Microbiological survey of commercial tattoo and permanent makeup inks available in the United States.

AIMS: Tattooing and use of permanent makeup (PMU) has dramatically increased over the last decade, with a concomitant increase in ink-related infections. The aim of this study was to determine whether micro-organisms are present, and if so, the number and their identification in the commercial tattoo and PMU inks available in the United States. METHODS AND RESULTS: We surveyed 85 unopened tattoo and PMU inks, purchased from 13 companies. We incubated 100 µl of ink samples on trypticase soy agar plates for bacterial growth, 7H10 Middlebrook medium for mycobacterial growth, and Sabouraud dextrose medium for fungal growth. In total, 42 inks were contaminated with micro-organisms (49%). Thirty-three inks were contaminated with bacteria, 2 inks with fungi, and 7 inks had both bacterial and fungal growth. Mycobacteria were not detected in any of the examined tattoo and PMU inks. In 26 inks, microbial concentrations ranged between 101 and 103 CFU per ml, but higher counts (>103 CFU per ml) were recorded in 16 inks. We identified 83 bacteria by their 16S rDNA sequences, including 20 genera and 49 species. Strains of Bacillus spp. (53%) were dominant, followed by Lysinibacillus fusiformis (7%) and Pseudomonas aeruginosa (5%). Thirty-four (41%) possibly clinically relevant strains were identified, including P. aeruginosa, Dermacoccus barathri and Roseomonas mucosa, some of which have been previously reported to be associated with human skin infections. CONCLUSIONS: The results indicate that commercial tattoo and PMU inks on the US market surveyed in this study contain a wide range of micro-organisms, including pathogenic bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Microbial contaminants in tattoo and PMU inks are an emerging safety concern for public health. This study provides evidence that microbial contamination of tattoo and PMU inks available in the United States is more common than previously thought and highlights the importance of monitoring these products for potentially pathogenic micro-organisms.

Exploring the FDA adverse event reporting system to generate hypotheses for monitoring of disease characteristics.

The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) is a database for postmarketing drug safety monitoring and influences changes in FDA safety guidance documents such as drug labels. The number of cases in the FAERS has rapidly increased with the improvement of submission methods and data standards and thus has become an important resource for regulatory science. Although the FAERS has been predominantly used for safety signal detection, this study explored its utility for disease characteristics.

Levels of retinyl palmitate and retinol in the skin of SKH-1 mice topically treated with retinyl palmitate and concomitant exposure to simulated solar light for thirteen weeks.

Retinyl esters account for more than 70% of the endogenous vitamin A found in human skin, and retinyl palmitate is one of the retinyl esters in this pool. Human skin is also exposed to retinyl palmitate exogenously through the topical application of cosmetic and skin care products that contain retinyl palmitate. To date, there is limited information on the penetration and distribution of retinyl palmitate and vitamin A within in the skin. In this study, the accumulation of retinyl palmitate and generation of retinol in the skin of male and female SKH-1 mice that received repeated topical applications of creams containing 0.0%, 0.1%, 0.5%, 1.0%, 5.0%, 10%, or 13% of retinyl palmitate 5 days a week for a period of 13 weeks were studied. Because products containing retinyl palmitate are frequently applied to sun-exposed skin, and because it is well established that exposure to sunlight and UV light can alter cutaneous levels of retinoids, mice in this study were additionally exposed 5 days a week to simulated solar light. The results showed that retinyl palmitate diffused into the skin and was partially hydrolyzed to retinol. The levels of retinyl palmitate in the skin of mice that were administered retinyl palmitate cream were higher than control values, and levels of both retinyl palmitate and retinol increased with the application of higher concentrations of retinyl palmitate in the cream. Our results indicate that topically applied retinyl palmitate may alter the normal physiological levels of retinyl palmitate and retinol in the skin of SKH-1 mice and may have a significant impact on vitamin A homeostasis in the skin.

Photoreaction, phototoxicity, and photocarcinogenicity of retinoids.

