On a new marine podocopid genus and species (Ostracoda: Hemicytheridae) from Brazil.

Bulbocythere calida gen. et sp. nov., a benthic marine ostracode, is herein described and illustrated. The geographic and bathymetric distributions of this new taxon are based on the analysis of 923 bottom samples collected along the entire Brazilian continental shelf in a depth range of about 11 to 280 m, plus sediments of 176 samples from the Sepetiba Bay and 37 samples from the Tamandaré Bay. In the study material, this ostracode was rare, and restricted to the warm waters of the E and NE shelves and to the substrates around the reefs of the Tamandaré Bay.

Dietary restraint: what's the harm? A review of the relationship between dietary restraint, weight trajectory and the development of eating pathology.

Dietary restraint has historically been implicated as a risk factor for the development of eating pathology. Despite existing findings, recent research suggests that many individuals are capable of practicing dietary restraint without negative effects. In order to successfully incorporate the positive aspects of dietary restraint into interventions for healthy weight management, a nuanced examination of the relationship between dietary restraint and resulting eating patterns is necessary. Accordingly, the current review seeks to clarify the existing literature with regard to dietary restraint. First, this review examines the construct of dietary restraint and differentiates dietary restraint from related constructs, such as weight loss dieting. Second, it identifies situations in which dietary restraint has been linked with positive outcomes, such as healthy weight management and prevention of eating pathology. Altogether, it appears that dietary restraint can prove a beneficial strategy for those attempting to control their weight, as it does not relate to increased levels of eating pathology when practiced as part of a well-validated weight management programme.

Social functioning and facial expression recognition in children with neurofibromatosis type 1.

BACKGROUND: This study examined social functioning and facial expression recognition (FER) in children with neurofibromatosis type 1 (NF1) compared to typically developing peers. Specifically, the current research aimed to identify hypothesised relationships between neurocognitive ability, FER and social functioning. METHOD: Children, ages 8 to 16, with NF1 (n = 23) and typically developing peers (n = 23) were recruited during regularly scheduled clinic visits and through advertisements on an institutional clinical trials website, respectively. Participants completed a measure of FER, an abbreviated intelligence test and questionnaires regarding their quality of life and behavioural functioning. Parents were also asked to complete questionnaires regarding the social-emotional and cognitive functioning of their child. RESULTS: As expected, there were significant differences between children with NF1 and typically developing peers across domains of social functioning and FER. Within the sample of children with NF1, there were no significant associations observed between cognitive measures, social functioning and facial recognition skills. CONCLUSION: Children with NF1 exhibited high rates of social impairment and weak FER skills compared to controls. The absence of associations between FER with cognitive and social variables, however, suggests something unique about this skill in children with NF1. Theoretical comparisons are made to children with autism spectrum disorders, as this condition may serve as a potentially useful model in better understanding FER in children with NF1.

Participation as a leader in immersion weight loss treatment: a 1-year follow-up study.

Non-overweight individuals may follow aggressive weight management approaches alongside overweight/obese friends or family members; thus, research has begun to evaluate subsequent effects among non-overweight populations. A prior study evaluated the short-term effects of an immersion weight loss programme on healthy young adult staff leaders. Results indicated that participation seemed to benefit, not harm, the young adults. The current investigation examined 1-year eating disorder and weight trajectories in this sample. The total sample (N = 244) consisted of staff leaders (44.3%) and demographically similar comparison participants who completed eating disorder and weight assessments across four time points: baseline, end of summer, 6-week follow-up and 1-year follow-up. Forty-seven per cent of the original sample responded to all time points (staff leaders n = 60; comparison n = 55). Over the course of 1 year, risk trajectories did not differ between groups. Staff leaders did not report significant changes in body mass index, suggesting that they maintained healthy weight over the course of 1 year. Participation as an immersion weight loss programme leader appeared to be protective against weight gain, without increasing eating disorder risk, for healthy young adults. This provides further support for using weight management interventions across a wide range of individuals.

miR-23b targets proline oxidase, a novel tumor suppressor protein in renal cancer.

