Metabolic activation/deactivation reactions during perinatal development.

Lucier, George W.; Lui, Edmund M.K.; Lamartiniere, Coral A.

doi:10.1289/ehp.79297

Cited by 28 publications

(5 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This conclusion is based on our findings that placentas from the Taiwanese non-smokers (exposed to PCBPCDF) and U.S. smokers (not exposed to PCBPCDF) were highly induced, but increased adducts were seen only i 7 the smokers. Furthermore, the magnitude of placental CYP 1Al induction in smokers seen in our data was similar to that observed in previous studies [3,5,30] and is consistent with the knowledge that some cigarette smoke constituents bind to the Ah receptor leading to transcriptional activation of the CYP 1Al gene. This mechanism should be fully operative in human placentas since the Ah receptor is present and apparently functional [32].…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Comparison of DNA adduct levels in human placenta from polychlorinated biphenyl exposed women and smokers in which CYP 1A1 levels are similarly elevated

Gallagher

Everson

Lewtas

et al. 1994

Teratog Carcinog Mutagen

View full text Add to dashboard Cite

Previous studies demonstrated that cigarette smoking is associated with high elevations in levels of both cytochrome P450 1A1 (CYP1A1) and DNA adducts in human placenta. To date, the identity of the smoking related DNA adducts is not known. The DNA adducts identified in placenta of smokers could result from chemicals present in cigarette smoke, substances formed by CYP 1A1 metabolic activation of endogenous compounds, noncigarette related exposures or a combination of these processes. Exposure to contaminated rice oil containing large doses of polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) also resulted in massive elevation of CYP 1A1 in human placenta but formation of DNA adducts directly from this exposure has not previously been reported. The purpose for comparing the two populations was to test the hypothesis that if CYP 1A1 induction results in the metabolic activation of endogenous compounds, then DNA adducts should also be present in PCB/PCDF exposed tissues exhibiting high CYP 1A1 activity and some of the adducts detected in the placental DNA from smokers may be identified as those derived from the metabolic activation of endogenous compounds. To test this hypothesis, we measured DNA adducts using 32P-postlabeling to analyze placental DNA from women exposed to PCB/PCDF and from cigarette smokers where levels of CYP 1A1 were similarly elevated. There was no evidence of DNA adducts among specimens obtained from PCB/PCDF exposed individuals. These data suggest that CYP 1A1 induction alone (in the absence of cigarette smoking) does not induce the formation of DNA adducts detectable by this approach, and that smoking related adducts are not a consequence of CYP 1A1 induction mediated activation of endogenous compounds or xenobiotics other than cigarette smoke.

show abstract

Section: Discussionsupporting

confidence: 93%

“…For example, in one model system, induction of CYP 1Al decreases the concentration of B(a)P DNA adducts in rats [ 121. The mechanism for this may be that CYP 1Al is both an activating and a deactivating system and most inducing agents also induce deactivating enzymes such as UDP glucuronyltransferase [30].…”

Section: Discussionmentioning

confidence: 99%

Comparison of DNA adduct levels in human placenta from polychlorinated biphenyl exposed women and smokers in which CYP 1A1 levels are similarly elevated

Gallagher

Everson

Lewtas

et al. 1994

Teratog Carcinog Mutagen

View full text Add to dashboard Cite

show abstract

“…This is consistent with the ontogeny of the UDPglucuronosyltransferases. UDP-glucuronosyltransferases increase postnatally (Lucier et al, 1979), and this is evident for the conjugation of daidzein and its primary metabolite, equol, culminating in conjugation of 99% of the equol in the adult female. In the neonatal females, only 14% of the equol is conjugated, but at that age only 28 nM and 107 nM equol were measured in offspring of dams eating the low and high daidzein-containing diets, respectively.…”

Section: Bioavailabilitymentioning

confidence: 99%

Daidzein: Bioavailability, Potential for Reproductive Toxicity, and Breast Cancer Chemoprevention in Female Rats