Sunlight is a human carcinogen. Many retinoid-containing cosmetics are used to protect damages caused by sunlight irradiation. Since retinol is thermally unstable and retinyl palmitate (RP) s relatively more stable, RP is also widely used as an ingredient in cosmetic formulations. In general, little is known about the photodecomposition of retinoids and the toxicity of retinoids and their photodecomposition products on the skin's responses to sunlight. This review focuses on the update information on photoreactions, phototoxicity, and photocarcinogenicity of the natural retinoids including retinol, retinal, retinoid acid (RA), retinyl acetate, and RP.

Quantification of glycolic acid in cosmetic products using reversed phase high performance liquid chromatography.

Many cosmetics contain keratolytic hydroxy acids to correct the effects of photoageing on human skin. Although methods exist for quantifying the alpha-hydroxy acid, glycolic acid in aqueous media, accurate methods for quantification in mixed hydrophobic and aqueous cosmetic creams and lotions are lacking. Glycolic acid was extracted from cosmetics using aqueous tetrahydrofuran (THF), separated with strong-anion exchange cartridges, and quantified by high performance liquid chromatography (HPLC) with UV-VIS detection without the paired-ion reagents. In a recovery experiment, the mean accuracy of the method was 100.6%. The dynamic range of the method allows for the detection of glycolic acid at concentrations used in over-the-counter cosmetics.

Basal cell proliferation in female SKH-1 mice treated with alpha- and beta-hydroxy acids.

Alpha- and beta-hydroxy acids are compounds that have been used extensively in cosmetic and dermatological formulations. Clinical and qualitative effects of alpha- and beta-hydroxy acids have been well characterized, but little is known about their mechanism of action or acute and chronic biochemical effects. In the present study, we examined the acute proliferative effects of glycolic and salicylic acids on cell proliferation in the epidermis of SKH-1 female mice, using BrdU incorporation as a marker of epidermal proliferation. In preliminary experiments, we observed an increase in the rate of proliferation after 3 days of treatment with 10% glycolic acid-containing cream and this was sustained throughout a 6.5-week (treatment 5 days/week) time course compared with untreated control animals. After each treatment with cream containing glycolic acid there was a wave of proliferation that was maximal 12 to 16 h (significant at p < 0.05) after treatment, followed by a subsequent increase in epidermal thickness at 18 to 20 h (significant at p < 0.05). The effects of the concentration and pH level of glycolic acid- and salicylic acid-containing creams on the rate of proliferation and increases in skin thickness in SKH-1 epidermis were also investigated. We observed a dose-dependent increase in epidermal proliferation of animals treated with either glycolic or salicylic acid. A similar time-dependent response was observed in the epidermal thickness in animals treated with salicylic acid, but not with glycolic acid. Differences in pH (3.5 or 4.0) had no significant effect on either epidermal proliferation or skin thickness. The data that we present here should be useful in characterizing not only the beneficial but also the adverse effects that occur following acute or chronic usage of alpha-hydroxy acids.

Rat kidney pathology induced by chronic exposure to fumonisin B1 includes rare variants of renal tubule tumor.