Proline oxidase (POX) is a novel mitochondrial tumor suppressor that can suppress proliferation and induce apoptosis through the generation of reactive oxygen species (ROS) and decreasing hypoxia-inducible factor (HIF) signaling. Recent studies have shown the absence of expression of POX in human cancer tissues, including renal cancer. However, the mechanism for the loss of POX remains obscure. No genetic or epigenetic variation of POX gene was found. In this study, we identified the upregulated miR-23b in renal cancer as an important regulator of POX. Ectopic overexpression of miR-23b in normal renal cells resulted in striking downregulation of POX, whereas POX expression increased markedly when endogenous miR-23b was knocked down by its antagomirs in renal cancer cells. Consistent with the POX-mediated tumor suppression pathway, these antagomirs induced ROS, inhibited HIF signaling and increased apoptosis. Furthermore, we confirmed the regulation of miR-23b on POX and its function in the DLD1 Tet-off POX cell system. Using a luciferase reporter system, we verified the direct binding of miR-23b to the POX mRNA 3'-untranslated region. In addition, pairs of human renal carcinoma and normal tissues showed a negative correlation between miR-23b and POX protein expression, providing its clinical corroboration. Taken together, our results suggested that miR-23b, by targeting POX, could function as an oncogene; decreasing miR-23b expression may prove to be an effective way of inhibiting kidney tumor growth.

The ERBB3 receptor in cancer and cancer gene therapy.

ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

Comparison of flavor changes in cooked-refrigerated beef, pork and chicken meat patties.

Beef and pork longissimus dorsi (LD) and semimembranosus (SM) and chicken breast (B) and thigh (T) muscles excised 24 h postmortem were ground by muscle/species group, formed into patties, pan-fried, refrigerated for 0, 3 or 6 days, and evaluated by a trained sensory panel for intensity of specific flavors. The rate of decline in species-specific natural meat flavor intensity and the rate of increase in "cardboard" (CBD) flavor intensity during the first half of the 6-day storage were fastest for beef, while such decline and increase during the entire storage period were slowest for chicken B. Overall trends of natural meat flavor and CBD intensity changes for chicken T appeared more like those for the red meats than chicken B. It was concluded that, while flavor deterioration can occur in cooked-stored meats from all the species, quantitative or the magnitude of differences between species would depend on muscle types and sensory terms/method used.

Expressions of hepatic genes, especially IGF-binding protein-1, correlating with serum corticosterone in microarray analysis.

Microarray technology was evaluated for usefulness in assessing relationships between serum corticosterone and hepatic gene expression. Nine pairs of female Swiss mice were chosen to provide a wide range of serum corticosterone ratios; cDNA microarray analysis (approximately 8000 genes) was performed on their livers. A statistical method based on calculation of 99% confidence intervals discovered 32 genes which varied significantly among the livers. Five of these ratios correlated significantly with serum corticosterone ratio, including tyrosine aminotransferase, stress-induced protein, pleiotropic regulator 1 and insulin-like growth factor-binding protein-1; the latter has a potential role in cancer development. Secondly, linear regression of gene expression vs corticosterone ratios was screened for those with r> or =0.8 (P<0.01), yielding 141 genes, including some known to be corticosterone regulated and others of interest as possible glucocorticoid targets. Half of these significant correlations involved data sets where no microarray ratio exceeded +/- 1.5. These results showed that microarray may be used to survey tissues for changes in gene expression related to serum hormones, and that even small changes in expression can be of statistical significance in a study with adequate numbers of replicate samples.

Heterozygous inactivation of TGF-beta1 increases the susceptibility to chemically induced mouse lung tumorigenesis independently of mutational activation of K-ras.

Mice heterozygous for deletion of the transforming growth factor beta1 (TGF-beta1) gene show an enhanced rate of lung tumorigenesis following carcinogen treatment. Since the growth inhibitory activity of TGF-beta1 in epithelial cells is associated with K-ras p21, and K-ras mutations commonly occur in chemically-induced mouse lung tumors, we postulated that tumors in heterozygous TGF-beta1 mice might be more likely to have K-ras mutations compared with tumors in wildtype TGF-beta1 mice. Urethane-induced lung tumors in AJBL6 TGF-beta1 +/- and +/+ mice were examined for K-ras mutations by polymerase chain reaction/single strand conformation polymorphism analysis and sequencing. Mutation frequencies were similar in both genotypes: 12/18 +/- tumors (67%) and 10/16 +/+ tumors (62%). Mutations occurred in 80% +/- and 75% +/+ carcinomas, but in only 50% of the adenomas of both TGF-beta1 genotypes. Codon 61 A-->G transition mutations were predominant, occurring in 61% +/- and 44% +/+ tumors. Three +/- (17%) and three +/+ (19%) tumors showed codon 12 mutations, mostly G-->A transitions. Two +/- tumors had both codon 61 and codon 12 mutations. Interestingly, carcinomas with mutations in codon 61 were larger than those with codon 12 changes. It appears that the mechanism of enhanced susceptibility of TGF-beta1+/- mice to urethane-induced lung carcinogenesis does not involve selective development of tumors with K-ras mutations.

