Environmental and Molecular Mutagenesis - Legacy Tobacco ...

12 1989 EMS Abstracts 7
THEORETICAL BASIS OF THE TRANSPLACENTAL CARCINOGENICITY AND TERATOGENICITY OF DIMETHY-
LNITROSAMINE AND N-ETHYL-N-NITROSOUREA . Dunstan A .A . Akintonwa, Department of Biochemistry,
College of Medical Sciences, University of Calabar, Calabar - Nigeria .
Dimethylnitrosamine and N-ethyl-N-nitrosourea are mutagens in the Ames test and they
are carcinogens whilst thalidomide is a teratogen and neither a mutagen nor a carcinogen
. The evidence that nitrosamines are not active in transplacental carcinogenesie
except when administered late in pregnancy has been challenged . Mechanism of transplacental
carcinogenesis of dimethylnitrosamine (DMNA) and N-ethyl-N-nitrosourea (ENU)
has been presented based on the presence of monooxygenases (EC1 .14 .14 and EC1 .14 :15)
and smooth endoplasmic reticulum and rough endoplasmic reticulum in 13 week and 16
week old human foetal livers . Plausible mechanism for the teratogenicity of ENU based
on chelating propensity of its metabolites has been presented . Probable mechanism for
the basis of the2#eratogenicity 21 a metabolite of thalidomide based on chelation
with calcium (Ca ) and zinc (Zn ) comparable to similare chelation of ethylene
diaminetetraacetate (EDTA) has also been presented . From the molecular basis of carcinogenesis
and teratogenesis DMNA was found to be negative (-) as a theoretical (T)
and experimental (E) traneplacental carcinogen in rodent and (-) and positive (+) for
T if the maternal metabolite or the intact DMNA passes through the placenta respectively
and not known (?) for (E) in human . For ENU, (+) for (T) and (E) in rodent
and (+) for (T) and (?) for (E) for human . In terstogenesis for DMNA, (-) for (T) and
(E) in rodent and (-) for (T) and (?) for (E) in human were obtained . Por ENU, (+)
for (T) and (E) in rodent and (+) and (?) for (T) and (E) respectively were obtained .
13
COMPARISON OF CTTOGBNETIC, SPRT uD GLLCOP80RIN A 8?UDIL9 IN A-B01D $URYIYORS
Mitoshi Akiyama, M .D .,?, Seishi Hyoisumi, Ph .~ .,1, Yuko Hirai, Ph .D .?,
Masayuki Hakoda, M .D .,1, Nori Nak~aura, Ph .D . and Akio A . Awa, Ph .D .
Department of Radiobiology and Department of Genetics,
Radiation Effects Research Foundation, Hiroshima 732, Japan
It is well known that somatic mutation are induced by various environmental
genotoxic substances including ionizing radiation . At present, only a few methods
are available for measuring the frequency of in vivo mutants in human somatic
cells . One such method is to detect the mutant lymphocytes lacking HPRT, and
second method is to detect the variant erythrocytes lacking surface protein,
glycoprotein A (GPA), third is the HLA somatic mutation method recently developed
by Morley et al . The frequencies of somatic mutation were measured by using the
former two methods in atomic bomb survivors in Hiroshima, and were found to be
significantly correlated with the DS 86 estimated dose and, as well, to the
chromosome aberration frequency of lymphocytes, respectively . However, the
variant frequency from HPRT and GPA study are not correlated significantly with
each other . One possible reason for this lack of correlation may be in the fact
that the lymphocytes bearing sex-linked HPRT mutations, presumably large
deletions (based on other studies) ∎ay have been at greater selective
disadvantage than erythrocytes containing glycophorin mutations .
14
hurt MUTATIONS IN VIVO IN HUMAN T-LYMP110CYTES : FREQUBNCIES, SPECTRA AND CLONALITY, R .J .
Albertini, J .P . O'Neill, J .A . Nicklas, M .J . McGinniss, L . Recio, and T .R . gkopek, VRCC
Genetics Lab, Univ . of Vermont . Burlington, VT and CIIT, Research Triangle Park, NC .
hort mutations in vivo in human T-lymphocytes reveal (i) mutant frequency values, (!i)
v v mutational spectra, (iii) pra- versus post-thymic origin of the !n vivo mutations
and (iv) clonality of )= mutants . Mean mutant frequency values differ by ten-fold
between newborns and young adults, being 0 .64 t 0 .41 x 10-6 for 45 placental blood samples
and 6 .5 ± 4 .8 x 10-6 for a large cohort of adults . h= mutational spectra also differ
between newborns and adults ; more than 85% of the newborn mutations show deletions of h=
exons 2 and 3 while only 151 of 326 b= mutants from normal adults show b= structural
alterations detectable by Southern blot analyses . In adults, no type of alteration
predominates . Deletions are common and deletion breakpoints are distributed randomly
along the length of the gene . Direct sequencing studies of adult b= mutants are
determining the actual mutations tn mutants with normal Southern blots . bQ=j, mutations
in newborns and adults differ also in their cells of origin with those recovered from
newborns tending to arise in pre-thymie cells while those recovered from adults tending
to arise in post-thymic T-cells . Iterative analyses of 1)= alterations and TCR gene
rearrangement patterns in wild type and b= mutant isolates from adults reveal clonality
among the mutant but not the wild type isolates . •Doublets•, 'triplets' and higher orders
of clonality are routinely observed among an individual's recovered mutants . This has
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Notes