The carcinogenicity of fumonisin B1 (FB1), a worldwide contaminant of corn produced by Fusaria species of fungi, has been tested recently in 2-year feeding studies in Fischer F344 rats and B6C3F1 mice. Inclusion of FB1 at 50 and 80 ppm in the diet induced liver tumors in female mice, and at 50 and 150 ppm induced renal tumors in male rats (22). In the present study, the kidneys from the rat bioassay were examined to characterize the various histopathological changes associated with renal tumor induction. In all high-dose (150 ppm) and mid-dose (50 ppm) male rats, and to a lesser extent in high-dose (100 ppm) female rats, there was evidence of sustained nephrotoxicity manifested as basophilia, apoptosis, cell regeneration, and simple tubule hyperplasia, affecting proximal convoluted tubules in the deep cortex, extending into the outer region of the outer stripe of outer medulla. A further alteration consisted of sporadic areas of interstitial hyalinization in deep cortex, suggestive of expanded basement membrane, coupled with tubule atrophy. The continued presence of nephrotoxicity throughout chronic exposure to FB1 suggested that renal tumor development may have been an outcome of sustained cell loss and compensatory regeneration. In some cases, preneoplastic tubules or incipient renal tumors presented an immature or fetal form in association with interstitial hyalinization. The renal tubule tumors induced by FB1 were typified by a rare, highly malignant, anaplastic variant capable of growth by infiltration. Of the 10 renal tubule tumors diagnosed in the mid-dose males, and the 16 in the high-dose males, 8 and 10, respectively, were graded as carcinomas. Anaplastic variants represented 50% of the mid-dose carcinomas and 80% of the high-dose carcinomas. One of the anaplastic carcinomas in a mid-dose male was a true sarcomatoid phenotype not previously recorded in the rodent. Metastatic invasion of the lung occurred with 25% of the mid-dose carcinomas and 50% of the high-dose carcinomas. It was speculated that FB1 may have been influencing the growth characteristics of the induced renal tumors via its inhibitory action on the synthesis of sphingolipids, which in turn, participate in regulating cell contact, growth, and differentiation, or alternatively by affecting cell adhesion molecules.

An overview of rodent toxicities: liver and kidney effects of fumonisins and Fusarium moniliforme.

Fumonisins are produced by Fusarium moniliforme F. verticillioides) and other Fusarium that grow on corn worldwide. They cause fatal toxicoses of horses and swine. Their effects in humans are unclear, but epidemiologic evidence suggests that consumption of fumonisin-contaminated corn contributes to human esophageal cancer in southern Africa and China. Much has been learned from rodent studies about fumonisin B1(FB1), the most common homologue. FB1 is poorly absorbed and rapidly eliminated in feces. Minor amounts are retained in liver and kidneys. Unlike other mycotoxins, fumonisins cause the same liver cancer promotion and subchronic (studies (3/4) 90 days) liver and kidney effects as (italic)F. moniliforme. FB 1 induces apoptosis of hepatocytes and of proximal tubule epithelial cells. More advanced lesions in both organs are characterized by simultaneous cell loss (apoptosis and necrosis) and proliferation (mitosis). Microscopic and other findings suggest that an imbalance between cell loss and replacement develops, a condition favorable for carcinogenesis. On the molecular level, fumonisins inhibit ceramide synthase, and disrupt sphingolipid metabolism and, theoretically, sphingolipid-mediated regulatory processes that influence apoptosis and mitosis. Liver sphingolipid effects and toxicity are correlated, and ceramide synthase inhibition occurs in liver and kidney at doses below their respective no-observed-effect levels. FB1 does not cross the placenta and is not teratogenic in vivoin rats, mice, or rabbits, but is embryotoxic at high, maternally toxic doses. These data have contributed to preliminary risk evaluation and to protocol development for carcinogenicity and chronic toxicity studies of FB1 in rats and mice.

Fumonisin b1 carcinogenicity in a two-year feeding study using F344 rats and B6C3F1 mice.

Fumonisin B1 (FB1) is a mycotoxin isolated from Fusarium fungi that contaminate crops worldwide. A previous study demonstrated that FB1 promoted preneoplastic foci in initiated rats and induced hepatocellular carcinomas in BD IX rats at 50 parts per million (ppm), but fundamental dose-response data were not available to assist in setting regulatory guidelines for this mycotoxin. To provide this information, female and male F344/N/Nctr BR rats and B6C3F1 Nctr BR mice were fed for two years a powdered NIH-31 diet containing the following concentrations of FB1: female rats, 0, 5, 15, 50, and 100 ppm; male rats, 0, 5, 15, 50, and 150 ppm; female mice, 0, 5, 15, 50, and 80 ppm; male mice, 0, 5, 15, 80, and 150 ppm. FB1 was not tumorigenic in female F344 rats with doses as high as 100 ppm. Including FB1 in the diets of male rats induced renal tubule adenomas and carcinomas in 0/48, 0/40, 9/48, and 15/48 rats at 0, 5, 15, 50, and 150 ppm, respectively. Including up to 150 ppm FB1 in the diet of male mice did not affect tumor incidence. Hepatocellular adenomas and carcinomas were induced by FB1 in the female mice, occurring in 5/47, 3/48, 1/48, 19/47, and 39/45 female mice that consumed diets containing 0, 5, 15, 50, and 80 ppm FB1, respectively. This study demonstrates that FB1 is a rodent carcinogen that induces renal tubule tumors in male F344 rats and hepatic tumors in female B6C3F1 mice.