Gene expression following acute morphine administration.

The long-term response to neurotropic drugs depends on drug-induced neuroplasticity and underlying changes in gene expression. However, alterations in neuronal gene expression can be observed even following single injection. To investigate the extent of these changes, gene expression in the medial striatum and lumbar part of the spinal cord was monitored by cDNA microarray following single injection of morphine. Using robust and resistant linear regression (MM-estimator) with simultaneous prediction confidence intervals, we detected differentially expressed genes. By combining the results with cluster analysis, we have found that a single morphine injection alters expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton-related proteins. RNAs for these proteins were mostly downregulated both in the medial striatum and in lumbar part of the spinal cord. These transitory changes were prevented by coadministration of the opioid antagonist naloxone. Data indicate that microarray analysis by itself is useful in describing the effect of well-known substances on the nervous system and provides sufficient information to propose a potentially novel pathway mediating its activity.

Responsiveness to transforming growth factor-beta (TGF-beta)-mediated growth inhibition is a function of membrane-bound TGF-beta type II receptor in human breast cancer cells.

Transforming growth factor-beta (TGF-beta) is a potent inhibitor of growth and proliferation of breast epithelial cells, and loss of sensitivity to its effects has been associated with malignant transformation and tumorigenesis. The biological effects of TGF-beta are mediated by the TGF-beta receptor complex, a multimer composed of TGF-beta receptor type I (TbetaR-I) and TGF-beta receptor type II (TbetaR-II) subunits. Evidence suggests that loss of expression of Tbeta3R-II is implicated in the loss of sensitivity of tumorigenic breast cell lines to TGF-beta-mediated growth inhibition. A panel of human breast cell lines, including the immortalized MCF-10F and tumorigenic MCF-7, ZR75-1, BT474, T47-D, MDA-MB231, BT20, and SKBR-3 cell lines, was characterized for responsiveness to TGF-beta-induced G1 growth arrest. Only the nontumorigenic MCF-10F and the tumorigenic MDA-MB231 cell lines demonstrated a significant inhibitory response to TGF-beta1 and a significant binding of 125I-labeled TGF-beta ligand. While expression of TbetaR-I mRNA was similar across the panel of cell lines, TbetaR-II mRNA expression was decreased significantly in all seven tumorigenic cell lines in comparison with the nontumorigenic MCF- 10F cell line. When total cellular protein was fractionated by centrifugation, TbetaR-I protein was observed in both the cytosolic and membrane fractions at similar levels in all cell lines; however, TbetaR-II protein was present in the cytosolic fraction in all cell lines, but was observed in the membrane fraction of only the TGF-beta-responsive MCF-10F and MDA-MB231 cells. Thus, lack of membrane-bound TbetaR-II protein appears to be an important determinant of resistance to TGF-beta-mediated growth inhibition in this group of breast cell lines.

Lobe-specific increases in malondialdehyde DNA adduct formation in the livers of mice following infection with Helicobacter hepaticus.

