1602

In-utero exposure to aflatoxin in West Africa is especially in parts of Africa and south-east Asia, where two major risk factors have been identified-namely, chronic hepatitis B virus (HBV) infection and aflatoxins.Aflatoxins are potent hepatotoxins and hepatocarcinogens in animals, with a widespread occurrence in foods eaten by man in parts of Africa and Asia. However, their contribution to PHC and other diseases2.3 remains unclear, partly because of the lack of a marker of individual exposure. Using a new immunoassay we report in-utero exposure in a West African population. Fetal exposure could contribute to the high prevalence and early onset of PHC and influence susceptibility to infectious diseases, including hepatitis B and malaria, in this community. The immunoassay reflects exposure in the previous 2-3 months, measuring aflatoxins covalently bound in peripheral blood albumin.4 This protein adduct is formed in hepatocytes after metabolic activation by specific P450 enzymes, and studies in rats show a correlation between the serum albumin adduct and liver DNA adduct levels. 30 pregnant women of mean age 24 years were recruited from the health centre at Basse, eastern Gambia. Upon delivery, sera processed from umbilical cord and maternal venous blood were assayed for the adducts 4 29 (97%) and 21 (70%) cord sera were positive for the aflatoxin-albumin adduct. This high prevalence is consistent with previous observations in children and adults in The Gambias and indicates exposure of the fetal liver to the mutagenic metabolite of aflatoxin. On the basis of the half-life of albumin these levels predominantly reflect exposure during the third trimester. There was a highly significant correlation between adduct levels in maternal venous and matched cord sera (figure; r = 0-52, p=0001) indicating maternal dietary intake to be one important determinant of the level of carcinogen-induced damage in the fetus. There was significant inter-individual variation, which may reflect differences in aflatoxin-metabolising capacity. Since a strong correlation was found for adduct levels in matched maternal venous and placental sera (r=0’97; data not shown) the inter-individual variation is unlikely to result from assay variability. To establish that aflatoxin was activated by fetal liver, demonstration of binding to a protein specific to the fetus, such as ot-fetoprotein, would be required. However, cord adduct levels were up to 10-fold lower than maternal levels, indicating that the albumin adduct does not easily cross the placenta. Cord blood was

SiR,—Primary hepatocellular carcinoma (PHC)

common

judged free from contamination by maternal blood (see figure legend). Thus the adducts in cord blood probably result from fetal metabolism of aflatoxins, and the lower level in cord than in maternal blood may result from lower exposure and/or lower efficiency of fetal metabolism. Unmetabolised aflatoxin in cord blood has been reported.6 Our data provide more substantial evidence of in-utero exposure, indicating the capacity of fetal liver to metabolise aflatoxins. This carcinogen seems to be largely metabolised in the adult liver by the P450 I IIA4 isoenzyme and in fetal liver by the closely related P450 IIIA6, one of the few P450 enzymes specifically expressed in fetal liver.7 Carcinogen exposure of liver cell populations, especially of putative stem cells (such as "oval cells"8), occurring during the differentiation, may be relevant to the carcinogenic process. Aflatoxin exposure in this instance could contribute to the unusually early onset of this disease within this population.9

International Agency for Research on Cancer, 69372 Lyon, France, MRC Laboratories, Fajara, The Gambia, and Family Planning Association of The Gambia, Kanifing, Banjul