Compensatory regeneration as a mechanism for renal tubule carcinogenesis of fumonisin B1 in the F344/N/Nctr BR rat.

Fumonisin B1(FB1) is a fungal metabolite of Fusarium verticillioides (= F. moniliforme), a fungus that grows on many crops worldwide. Previous studies demonstrated that male BD IX rats consuming diets containing 50 ppm fumonisin B1 developed hepatocellular carcinomas. In our recent studies, diets containing FB1 at 50 ppm or higher concentrations induced renal tubule carcinomas in male F344/N/Nctr BR rats and hepatocellular carcinomas in female B6C3F1/Nctr BR mice. The carcinogenicity of FB1 in rats and mice is not due to DNA damage, as several laboratories have demonstrated that FB1 is not a genotoxin. FB1 induces apoptosis in cells in vitro. Including FB1 in the diets of rats results in increased hepatocellular and renal tubule epithelial cell apoptosis. In studies with F344/N/Nctr BR rats consuming diets containing up to 484 ppm FB1 for 28 days, female rats demonstrated more sensitivity than male rats in the induction of hepatocellular apoptosis and mitosis. Conversely, induction of renal tubule apoptosis and regeneration were more pronounced in male than in female rats. Induction of renal tubule apoptosis and hyperplasia correlated with the incidence of renal tubule carcinomas that developed in the 2-year feeding study with FB1 in the F344/N/Nctr BR rats. The data are consistent with the hypothesis that the induction of renal tubule carcinomas in male rats could be partly due to the continuous compensatory regeneration of renal tubule epithelial cells in response to the induction of apoptosis by fumonisin B1.

A mechanistic approach to modelling the risk of liver tumours in mice exposed to fumonisin B1 in the diet.

Data from the National Toxicology Program's carcinogenesis study of fumonisin B1 in B6C3F1 mice, conducted at the National Center for Toxicological Research, were used to fit the Moolgavkar-Venzon-Knudson (MVK) two-stage, clonal-expansion model of carcinogenesis. In addition to tumour data from the conventional 2-year bioassay, the study included data on tissue weights, cell proliferation, cell death, and sphingolipid metabolism in primary target organs. The model was used to predict 2-year liver tumour rates in female and male mice based on differences among dose groups in the effect of fumonisin B1 on the growth of normal tissue and on the proliferation of preneoplastic cells as a compensatory response to sphinganine-induced cell death. Fumonisin B1 was assumed to be non-genotoxic, i.e. the model did not include any effect of fumonisin B1 on either of the two mutation rates of the MVK model. The model was able to reproduce reasonably well the observed tumour rates in both female and male mice, predicting substantially increased rates above background only at the highest doses of fumonisin B1 in females.

Implications of apoptosis for toxicity, carcinogenicity, and risk assessment: fumonisin B(1) as an example.

The rates of cell proliferation and cell loss in conjunction with the differentiation status of a tissue are among the many factors contributing to carcinogenesis. Nongenotoxic (non-DNA reactive) chemicals may affect this balance by increasing proliferation through direct mitogenesis or through a regenerative response following loss of cells through cytotoxic (oncotic) or apoptotic necrosis. In a recent NTP study in Fischer rats and B6C3F(1) mice, the mycotoxin fumonisin B(1) caused renal carcinomas in male rats and liver cancer in female mice. In an earlier study in male BD-IX rats, fumonisin B(1) caused hepatic toxicity and hepatocellular carcinomas. An early effect of fumonisin B(1) exposure in these target organs is apoptosis. However, there is also some evidence of oncotic necrosis following fumonisin B(1) administration, especially in the liver. Induction of apoptosis may be a consequence of ceramide synthase inhibition and disruption of sphingolipid metabolism by fumonisin B(1). Fumonisin B(1) is not genotoxic in bacterial mutagenesis screens or in the rat liver unscheduled DNA-synthesis assay. Fumonisin B(1) may be the first example of an apparently nongenotoxic (non-DNA reactive) agent producing tumors through a mode of action involving apoptotic necrosis, atrophy, and consequent regeneration.

