Hypothesis

Is Bisphenol A a Weak Carcinogen like the Natural Estrogens andDiethylstilbestrol?

Ercole L. Cavalieri1,2 and Eleanor G. Rogan1,21Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center,986805 Nebraska Medical Center, Omaha, NE2Department of Environmental, Agricultural and Occupational Health, College of Public Health,University of Nebraska Medical Center, 985110 Nebraska Medical Center, Omaha, NE

Summary

Bisphenol A (BPA) displays weak estrogenic properties andcould be a weak carcinogen by a mechanism similar to that of es-trone (E1), estradiol (E2) and the synthetic estrogen diethylstil-bestrol, a human carcinogen. A wide variety of scientific evidencesupports the hypothesis that certain estrogen metabolites, pre-dominantly catechol estrogen-3,4-quinones, react with DNA tocause mutations that can lead to the initiation of cancer. One ofthe major pathways of estrogen metabolism leads to the 4-cate-chol estrogens, 4-OHE1(E2), which are oxidized to their quinones,E1(E2)-3,4-Q. The quinones react with DNA to form predomi-nantly the depurinating adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua. This process constitutes the predominantpathway in the initiation of cancer by estrogens. One pathway ofBPA metabolism is hydroxylation of one of its symmetric ben-zene rings to form its catechol, 3-OHBPA. Subsequent oxidationto BPA-3,4-quinone would lead to reaction with DNA to formpredominantly the depurinating adducts 3-OHBPA-6-N3Ade and3-OHBPA-6-N7Gua. The resulting apurinic sites in the DNAcould generate mutations in critical genes that can initiatehuman cancers. The catechol of BPA may also alter expressionof estrogen-activating and deactivating enzymes, and/or competewith methoxylation of 4-OHE1(E2) by catechol-O-methyltransfer-ase, thereby unbalancing the metabolism of estrogens to increaseformation of E1(E2)-3,4-Q and the depurinating estrogen-DNAadducts leading to cancer initiation. Thus, exposure to BPAcould increase the risk of developing cancer by direct and/orindirect mechanisms. Knowledge of these mechanisms wouldallow us to begin to understand how BPA may act as a weak car-cinogen and would be useful for regulating its use. � 2010 IUBMB

IUBMBLife, 62(10): 746–751, 2010

Keywords estrogens; bisphenol A as carcinogen; molecular mecha-

nism of cancer initiation; catechol estrogen; catechol qui-

nones.

Bisphenol A (BPA) and diethylstilbestrol (DES) were syn-

thesized in the 1930’s as potential inexpensive synthetic estro-

gens. BPA, however, displayed very weak estrogenic properties.

It was rediscovered by polymer scientists and utilized as the

building block of polycarbonate plastic and in the manufacture

of epoxy resins and other plastics such as polyester and styrene.

The worldwide production of BPA is greater than 6 billion

pounds per year, and more than one million pounds of BPA are

released into the atmosphere per year in the U.S. BPA can con-

taminate food by leaching from plastic packaging when it is

heated or gets old. Adverse effects have been observed in ex-

perimental animals exposed to low doses of BPA (1). BPA was

detected in 93% of 2517 urine specimens from a broad national

sample of adults (2), indicating that exposure to BPA is perva-

sive throughout the U.S. population.

BPA could be a weak carcinogen by a mechanism of activa-

tion similar to that of the natural estrogens (3, 4) and the human

carcinogen diethylstilbestrol (5, 6). This line of reasoning builds

on the basic principles of chemical carcinogenesis established

by James and Elizabeth Miller in the 1960’s (7, 8). Experiments

on estrogen metabolism (9–15), formation of DNA adducts (12–

21), mutagenicity (3, 22–25), cell transformation (26–29) and

carcinogenicity (30–33) led to and support the hypothesis that

reaction of specific estrogen metabolites, mostly E1(E2)-3,4-qui-

none, with DNA by 1,4-Michael addition can generate the criti-

cal mutations to initiate breast, prostate and other human can-

cers (3, 4). The major initiating pathway is illustrated in Fig. 1.