C. P. WILD F. N. RASHEED M. F. B. JAWLA A. J. HALL L. A. M. JANSEN R. MONTESANO

1. Bosch FX, Muñoz N. Epidemiology of hepatocellular carcinoma. In: Bannasch P, Keppler D, Weber G, eds. Liver cell carcinoma. Dordrecht: Kluwer Academic, 1989: 3-14. 2. Denning DW. Aflatoxin and human disease. Adv Drug React Acute Poisons Rev 1987, 4: 175-209. 3. Ngindu A, Johnson BK, Kenya PR, et al. Outbreak of acute hepatitis caused by aflatoxin poisoning in Kenya. Lancet 1982; i: 1346-48. 4. Wild CP, Jiang Y-Z, Sabbioni G, Chapot B, Montesano R. Evaluation of methods for quantitation of aflatoxin-albumin adducts and their application to human exposure assessment. Cancer Res 1990; 50: 245-51. 5. Wild CP, Jiang Y-Z, Allen SJ, Hall AJ, Jansen LAM, Montesano R Aflatoxinalbumin adducts in human sera from different regions of the world. Carcinogenesis 1990; 11: 2271-74. 6. Denning DW, Allen R, Wilkmson AP, Morgan MRA. Transplacental transfer of aflatoxm in humans. Carcinogenesis 1990; 11: 1033-35. 7. Kitada M, Taneda M, Ohta K, Nagashima K, Itahashi K, Kamataki T. Metabolic activation of aflatoxin B1 and 2-amino-3-methyl-imidazo[4,5-f]quinoline by human adult and fetal liver. Cancer Res 1990; 50: 2641-45. 8. Sell S. Is there a liver stem cell? Cancer Res 1990; 50: 3811-15. 9. Bah E, Hall AJ, Inskip HM. The first two years of The Gambian National Cancer Registry. Br J Cancer 1990; 62: 647-50.

Deafness and vasculitis SIR,-Your April 24 editorial on Cogan’s syndrome, focuses on the ophthalmic features that are associated with vasculitic vestibuloauditory disease in this rare syndrome.’ We were prompted to open discussion on the presentation of deafness by reporting two

Correlation between aflatoxin-albumin adduct maternal venous and umbilical cord sera.

levels

in

Aflatoxin-albumm assayed essentially as described’* except that for samples albumm was isolated from serum by precipitating immunoglobulin with 05 volumes of saturated ammonium sulphate; a further one volume was added to supernatant before acid precipitation. This modification did not affect positive and negative controls. A small amount of binding to a-fetoprotein in cord blood cannot be ruled out but since this protein is present at concentrations two orders of magnitude less than albumin at parturition any contribution is likely to be minor. Limit of detection 4-5 pg aflatoxin B,-lysme equivalent per mg albumin. Cord blood judged free from contamination with maternal blood because of inability to detect malana-specific IgM AflatoxinB,-Iysine adducts confirmed by high performance liquid chromatography-fluorescence in umbilical cord sample with highest level of albumin adduct. some

illustrative cases of vasculitis. Patient 1-A 65-year-old man had been treated for presumed polymyalgia rheumatica with low-dose corticosteroids for two years. On gradual withdrawal of this medication he had episodic deafness associated with tinnitus and vertigo, which was thought to be due to Meniere’s syndrome. However, on the fourth episode he became profoundly deaf, and on examination proved to have severe bilateral sensorineural deafness, brisk reflexes, upgoing plantars, a possible left seventh cranial nerve lesion, absent gag reflex, and a left twelfth-nerve lesion. He had bullous vasculitic rash on his legs which had developed over two months, and skin biopsy confirmed small vessel leucocytoclastic vasculitis. Magnetic resonance imaging showed an oedematous area in the brain stem, but no abnormality in the eighth cranial nerve was detected. Urinalysis showed glomerular proteinuria, and creatinine clearance was 47 ml/min. Renal biopsy confirmed an aggressive crescentic nephritis and serum cANCA was positive at 1 in 100. White blood cell count (13-2 x 109/1), C3 (1-89 g/1), and C reactive protein (35 mg/1) were raised. There was a mild eosinophilia but Clq binding and immunoglobulin concentration were normal. Intravenous methylprednisolone and oral cyclophosphamide controlled his cutaneous and renal disease but, despite complete recovery of other neurological lesions, he has remained profoundly deaf. Patient 2-A 57-year-old man had mild polyarthritis in 1979. In 1980 he had sensorineural deafness and vertigo, thought to be due to

In-utero exposure to aflatoxin in west Africa.

1602 In-utero exposure to aflatoxin in West Africa is especially in parts of Africa and south-east Asia, where two major risk factors have been ident...
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