Corn and corn-derived products: sources of endocrine disruptors.

Markaverich et. al (2002a, 2002b) recently reported the recovery of a mitogen from corn that disrupts sexual behavior and completely blocks estrous cyclicity in rats at 0.32 mg/kg/day. The agent is a tetrahydrofuran diol (THF-diol) that also stimulates proliferation of prostate cancer cells and estrogen-dependent and -independent breast cancer cells in micromolar concentrations. It does not appear to exert its effects through the estrogen receptor, as it does not cause uterine hypertrophy. The authors speculated that the agent interferes with normal functioning of the hypothalamic--pituitary--ovarian axis. The compound is recoverable from corn cobs, whole corn kernels, and corn tortillas.

Evidence of estrogenic activity in corn oil was reported more than 40 years ago (Booth et al. 1960). This study concluded that dietary administration of oils obtained from corn, peanuts, olives, soybeans, coconuts, and rice bran increased uterine weight in mice. A 1986 study was unable to reproduce these results with corn, safflower, sunflower, or soya-bean oil (Bieber 1986). In this study, however, the control diet contained 75% corn starch and 0.5% corn oil. Test oils were substituted for corn starch at 5% or 20% of the diet.

In a study in mice, Thigpen et al. (1987) reported stimulation of uterine growth in mice by dextrose, sucrose, corn starch, corn oil, and soybean oil. Using diethylstilbestrol (DES) as a positive control, investigators determined that the relative potency of the test compounds was DES 4 ppb < sucrose < soybean oil < corn starch < dextrose < corn oil < DES 6 ppb. These results suggest that the conclusions of the 1986 study of vegetable oils (Bieber 1986) may have been influenced by the use of corn starch as a "negative" control. Other studies have also reported estrogenic activity in cane and beet molasses (Feldman et al. 1995; Miller et al. 1986).

Many plants contain estrogenic isoflavones, but they have not been specifically identified in corn that is not genetically modified. Yet, the studies cited above show that estrogenic and other endocrine-disrupting compounds are present in corn and cornderived products, as well as other sweeteners in the human diet, though mechanistic understanding of effects is incomplete.

Some authors suggest that the n-6 fatty acid content of corn oil plays an important role in its developmental impacts. Hilakivi-Clarke et al. (1997) reported that pregnant rodents given a diet with 45% versus 15-20% of calories coming from corn oil gave birth to female offspring with earlier onset of puberty, altered mammary gland development, and increased mammary cancer risk after exposure to a carcinogen. In humans, the influence of maternal diet on breast cancer risk among daughters is of increasing concern (Hilakivi-Clarke et al. 1999).

The potential health impacts of estrogenic and other endocrine-disrupting substances present in corn, corn-derived products, and sweeteners deserve attention. Many food products contain high fructose corn syrup. Corn starch, corn oil, and corn cob bedding are used in laboratory animal studies and may be influencing results in undetected ways. Corn oil, often used as a negative control and as a vehicle for administering test substances, may have biological effects that influence outcomes and data interpretation. It is important for researchers to take this into account. Many questions remain unanswered, including the identity of the substances with hormonal activity, their origin, whether they are present in all corn hybrids, and the impact of refinement processes. The widespread use of corn oil, high fructose corn syrup, and other sweeteners in human diets lends a sense of urgency to further investigation.

The author declares he has no conflict of interest.

REFERENCES

Bieber M. 1986. Lack of oestrogen-like activity in commercially refined vegetable oils. Food Chem Toxico124(3):251-253.

Booth A, Bickoff E, Kohler G. 1960. Estrogen-like activity in vegetable oils and mill by-products. Science 131:1807-1808.

Feldman D, Krishnan A. 1995. Estrogens in unexpected places: possible implications for researchers and consumers. Environ Health Perspect 103(suppl 7):129-133.

Hilakivi-Clarke L, Clarke R, Lippman M. 1999. The influence of maternal diet on breast cancer risk among female offspring. Nutrition 15(5):392-401.

Hilakivi-Clarke L, Clarke R, Onojafe I, Raygada M, Cho E, Lippman M. 1997. A maternal diet high in n-6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring. Proc Natl Acad Sci USA 94(17):9372-9377.

Markaverich B, Alejandro M, Markaverich D, Zitzow L, Casajuna N, Camarao N, et al. 2002a. Identification of an endocrine disrupting agent from corn with mitogenic activity. Biochem Biophys Res Commun 291:692-700.

Markaverich B, Mani S, Alejandro MA, Mitchell A, Markaverich D, Brown T, et al. 2002b. A novel endocrine-disrupting agent in corn with mitogenic activity in human breast and prostatic cancer cells. Environ Health Perspect 110:169-177.

Miller S, Bottema C, Stathis PA, Tokes LG, Feldman D. 1986. Unexpected presence of estrogens in culture medium supplements: subsequent metabolism by the yeast Sacchromyces cerevisiae Endocrinology 119:1362-1369.

Thigpen J, Lebetkin E, Dawes M, Richter C, Crawford D. 1987. The mouse bioassay for the detection of estrogenic activity in rodent diets: III. Stimulation of uterine weight by dextrose, sucrose, and corn starch. Lab Animal Sci 37(5):606-609.

Ted Schettler

Boston Medical Center Science and Environmental Health Network Boston, Massachusetts E-mail: [e-mail]