Identification of fumonisin B1 as an inhibitor of argininosuccinate synthetase using fumonisin affinity chromatography and in vitro kinetic studies.

Fumonisin B1, a fungal mycotoxin that grows on corn and other agricultural products, alters sphingolipid metabolism by inhibiting ceramide synthase. The precise mechanism of fumonisin B1 toxicity has not been completely elucidated; however, a central feature in the cytotoxicity is alteration of sphingolipid metabolism through interruption of de novo ceramide synthesis. An affinity column consisting of fumonisin B1 covalently bound to an HPLC column matrix was used to isolate a rat liver protein that consistently bound to the column. The protein was identified as argininosuccinate synthetase by protein sequencing. The enzyme-catalyzed formation of argininosuccinic acid from citrulline and aspartate by recombinant human and rat liver argininosuccinate synthetase was inhibited by fumonisin B1. Fumonisin B1 showed mixed inhibition against citrulline, aspartate, and ATP to the enzyme. Fumonisin B1 had a Ki' of approximately 6 mM with the recombinant human argininosuccinate synthase and a Ki' of 35 mM with a crude preparation of enzyme prepared from rat liver. Neither tricarballylic acid nor hydrolyzed fumonisin B1 inhibited recombinant human argininosuccinate synthetase. This is the first demonstration of fumonisin B1 inhibition of argininosuccinate synthethase, a urea cycle enzyme, which adds to the list of enzymes that are inhibited in vitro by fumonisin B1 (ceramide synthase, protein serine/threonine phosphatase). The extent of the inhibition of argininosuccinate synthetase in cells, and the possible role of this enzyme inhibition in the cellular toxicity of FB1, remains to be established.

DNA adduct formation by Fusarium culture extracts: lack of role of fusarin C.

Fusarium fungi have been shown to infect corn and other crops worldwide, and have a significant impact on human health through loss of crops or contamination of food with mycotoxins. Isolates of Fusarium fungi from an area of South Africa with high incidence of esophageal cancer have been shown to induce esophageal and liver cancer in rats. Several isolates of Fusarium fungi were grown on corn to determine if genotoxic products were produced. We report the incubation of methanol extracts of Fusarium verticillioides cultures with DNA in the presence of rat liver fractions (S9) resulted in the formation of a unique DNA adduct that was detected by (32)P-postlabeling. Fusarin C was purified from cultures of Fusarium verticillioides RRC 415, and was not responsible for the formation of the DNA adduct. Treatment of the methanolic extracts with ultraviolet B radiation reduced the fusarin C content in the extract; however, this had no effect on the formation of the DNA adduct following incubation of the extract with DNA and S9. The unique DNA adduct was formed following the incubation of several Fusarium verticillioides isolates from the US and South Africa, while extracts of cultures of Fusarium graminearium and Fusarium sacchari isolates formed very little of the DNA adduct when incubated with DNA and S9. These data suggest that neither fusarin C nor any of its metabolites are responsible for formation of the DNA adduct, and that an unidentified compound is present in F. verticillioides cultures that forms a DNA adduct, and may be important in the etiology of human esophageal cancer.

Fumonisin B1 induces apoptosis in cultured human keratinocytes through sphinganine accumulation and ceramide depletion.

