Biotransformation of Bisphenol A and Its Adverse Effects on the Next Generation

Although we are exposed to many chemical substances in routine daily life, the body has metabolic systems capable of detoxifying and eliminating these chemicals. Bisphenol A (BPA) is an endocrine disrupter of great concern because of its estrogenic activity, but studies have indicated no severe adverse effects in adult rodents exposed to BPA due to metabolic detoxification. BPA is metabolized by glucuronidation mediated by phase II enzymes such as UDP-glucuronosyltransferase. Numerous recent studies in rodents have indicated that maternal BPA exposure causes adverse effects in offspring. It was also shown that bisphenol analogs are efficiently absorbed via the oral route and distributed to the reproductive tract in pregnant rats, with its residue capable of crossing the placental barrier in the late stage of gestation. Both animal and human studies have demonstrated that BPA and the BPA metabolite BPA-GA are detectable in fetal and amniotic fluid, suggesting the presence of a placental transfer mechanism. In this review, we discuss the pharmacokinetics of BPA, particularly its (1) metabolism and disposition in the intestine, (2) metabolism and disposition in the liver, and (3) transfer from maternal tissues to the fetus

Phage therapy: Targeting intestinal bacterial microbiota for the treatment of liver diseasesKey points

Summary: Phage therapy has been overshadowed by antibiotics for decades. However, it is being revisited as a powerful approach against antimicrobial-resistant bacteria. As bacterial microbiota have been mechanistically linked to gastrointestinal and liver diseases, precise editing of the gut microbiota via the selective bactericidal action of phages has prompted renewed interest in phage therapy. In this review, we summarise the basic virological properties of phages and the latest findings on the composition of the intestinal phageome and the changes associated with liver diseases. We also review preclinical and clinical studies assessing phage therapy for the treatment of gastrointestinal and liver diseases, as well as future prospects and challenges

Glucuronidation as a metabolic barrier against zearalenone in rat everted intestine

Zearalenone (ZON), produced by Fusarium fungi, exhibits estrogenic activity. Livestock can be exposed to ZON orally through contaminating feeds such as cereals, leading to reproductive disorders such as infertility and miscarriage via endocrine system disruption. However, the details of ZON metabolism remain unclear, and the mechanism of its toxicity has not been fully elucidated. In this study, we investigated the kinetics of ZON absorption and metabolism in rat segmented everted intestines. ZON absorption was confirmed in each intestine segment 60 min after application to the mucosal buffer at 10 µM. Approximately half of the absorbed ZON was metabolized to α-zearalenol, which tended to be mainly glucuronidated in intestinal cells. In the proximal intestine, most of the glucuronide metabolized by intestinal cells was excreted to the mucosal side, suggesting that the intestine plays an important role as a first drug metabolism barrier for ZON. However, in the distal intestine, ZON metabolites tended to be transported to the serosal side. Glucuronide transported to the serosal side could be carried via the systemic circulation to the local tissues, where it could be reactivated by deconjugation. These results are important with regard to the mechanism of endocrine disruption caused by ZON

Analysis of Corticosterone and Testosterone Synthesis in Rat Salivary Gland Homogenates

Extra-adrenal steroid hormone production has been reported in several tissues, the biological role of which is interesting in terms of hormonal regulation of metabolism, growth, and behavior. In this report, we describe for the first time steroidogenesis in rat salivary glands. Enzyme activities associated with corticosterone and testosterone production were detected in rat salivary glands by LC-MS analysis. In tissue homogenates of rat salivary glands, progesterone was produced enzymatically in vitro from pregnenolone in the presence of NADPH and NADH. Deoxycorticosterone was produced from progesterone, corticosterone from deoxycorticosterone, and testosterone from androstenedione (but not pregnenolone from cholesterol) via enzymatic reactions using the same tissue homogenates. Immunoblotting analysis indicated the expression of 11β-hydroxylase (cytochrome P450 11β1; CYP11β1), which mediated the production of corticosterone from deoxycorticosterone. However, CYP family 11 subfamily A member 1 (CYP11A1)-mediated production of pregnenolone from cholesterol was not detected in the salivary glands by immunoblotting using a specific antibody. These results indicate that corticosterone and testosterone are produced from pregnenolone in rat salivary glands. The initial substrate in salivary steroidogenesis and the roles of salivary corticosterone and testosterone are discussed

Lytic Activity of Polyvalent Staphylococcal Bacteriophage PhiSA012 and Its Endolysin Lys-PhiSA012 Against Antibiotic-Resistant Staphylococcal Clinical Isolates From Canine Skin Infection Sites

The spread of antibiotic-resistant bacteria (ARB) in human and veterinary medicine is of global concern. Notably, the emergence of methicillin-resistant Staphylococcus pseudintermedius has become a serious problem. In this context, bacteriophages and their lytic enzymes, endolysins, have received considerable attention as therapeutics for infectious diseases in place of antibiotics. The aim of the present study was to investigate the antibiotic-resistance patterns of staphylococcal species isolated from canine skin at a primary care animal hospital in Tokyo, Japan and evaluate the lytic activity of the staphylococcal bacteriophage phiSA012 and its endolysin Lys-phiSA012 against isolated antibiotic-resistant staphylococcal strains. Forty clinical staphylococcal samples were isolated from infection sites of dogs (20 from skin and 20 from the external ear canal). Susceptibility to antimicrobial agents was determined by a disk diffusion method. The host range of phiSA012 was determined by using a spot test against staphylococcal isolates. Against staphylococcal isolates that showed resistance toward five classes or more of antimicrobials, the lytic activity of phiSA012 and Lys-phiSA012 was evaluated using a turbidity reduction assay. Twenty-three S. pseudintermedius, 16 Staphylococcus schleiferi, and 1 Staphylococcus intermedius were detected from canine skin and ear infections, and results revealed 43.5% methicillin resistance in S. pseudintermedius and 31.3% in S. schleiferi. In addition, the prevalence multidrug resistance (MDR) S. pseudintermedius was 65.2%. PhiSA012 could infect all staphylococcal isolates by spot testing, but showed little lytic activity by turbidity reduction assay against MDR S. pseudintermedius isolates. On the other hand, Lys-phiSA012 showed lytic activity and reduced significantly the number of staphylococcal colony-forming units. These results demonstrated that ARB issues underlying in small animal hospital and proposed substitutes for antibiotics. Lys-phiSA012 has broader lytic activity than phiSA012 against staphylococcal isolates; therefore, Lys-phiSA012 is a more potential candidate therapeutic agent for several staphylococcal infections including that of canine skin