E1 and E2 can be metabolically converted to 4-hydroxyE1(E2)

[4-OHE1(E2)] by cytochrome P540 (CYP)1B1. Oxidation of

these catechol estrogens leads to the corresponding E1(E2)-3,4-Q.

These quinones can react with DNA to form small amounts (1%)

Address correspondence to: Ercole L. Cavalieri, Eppley Institute for

Research in Cancer and Allied Diseases, University of Nebraska Medi-

cal Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805,

USA. Tel.: 402-559-7237. Fax: 402-559-8068.

E-mail: ecavalie@unmc.edu

Received 13 July 2010; accepted 5 August 2010

ISSN 1521-6543 print/ISSN 1521-6551 online

DOI: 10.1002/iub.376

IUBMB Life, 62(10): 746–751, October 2010

of stable adducts (not shown), which remain in DNA unless

removed by repair, and predominant amounts (99%) of the depu-

rinating adducts 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua

(Fig. 1), which detach from DNA, leaving behind apurinic sites

(20). Errors in the repair of these sites can lead to the critical

mutations initiating breast, prostate and other human cancers (3,

22–25). We think this process constitutes the predominant path-

way in the initiation of cancer by estrogens. The effects of this

pathway of cancer initiation can be seen in the relatively high

levels of depurinating estrogen-DNA adducts in urine samples

not only from women with breast cancer, but also women at

high risk for the disease, as identified by the Gail model score

(Fig. 2) (13, 14).

Analogously, the human carcinogen DES is metabolized to

its catechol, and then oxidized to its quinone, which can react

with DNA to form the 30-OHDES-60-N3Ade and 30-OHDES-60-N7Gua adducts (Fig. 3) (6), which correspond to the depurinat-

ing estrogen-DNA adducts (Fig. 3). Therefore, the common

Figure 1. Major metabolic pathway in cancer initiation by estrogens.

Figure 2. Levels of estrogen-DNA adducts in urine samples from women at normal-risk or high-risk for breast cancer or with the

disease. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

747IS BPA A WEAK CARCINOGEN?

Figure 3. Common pathways of metabolic activation for natural estrogens, diethylstilbestrol, and bisphenol A.

748 CAVALIERI AND ROGAN

denominator of tumor-initiation by the synthetic estrogen DES

and the natural estrogen E2 is formation of their catechol qui-

nones, which react with DNA to afford the depurinating N3Ade

and N7Gua adducts.

POSSIBLE MECHANISMS OF CANCERINITIATION BY BPA

One major pathway of BPA metabolism is hydroxylation of

one of its symmetric rings to form its catechol, 3-OHBPA (Fig.

3) (34, 35). Subsequent oxidation to the electrophilic BPA-3,4-

Q would lead to its reaction with DNA to form predominantly

the depurinating adducts 3-OHBPA-6-N3Ade and 3-OHBPA-6-

N7Gua (Fig. 3). The N7Gua adduct has already been obtained

by reaction of BPA-3,4-Q with DNA (36, 37). The resulting

apurinic sites in the DNA could generate mutations in critical

genes that may initiate breast and other human cancers. The

same mechanism for metabolic activation has been elucidated

not only for the natural estrogens, E1 and E2, and DES (Fig. 3),

but also for several other carcinogens. These include the leu-

kemogen benzene (38, 39), the weak carcinogen naphthalene

(40), and the synthetic estrogen hexestrol (41).

In addition to forming DNA adducts itself, BPA may act

indirectly by imbalancing estrogen metabolism, such that

increased levels of depurinating estrogen-DNA adducts are

formed. These effects could be additive, increasing even further

the risk of BPA to initiate cancer. The first indirect mechanism

would entail the catechol of BPA as a possible competitive in-

hibitor of the methoxylation of 4-OHE1(E2) by the protective

enzyme catechol-O-methyltransferase (COMT) (Fig. 4), analo-

gously to quercetin (42). This event would increase further the

levels of depurinating estrogen-DNA adducts that could lead to

mutations that initiate cancer.