Fumonisin B1 stimulates apoptosis in a variety of cell types and tissues. We examined the role of sphingolipid changes in fumonisin B1-stimulated apoptosis. Sphinganine accumulated rapidly, sphingosine levels remained unchanged, and ceramides decreased during fumonisin B1 exposure. Increased DNA fragmentation, decreased viability, and apoptotic morphology were observed in cells exposed to fumonisin B1, sphinganine, or N-acetylsphingosine. Co-exposure to N-acetylsphingosine or beta-chloroalanine, which blocks sphinganine accumulation, partially protected cells from fumonisin B1-induced apoptosis. These results illustrate three sphingolipid-dependent mechanisms for inducing apoptosis: accumulation of excess ceramide, accumulation of excess sphinganine, and depletion of ceramide or complex sphingolipids derived from ceramide.

Effects of fumonisin B1 in pregnant rats. Part 2.

The developmental toxicity of purified fumonisin B1 (FB1), a mycotoxin from the common corn fungus Fusarium moniliforme, was examined in Charles River rats. Pregnant rats were dosed orally on gestation days 3-16 at 0, 6.25, 12.5, 25 or 50 mg FB1/kg body weight/day. FB1 was not teratogenic at the doses tested. At 50 mg/kg, maternal toxicity (inappetence, emaciation, lethargy, death, resorption of entire litters) and foetal toxicity (increased number of late deaths, decreased foetal body weight, decreased crown rump length, increased incidence of hydrocephalus, increased incidence of skeletal anomalies) were seen. The foetal toxicity observed at 50 mg/kg may be related to maternal toxicity. Histopathological evaluation of tissues from dams of control and all treated groups revealed dose-related toxic changes in kidney and liver tissues. Acute toxic tubular nephrosis was seen in kidneys from all treated groups. Hepatocellular cytoplasmic alteration and individual cellular necrosis of the liver was seen in the two high-dose groups. Sphinganine (Sa) and sphingosine (So) were measured in day-17 adult and foetal tissues. Dose related increases in Sa/So ratios were seen in maternal liver, kidney, serum and brain, but there was no effect on foetal liver, kidney and brain. These data suggest that FB1 does not cross the placenta and further suggest that the observed foetal toxicity is a secondary response to maternal toxicity.

Effects of fumonisin B1 in pregnant rats.

Fumonisin B1 (FB1), the major mycotoxin from Fusarium moniliforme, has been implicated as a causative agent in several animal and human diseases. Despite animal toxicity studies and human epidemiological studies of FB1, knowledge of its reproductive effects is scarce. In this study, one of a series of proposed studies that will allow extrapolation to humans, pregnant rats were given oral doses of 0, 1.875, 3.75, 7.5 or 15 mg FB1/kg on gestation days 3 16. Caesarean sections were performed on day 17 or 20, and maternal condition, implantation efficiency, foetal viability and foetal development were measured. Dose-related decreases in overall feed consumption and body weight gain were seen, but only the feed consumption decrease at 15 mg/kg, and the decreased body weight gain at 15 mg/kg on days 0-17 were statistically significant. Foetal body weights at day 17 were similar in control and treated groups; but in day-20 foetuses, female weight and crown-rump length were significantly decreased at 15 mg/kg. FB1 was not teratogenic at the doses tested, and no dose-related effects were seen in either skeletal or soft-tissue development. In day-17 animals, maternal and foetal brain, liver and kidney tissues, and maternal serum were preserved to study the levels of sphinganine (Sa), sphingosine (So), and the Sa/So ratios. Dose-related increases were seen in Sa/So ratios in maternal livers, kidneys and serum. Sa/So ratios of maternal brains were not affected, nor were those of foetal kidneys, livers or brains.

Polycyclic aromatic hydrocarbons enhance terminal cell death of human ectocervical cells.