Helicobacter hepaticus infection is associated with chronic hepatitis and the development of liver tumours in mice. The underlying mechanism of this liver carcinogenesis is not clear but the oxidative stress associated with H. hepaticus infection may result in induction of lipid peroxidation and the generation of malondialdehyde. Malondialdehyde can react with deoxyguanosine in DNA resulting in the formation of the cyclic pyrimidopurinone N-1,N(2) malondialdehyde-deoxyguanosine (M1dG) adduct. This adduct has the potential to cause mutations that may ultimately lead to liver carcinogenesis. The objective of this study was to determine the control and infection-related levels of M1dG in the liver DNA of mice over time, using an immunoslot-blot procedure. The level of M1dG in control A/J mouse livers at 3, 6, 9 and 12 months averaged 37.5, 36.6, 24.8 and 30.1 adducts per 10(8) nucleotides, respectively. Higher levels of M1dG were detected in the liver DNA of H. hepaticus infected A/JCr mice, with levels averaging 40.7, 47.0, 42.5 and 52.5 adducts per 10(8) nucleotides at 3, 6, 9 and 12 months, respectively. There was a significant age dependent increase in the level of M1dG in the caudate and median lobes of the A/JCr mice relative to control mice. A lobe specific distribution of the M1dG adduct in both infected and control mice was noted, with the left lobe showing the lowest level of the adduct compared with the right and median lobes at all time points. In a separate series of mice experimentally infected with H. hepaticus, levels of 8-hydroxy-deoxyguanosine were significantly greater in the median compared with the left lobe at 12 weeks after treatment. In conclusion, these results suggest that M1dG occurs as a result of oxidative stress associated with H. hepaticus infection of mice, and may contribute to liver carcinogenesis in this model.

Hydrocarbon carcinogens evade cellular defense mechanism of G1 arrest in nontransformed and malignant lung cell lines.

In previous studies using human breast carcinoma cells (MCF-7) and human colon carcinoma cells (RKO) we have shown that, in response to treatment with hydrocarbon carcinogens, these cell lines failed to undergo a p53-mediated cell cycle arrest in G1 phase; rather, the cells were accumulated in the S phase with damaged DNA, a situation that may lead to replication of DNA on a damaged template, resulting in the enhanced frequency of mutations in the daughter cells. This has been termed a stealth effect. In the present work we have demonstrated that the stealth effect also pertains for lung cells. In E10 nontransformed mouse lung type II cells, two potent hydrocarbon carcinogens, benzo[a]pyrene dihydrodiol epoxide and benzo[g]chrysene dihydrodiol epoxide, damaged DNA as suggested by retardation in S phase, but did not cause G1 arrest, in contrast to the positive control, actinomycin D. Human lung adenocarcinoma A549 cells, with normal p53, likewise exhibited G1 arrest after actinomycin D, but not after treatment with the diol epoxides. Several human lung cancer cell lines with absent or mutant p53, such as H358, H1734, and H82, exhibited no G1 arrest after any of the compounds. However, lung H441 adenocarcinoma cells, with a mutation in exon 5, codon 158 of p53, exhibited partial G1 arrest after the diol epoxides as well as actinomycin D, and H2030 adenocarcinoma cells did not show G1 arrest after any of the chemicals despite a normal p53. The stealth effect of evasion of G1 arrest may contribute to initiation of lung adenocarcinomas and to progression of tumors. A role in resistance to chemotherapy by certain drugs is also likely.

K-ras mutations in mouse lung tumors of extreme age: independent of paternal preconceptional exposure to chromium(III) but significantly more frequent in carcinomas than adenomas.

Preconceptional exposure of male NIH Swiss mice to chromium(III) chloride resulted in increased incidence of neoplastic and non-neoplastic changes in their progeny, including lung tumors in females [Toxicol. Appl. Pharmacol. 158 (1999) 161-176]. Since mutations in the K-ras protooncogene are frequent, early changes in mouse lung tumors, we investigated possible mutational activation of this gene as a mechanism for preconceptional carcinogenesis by chromium(III). These offspring had lived until natural death at advanced ages (average 816+/-175 days for controls, 904+/-164 for progeny of chromium-treated fathers). Mutations of K-ras, analyzed by single-strand conformation polymorphism and sequencing, were, in codon 12, wild type GGT (glycine), to GAT (aspartic acid); to GTT (valine); and to CGT (arginine); and in codon 61, wild-type CAA (glutamine), to CGA (arginine). K-ras mutation frequencies in lung tumors were very similar in control progeny (4/14) and in progeny of chromium-treated fathers (5/15). Thus, germline mutation or tendency to spontaneous mutation in K-ras does not seem to be part of the mechanism of preconceptional carcinogenesis here. However, an additional interesting observation was that K-ras mutations were much more frequent in lung carcinomas (8/16) than in adenomas (1/13) (P=0.02), for all progeny combined. This was not related to age of the tumor-bearing mice or the size of the tumors. K-ras mutations may contribute to malignant tumor progression during aging, of possible relevance to the putative association of such mutations with poor prognosis of human lung adenocarcinomas.

