhibition of 60 and 69% respectively after treatment of RAW 264.7 macrophages with lipopolysaccharide. These results demonstrated the role of isolated corilagin as a promising potent antioxidant while the ethylacetate and butanol fractions suppressed the expression of an inflammation mediator by inhibiting nitric oxide.

Time-Course Effects of Acute Aflatoxin B1 Exposure on Hepatic Mitochondrial Lipids and Oxidative Stress in Rats.

Aflatoxins are secondary metabolites of certain Aspergillus species, that contaminate staple foods, particularly in developing countries. Aflatoxin B1 (AFB1) is the most toxic and common of the major types of aflatoxins. AFB1 is hepatotoxic and has been implicated in increasing the risk of hepatocellular carcinoma (HCC). We have previously shown that subacute exposure to AFB1 for 7 days disrupts hepatic lipids; therefore, this study determined the time-course effects of acute aflatoxin exposure on hepatic mitochondrial lipids and oxidative stress. To achieve this, thirty male albino rats were randomly assigned to six groups. The groups received an oral dose of 1 mg/kg body weight AFB1 or vehicle only (controls) for one, four, or seven days, respectively. Twenty-four hours after the last dose, the animals were sacrificed and liver excised. Mitochondria and cytosolic fractions were obtained from the liver after which lipids (cholesterol, triacylglycerols) were determined in the mitochondria while biomarkers of oxidative stress (glutathione, glutathione transferase (GST), glutathione peroxidase (GPx), glutathione reductase, nitric oxide (NO), malonaldehyde (MDA), thioredoxin reductase (TR), and superoxide dismutase (SOD) were determined spectrophotometrically in the mitochondria and cytosolic fractions. The expression of genes (Nrf2, Acc, Nqo1, and HmgCoa) were determined using quantitative RT-PCR. Results showed that AFB1 significantly increased mitochondrial cholesterol at day seven (treatment vs. control, p = 0.016). It also increased the concentrations of NO and MDA at day one and day seven while the activity of GPx and concentration of GSH were increased at day seven (p = 0.030) and day one (p = 0.025) alone, respectively, compared to control. The activities of cytosolic GR (p = 0.014), TR (p = 0.046) and GST (p = 0.044) were increased at day seven. AFB1 significantly increased the expression of Nrf2 (p = 0.029) and decreased the expression of Acc (p = 0.005) at day one. This study revealed that AFB1 disrupts hepatic mitochondrial lipids and antioxidant capacity. These changes were dependent on the timing of exposure and did not follow a linear time-course trend. These alterations could be part of the hepatic mitochondria response mechanism to acute AFB1 toxicity.