Lamartiniere¹

2002

Toxicological Sciences

104

View full text Add to dashboard Cite

Soy products containing phytoestrogens have received much attention as dietary components to promote better health. Daidzein, an isoflavone and phytoestrogen component of soy, was investigated for its potential to alter fertility and cause developmental toxicity to the reproductive tract in female rats, for chemoprevention to the mammary gland, and to study its bioavailability. Diets containing 0 mg, 250 mg (low dose), and 1000 mg (high dose) daidzein/kg feed were fed to virgin female rats, starting 2 weeks prior to breeding and continued until the offspring were 50 days postpartum. The serum daidzein concentrations in adult female rats fed the low and high daidzein-containing diets were determined to be 6- and 13-fold higher than serum daidzein concentrations of Asians eating a traditional diet high in soy. Both daidzein doses had no significant effect on fertility, numbers of male and female offspring, and anogenital distances. The high, but not the low, daidzein dose resulted in reduced body weight, a fact that may be explained by reduced feed consumption. Circulating progesterone, but not estrogen, levels were statistically reduced with the high, but not low daidzein-containing diet. Both daidzein doses resulted in slight, but not significant, decreases in ovarian and uterine weights, and mammary gland size. Histomorphological analysis of the reproductive tracts of female offspring 50 days of age exposed perinatally to daidzein did not reveal any pathology in the vaginal, uterine, ovarian, and mammary tissues. Perinatal exposure of female offspring to 250 mg daidzein/kg diet did not alter mammary gland development or ontogeny of chemically induced mammary tumors in rats treated with dimethylbenz(a)anthracene on day 50. With the low dietary daidzein dose, total equol (major metabolite) and daidzein concentrations in the blood of pregnant females, 7-day-old, 21-day-old, and 50-day-old female offspring were 529 and 303 nM, 163 and 982 nM, 1188 and 1359 nM, and 3826 and 630 nM, respectively. With the high daidzein diet, equol and daidzein concentrations in the blood of pregnant females, 7-day-old, 21-day-old, and 50-day-old female offspring were 4462 and 407 nM, 1013 and 3841 nM, 6472 and 3308 nM, and 7228 and 1430 nM, respectively. Eighty-nine to 99% of daidzein and equol were in the conjugated form. In the 21-day-old postconceptus exposed to the low and high daidzein diets, total equol and daidzein blood concentrations were 59 and 34 nM, and 358 and 132 nM, respectively. Virtually all of the daidzein in the milk of 7-day-old rats exposed to the low and high daidzein-containing diet were unconjugated, 2.6 microM and 7.3 microM, respectively. Total milk equol concentrations were 654 nM and 3.8 microM, of which 94% and 44% were unconjugated. In mammary glands of 7-day-old offspring exposed to 250 mg daidzein/kg diet, total daidzein concentrations were 407 nM (98% aglycone). We conclude that supraphysiological concentrations of daidzein administered via the diet did not cause significant toxicity to the female repr...

show abstract

“…The vast majority of genotoxic chemical carcinogens are not direct-acting, but, as indicated previously, require metabolic conversion to a chemically reactive ultimate carcinogen in order to effect carcinogenesis. It has been shown that in rodents, the mixed function oxidase enzymes principally involved in activation of chemical carcinogens are present at low or virtually undetectable levels in fetal tissues until immediately prior to parturition, and even then are present at levels that are minuscule in comparison with those in adult tissues (10). The picture is complicated by the fact that these enzymes are inducible, and their levels in tissues such as the liver may be significantly altered by exposure to chemical agents that are substrates for these enzymes, including carcinogens such as methylcholanthrene (3).…”

Section: Transplacental Carcinogenesis By Metabolism-dependent Carcinogensmentioning

confidence: 99%

Prenatal susceptibility to carcinogenesis by xenobiotic substances including vinyl chloride.

Rice¹

1981

Environ Health Perspect

View full text Add to dashboard Cite

The carcinogenicity of vinyl chloride for experimental animals when administered transplacentally is reviewed in comparison with known transplacental carcinogens, including those that, like vinyl chloride, are dependent on enzyme-mediated metabolic conversion to a reactive intermediate in maternal or fetal tissues. Vinyl chloride is converted by mixed-function oxidases to the reactive metabolite chlorooxirane, the carcinogenicity of which is also reviewed. Vinyl chloride is unequivocally a transplacental carcinogen for the rat. No evidence exists, however, to support the hypothesis that exposure of male rats to vinyl chloride or any other carcinogen confers an increased risk of tumor development on their progeny. Many structural analogs of vinyl chloride, i.e., substituted ethylenes, are also carcinogenic for adult animals, and can with confidence likewise be predicted to be effective transplacental carcinogens.

show abstract

Metabolic activation/deactivation reactions during perinatal development.

Cited by 28 publications

References 53 publications

Comparison of DNA adduct levels in human placenta from polychlorinated biphenyl exposed women and smokers in which CYP 1A1 levels are similarly elevated

Comparison of DNA adduct levels in human placenta from polychlorinated biphenyl exposed women and smokers in which CYP 1A1 levels are similarly elevated

Daidzein: Bioavailability, Potential for Reproductive Toxicity, and Breast Cancer Chemoprevention in Female Rats

Prenatal susceptibility to carcinogenesis by xenobiotic substances including vinyl chloride.

Contact Info

Product

Resources

About