Coexposure to ethanol with N-nitrosodimethylamine or 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone during lactation of rats: marked increase in O(6)-methylguanine-DNA adducts in maternal mammary gland and in suckling lung and kidney.

Use of alcoholic beverages increases risk of cancer at several target sites, including the breast. Of several possible mechanisms for this effect, competitive inhibition by ethanol of hepatic clearance of nitrosamines, resulting in increased dose delivery to posthepatic tissues, gives the quantitatively most pronounced enhancement. We investigated whether this effect would pertain to the mammary gland, and to ethanol and nitrosamines delivered translactationally to sucklings. Ethanol (1.6 g/kg) was administered by gavage to nursing Sprague-Dawley rats 10 min before 5 mg/kg N-nitrosodimethylamine (NDMA) or 50 mg/kg 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); treatment was on postnatal days 1, 7, or 14. Tissues taken 4 h later for analysis of O(6)-methylguanine in DNA were liver, blood, and mammary glands from the mothers, and liver, lung, kidney, and blood from the sucklings. Ethanol cotreatment resulted in a marked, 10-fold increase in O(6)-methylguanine adducts from NDMA in mammary gland, as well as smaller but significant increases in this tissue from NNK and in maternal blood cells from both chemicals; adducts in maternal liver decreased slightly. In the sucklings, ethanol cotreatment also lowered adducts in liver after NDMA or NNK treatment. After NDMA, adducts were also detected in suckling lung and kidney and were increased five- to 10-fold after ethanol coexposure. Adducts from either chemical, with or without ethanol, decreased markedly in all suckling tissues with development from postnatal day 1 to day 14. Thus ethanol coexposure with nitrosamines increases O(6)-methylguanine DNA adducts in mammary gland and strongly influences adduct formation in suckling tissues after translactational delivery.

Age-related alterations in 32P-postlabeled DNA adducts in livers of mice infected with the tumorigenic bacterial pathogen, Helicobacter hepaticus.

Helicobacter hepaticus causes chronic active hepatitis and liver tumors in mice, with associated increase in reactive oxygen species. Indigenous (I)-compounds are bulky DNA adducts present at low levels and detected by 32P-post-labeling. Some may be caused by reactive oxygen species; others occur normally and decrease during liver tumorigenesis. The identity of most is unknown. We investigated whether mouse liver infection by H. hepaticus and resulting progression of hepatic lesions would be associated with qualitative or quantitative changes in I-compounds. Mice were 3, 6, 9, and 12 months of age; liver disease ranged from minimal through marked. In control A/J mice, up to 20 I-compounds were detected, and the total level of these did not change with age, whereas 11 individual I-compounds showed marked age-related differences. These appeared to be coordinately regulated, as the total of these 11 adducts was constant at 6-12 months. In A/JNCr mice naturally infected with H. hepaticus, up to 12 hepatic I-compounds were found. Total levels varied markedly with age and were high at 6 and 12 months. Neither total adduct levels, nor the amount of any individual adduct, correlated positively with severity of hepatic lesions; in some cases, highest levels were found in livers with least disease. Thus, liver infection and tumorigenesis by H. hepaticus was not associated with an increase in any 32P-postlabeled DNA adduct. Marked, and distinct, age-related changes in total or individual adducts in control and infected mice suggest a role in the physiological alterations of aging and in host response to infection.

Ki-ras and the characteristics of mouse lung tumors.