The second indirect mechanism concerns the four key

enzymes CYP19 (aromatase), CYP1B1, COMT, and NQO1

(quinone reductase) that maintain the balanced estrogen metabo-

lism (Fig. 4). Under normal conditions, metabolism of estrogens

is balanced, and formation of estrogen-DNA adducts is rela-

tively low, as seen in women at normal risk for breast cancer

(Fig. 2) (13, 14). The primary circulating estrogen is E2, which

is produced by conversion of testosterone to E2 by aromatase,

CYP19. E1 and E2 are metabolized by two major pathways: for-

mation of catechol estrogens, 2-OHE1(E2) (not shown in Fig. 4)

and 4-OHE1(E2) (Fig. 4), and 16a-hydroxylation (not shown in

Fig. 4). The most common pathway of conjugation to inhibit

catechol estrogen oxidation occurs by O-methylation catalyzed

by COMT (12, 16, 43). If the expression of CYP19 and/or

CYP1B1 is increased by the presence of BPA, this could

increase the formation of E1(E2) and/or 4-OHE1(E2), respec-

tively, and could result in higher levels of estrogen-DNA

adducts (Fig. 4). If BPA represses expression of NQO1, this

would also result in higher levels of quinones and increased

likelihood of forming the estrogen-DNA adducts. Therefore, it

is possible that BPA could affect the risk of initiating cancer

through imbalances in the metabolism of estrogens.

POSSIBLE CARCINOGENICITY OF BPA IN HUMANS

From all of our studies conducted with the natural estrogens

E1 and E2, the synthetic estrogens DES and hexestrol, benzene

Figure 4. Formation, metabolism, and DNA adducts of 4-catechol estrogens. Activating enzymes and depurinating DNA adducts are in

red and protective enzymes are in green. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

749IS BPA A WEAK CARCINOGEN?

and naphthalene, it is evident that the mechanism of metabolic

activation that leads to their cancer initiation is the formation of

catechols, their oxidation to their respective quinones, and reac-

tion of these electrophilic compounds with DNA at the N-3 of

Ade and N-7 of Gua by 1,4-Michael addition. We knew that all

of the above compounds had weak carcinogenic activity when

we studied their mechanism of metabolic activation. By demon-

strating that BPA has the same mechanism of metabolic activa-

tion as the above compounds, we will gain initial evidence that

BPA could be an extremely weak human carcinogen. Once we

have established the formation of BPA-DNA adducts, we plan

to pursue further studies to investigate the possible weak carci-

nogenicity of BPA. In our opinion, studies with animal models

would be fruitless, because BPA is at most an extremely weak

carcinogen and would not induce tumors within the animal’s

lifetime. For example, the carcinogenic activity of naphthalene

was studied for more than 50 years, and the results were nega-

tive until Abdo et al., found that lifetime treatment of rats by

inhalation of naphthalene vapors induced nasal tumors in 10%

of the animals (44). Additional evidence for the possible carci-

nogenicity of BPA could be obtained by studies of human cell

transformation, as conducted by Russo et al. and in our labora-

tory, with E2 and 4-OHE2 (26–29). In fact, Fernandez and

Russo have recently reported that BPA induces cell transforma-

tion of the MCF-10F human breast epithelial cells (45). In addi-

tion, spot urine samples could be collected from people, in par-

ticular those known to have higher exposure to BPA, and ana-

lyzed for the presence of the two depurinating BPA-DNA

adducts. In conclusion, since 93% of people studied had BPA

present in their urine (2), positive results from the proposed

studies would indicate that exposure to BPA should be elimi-

nated from the environment.

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