Polycyclic aromatic hydrocarbons (PAH) are a class of chemical carcinogens whose active metabolites form DNA adducts, resulting in specific mutational events. The tumor suppressor protein p53 is believed to play a pivotal role in the ability of cells to response to DNA damage, resulting in either cell cycle arrest in G1 or apoptosis under conditions of excessive damage. This growth inhibition is associated with the concomitant induction of p53 and enhanced terminal cell differentiation. In this study we evaluated the effects of PAH on cell growth, cell differentiation, xenobiotic metabolism, and DNA adduct levels in normal ectocervical epithelial cells (ECE) and compared them to cervical cells whose p53 have been inactivated either by binding to viral HPV E6 oncogene (ECE16-1) or by mutation (C33A). The PAH 3-methylcholanthrene (3MC) inhibited normal ECE and to a lesser extent ECE16-1 cell proliferation. Not only did the growth inhibition occur at lower concentrations in the normal cells but the extent of inhibition was also greater in normal as compared to immortalized cells. Benzanthracene (BA) had a minor effect on normal ECE cells with no effect on immortalized ECE16-1 cells. C33A cell growth was unaffected by 3MC and BA. Terminal cell death was enhanced only in normal ECE cells as evidenced by increased envelope formation and was paralleled by an increase in the level of p53 following 3MC treatment. The differentiation status of the 3MC-treated cells was similar to untreated cells as indicated by three independent markers of cell differentiation; transglutaminase, involucrin, keratin expression. There was no difference in the pattern or level of DNA adducts formed in normal and immortalized cells following 3MC treatment. In addition the basal level of metabolism of 14C-BaP to phenols, diols and quinnones was unaltered by pretreatment with either 3MC or BA. These results demonstrate that immortalized cervical cells are less sensitive to toxicant damage [i.e. cell proliferation and terminal differentiation], and as a result, immortalized cells proliferate in the presence of genotoxic damage and are at increased risk for mutations and cancer.

Renal effects of fumonisin mycotoxins in animals.

Fumonisins are mycotoxins produced worldwide by Fusarium fungi, principally F. moniliforme. The fungus is present in virtually all harvested corn, but the toxins produced are variable. The toxins, especially fumonisin B1, cause mild to fatal diseases in animals, with peculiar species specificity for the dominant signs of toxicity. The mechanism of toxicity is poorly understood, but it appears to be related to interference with sphingolipid biosynthesis in multiple organs. Whereas brain, lung, and liver are well-known target organs, toxic effects on the kidney are also widespread and have only recently begun to be characterized. Increased urine volume and decreased osmolarity are early changes associated with the toxin, as are increased excretions of high- and low-molecular-weight proteins. Enzymuria in vivo, reduced ion transport in vitro, and elevation of free sphinganine in renal tissue and in urine are present. An increase in serum creatinine and blood urea nitrogen and histopathologic change in renal tubules occur later and at higher doses. The morphologic change principally affects the junction of cortex and medulla and includes prominent apoptosis of epithelial cells of proximal convoluted tubules. Nephrotoxicity has been reported in several species, and in rats and rabbits, the kidney appears to be the most sensitive target organ.

Lack of embryotoxicity of fumonisin B1 in New Zealand white rabbits.

Fumonisin B1 (FB1) is one of a number of mycotoxins produced by fungi, especially Fusarium sp. As a contaminant of many maize-derived products, this toxin is associated with a variety of animal diseases, including esophageal cancer and possibly neural tube defects in humans. We have investigated the embryotoxic potential of this compound in New Zealand White rabbits. Animals were dosed by gavage daily on GD 3-19 with purified FB1 at 0.10, 0.50, or 1.00 mg/kg/day. Maternal lethality occurred at the 0.50 and 1.00 mg/kg/day doses. When examined on GD 29, there were no differences in maternal body weight, maternal weight gain, maternal organ weights, number of nonlive implantations, and number of malformations. Fetal weight was decreased at 0.50 and 1.00 mg/kg/day (13 and 16%, respectively); this was true for male and female pups. Fetal liver and kidney weights were also decreased at these doses. Analysis of embryonic sphinganine to sphingosine ratios demonstrated no differences between control and treated embryos on GD 20, although these ratios were increased in maternal urine, serum, and kidney when compared to control animals. These data suggest that FB1 did not cross the placenta and that the observed decreased fetal weight was probably the result of maternal toxicity, rather than any developmental toxicity produced by FB1.