Codon 12 mutations are frequent in the Ki-ras oncogene in human lung adenocarcinomas, but the effects of these alterations have not been well characterized in lung epithelial cells. Murine primary lung tumors derived from peripheral epithelial cells also may present Ki-ras mutations and are useful models for study of early phases of tumor development. One hypothesis is that Ki-ras mutation and/or a Ki-ras p21 increase could enhance Ki-ras p21-GTP and cell-cycle stimulation through raf-1 and extracellularly regulated protein kinases (Erks). We examined lung tumors 1-7 mm in largest dimension initiated in male Swiss mice by N-nitrosodimethylamine for pathologic type, Ki-ras mutations and levels of total Ki-ras p21, Ki-ras p21 bound to GTP, raf-1, Erk1 and Erk2 and their phosphorylated (activated) forms, and proliferating cell nuclear antigen. Total Ki-ras p21 and activated ras-GTP were not significantly greater in tumors than in normal lung or in tumors with versus those without Ki-ras mutations. Carcinomas with Ki-ras mutations were significantly smaller than those without mutations. Carcinomas were significantly larger than adenomas only for tumors without mutations. High levels of Erk2 and correlation of Erk2 amount with ras-GTP were specific characteristics of tumors with Ki-ras mutations. Size of all tumors correlated with ras-GTP but not with proliferating cell nuclear antigen. Raf-1 was expressed mainly in alveolar macrophages in normal lung but was focally upregulated in papillary areas of some tumors. The results indicate that Ki-ras influences the characteristics of lung tumors, but a linear ras-raf-Erk-cell-cycle control sequence does not adequately characterize tumorigenic events in this model. Mol. Carcinog. 28:156-167, 2000.

Overexpression of Grb2 in inflammatory lesions and preneoplastic foci and tumors induced by N-nitrosodimethylamine in Helicobacter hepaticus-infected and -noninfected A/J mice.

Growth factors bind to membrane receptor tyrosine kinases, resulting in autophosphorylation and subsequent binding to proteins with SH2 domains, including growth factor receptor-bound protein 2 (Grb2). Grb2 bridges receptors to tyrosine kinase substrates such as SHC and SOS, which in turn facilitate the activation of downstream signaling pathways, including Ras and mitogen-activated protein kinase (MAPK). Overexpression of Grb2 has been demonstrated in several types of neoplasia but has not been investigated in liver tumorigenesis. Here we investigated Grb2 expression in liver lesions in N-nitrosodimethylamine (NDMA)-treated Helicobacter hepaticus-infected and -noninfected A/J mice at 1 year of age. Previously, we reported (6) that infection promotes the development of these NDMA-initiated tumors. In controls, Grb2 immunostaining was absent from normal hepatic tissues, whereas the inflammatory lesions in infected livers were positive for cytoplasmic Grb2 in both hepatocytes and infiltrating leukocytes. All preneoplastic foci (7 of 7), 15 of 27 adenomas, and 3 of 7 carcinomas were positive for Grb2 by immunostaining in both infected and noninfected NDMA-initiated livers. Involvement of Grb2 was confirmed by immunoblotting of similarly infected mice at 9 to 18 months of age, showing a 2.5- to 3.3-fold increase in Grb2 protein in infected livers (p < 0.05 compared with uninfected controls) as well as in preneoplastic foci, adenomas, and carcinomas. These livers also showed a 2.5- to 2.8-fold increase in total Ras protein. The results suggest that upregulation of Grb2 is an early event in liver carcinogenesis, whether caused by the bacterial infection or by NDMA. Concomitant upregulation of Ras p21 would ensure transmission of amplified signal from growth factors via Grb2.

DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in fetal tissues of patas monkeys after transplacental exposure.

Transplacental genotoxicity of the heterocyclic amine food-derived mutagen/carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) has been investigated by (32)P-postlabeling assay for IQ-DNA adducts in maternal liver, placenta, and several fetal tissues of patas monkeys, after exposure to 15, 35, or 50 mg/kg IQ near the end of gestation or to the highest dose in the first or second trimester. Dose-dependent adduct formation occurred in all tissues, with the highest levels occurring in maternal liver. Adduct amounts were similar among fetal tissues and placenta, except for lower levels in fetal brain and slightly more adducts in fetal liver. Adducts in placenta, fetal liver, lung, kidney, skin, and adrenal gland, but not in maternal liver or fetal brain, increased significantly as gestation progressed. Pretreatment with phenobarbital, which induces CYP enzymes that detoxify IQ, decreased adducts in maternal liver and possibly placenta, but not in fetal tissues. The CYP inducer beta-naphthoflavone caused a significant increase in IQ-DNA adducts in fetal lungs. Regression analysis suggested that IQ activation in maternal and fetal liver and possibly placenta contributed to adduct formation in fetal tissues; adducts in placenta and/or fetal liver were strong predictors for those in most fetal tissues. The results indicate that exposure of pregnant primates to IQ results in DNA adduct formation in most fetal tissues, especially late in gestation; that upregulation of maternal detoxification does not provide fetal protection; and that adducts in placenta indicate adduct levels in fetal tissues.