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September 2005, Vol. 11, No. 3 Biomedicine A recent, much-publicized study highlighted the adverse effects that prenatal exposure to chemicals known as phthalates has on the genital development of male infants. Population Council biomedical researchers are now studying the effect of prepubertal exposure to these chemicals on the onset of male puberty. They have found that exposure to low levels of the chemicals can alter levels of a number of sex hormones, increase the proliferation of cells in the testes, and significantly accelerate the onset of puberty. Phthalates are chemicals used to make plastics—such as those used in food packaging and infant toys—more flexible. They are also used as stabilizers in many common cosmetic products, such as nail polish, shampoo, and lotion. Because they are used so widely, exposure to these chemicals is difficult to avoid. In fact, a recent study by the U.S. Centers for Disease Control and Prevention (CDC) found low but relatively widespread exposure to phthalates among the U.S. population. Levels of 11 of the 12 phthalates for which the CDC tested were higher in children than adults. The most abundant phthalate Many studies of these and other chemicals have been criticized because the studies use very high chemical exposures, much higher than people would likely experience in the normal course of their lives. (Industrial accidents can result in very high exposures to chemicals, but these are rare.) Hardy and his colleagues have made a point of using low, chronic chemical exposures in their experiments. Humans encounter DEHP primarily through residues in foods. “We gave rats DEHP orally in corn oil at levels proportional to those to which humans might be exposed,” explains biomedical scientist Benson T. Akingbemi of Auburn University. Akingbemi was previously a postdoctoral researcher in Hardy’s laboratory. For four weeks or longer, Hardy and his team exposed male prepubertal rats to DEHP. They found that prolonged exposure to DEHP induced high levels of luteinizing hormone (LH), which primarily regulates testosterone levels. Similarly, the researchers found that blood levels of the sex hormones estradiol and testosterone increased by more than 50 percent in exposed rats. Paradoxically, however, testosterone output by individual Leydig cells, which produce the hormone, actually decreased. The rise in blood hormone levels came about because the total number of these hormone-producing cells increased. The number of Leydig cells in rats exposed to DEHP was 40 to 60 percent higher than in control rats. While none of the DEHP rats developed cancer, proliferation of Leydig cells has been implicated in some testicular cancers. Onset of puberty During each of the 28 days of the study, the researchers gave rats either a low oral dose of DEHP in vegetable oil, a high oral dose of the chemical in vegetable oil, or vegetable oil alone. They measured blood testosterone levels in the rats on day 14 and day 28 of the experiment. Although testosterone levels in control rats and in those receiving a low dose of DEHP were the same at day 14, testosterone levels were significantly higher in the low-dose rats at day 28. In contrast, testosterone levels were significantly lower in high-dose rats than in control rats by day 14. By day 28, testosterone levels in high-dose rats had returned to control levels. Moreover, puberty started significantly earlier in rats receiving a low dose of DEHP than in high-dose or control rats. “We think all of these findings fit with the idea that DEHP is an anti-androgen. We propose that DEHP inhibits the production of testosterone by Leydig cells. The lowered testosterone levels signal the brain to release luteinizing hormone,” explained Hardy. “We think that a chronic over-stimulation with LH may cause the proliferation in Leydig cells that we observed. Though individual Leydig cells are producing less testosterone, there are significantly more cells, so the blood testosterone level increases. Thus, our findings indicate that low levels of DEHP may shift the body’s hormonal equilibrium to a higher level as the endocrine system struggles to overcome the anti-androgenic propensities of the chemical. The overall increase in circulating testosterone is sufficient to significantly speed the onset of puberty in male rats.” Source Outside funding See Also
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