Myths about endocrine disruption and the male reproductive system should not be propagated

Kristina Thayer1,3 and Frederick S. vom Saal2

1 Wildlife and Contaminants Program, World Wildlife Fund, 1250 24th Street, NW Washington, DC 20036 and 2 114 Lefevre Hall, Division of Biological Sciences, University of Missouri, Columbia, MO 65211, USA

Dear Sir,

We find the response by Mike Joffe to our article showing that fetal exposure to sub-clinical doses of ethinyl estradiol (EE) alters development of the prostate and testes in male mice perplexing on a number of counts.

First, Joffe challenges the statement we made in the introduction of our paper concerning the proportion of pregnant women who become pregnant while using oral contraceptives. In a recently published guide for physicians concerning the use of oral contraceptives (Dickey, 1998Go), the `typical' pregnancy rate for both combination oral contraceptives and progestin-only oral contraceptives is presented as 3% for women of all ages. In discussing the number of live births, Joffe appears to neglect the issue of elective abortion and how many women who are using oral contraceptives and experience an unintended pregnancy are choosing not to carry the fetus to term.

Second, in our paper we were very cautious concerning the relationship between the effects we observed due to exposure to low doses of ethinyl estradiol and effects due to fetal exposure to very high doses of the drug diethylstilboestrol (DES), which was prescribed to millions of pregnant women in the 1950s and 1960s. In particular, we pointed out that studies of `DES sons' have involved many fewer cases than were followed for `DES daughters', thus limiting our ability to draw strong conclusions from the studies of DES sons. We thus feel that Joffe does not accurately portray our view of the literature regarding effects of DES in men. We recently reviewed this literature (Swan and vom Saal, 2001Go), and urge readers to reject the suggestion at the end of Joffe's letter that based on these small studies with limited power, the medical community should conclude that there is `strong evidence' of no harm due to fetal exposure to DES in males, while females were severely affected. This conclusion of harm to females but not males is certainly not consistent with an extensive literature concerning developmental exposure to DES in experimental animals, where evidence for adverse developmental effects of DES in both males and females is clear and convincing (Newbold, 1995Go). What is also clear and convincing is that effects of DES in mice are very similar to effects in humans, and it is odd that Joffe avoids any mention of this extensive literature from experimental animal studies. Importantly, our findings concerning developmental effects of EE in mice are consistent with prior reports (vom Saal et al., 1997Go; Gupta, 2000Go) of similar effects of very low doses of DES as well as estradiol.

Third, the title of Joffe's letter concerns a topic that was not the subject of our study, namely, the issue of environmental chemicals that disrupt hormones, called endocrine disruptors. We were certainly surprised to find that our paper on fetal exposure to a drug used by millions of women would be identified as `propagating myths about endocrine disruption'. The issue of endocrine-disrupting environmental chemicals is a highly politicized area of science, as findings have immense implications for the corporations that produce these chemicals. Joffe appears to be more concerned with this issue than with our findings concerning EE. This is possibly because findings regarding effects of very low doses of estrogenic drugs, such as EE, are relevant to the issue of whether exposure during development to low levels of endocrine disrupting chemicals encountered by many human populations might pose a threat to human fetuses. Specifically, in our article in Human Reproduction we reported that a maternal dose of EE (0.002 µg/kg body weight/day) —250-times lower than doses currently used in oral contraceptives—alters development of the testes and prostate in male offspring. There are chemicals used in household products detected in human fetuses that are ~1000-times less potent as estrogens relative to EE. One such chemical is bisphenol A, which is polymerized to make polycarbonate products, such as baby bottles. It is not surprising that a 2 µg/kg/day maternal dose of bisphenol A, which is within the range of exposure of human fetuses (Kuribayashi et al., 1999Go) and 1000-times higher than the active dose of EE, caused the same types of effects as those described for the 0.002 µg/kg/day dose of EE (Nagel et al., 1997Go; vom vom Saal et al., 1998Go; Gupta, 2000Go). Recently, the US National Toxicology Program (NTP) and National Institute of Environmental Health Sciences (NIEHS) conducted an independent and open peer review to evaluate the scientific evidence on low-dose effects of endocrine disrupting chemicals. The final report issued in August 2001 (NTP, N.T.P., 2001Go) states that certain chemicals can have endocrine disrupting effects at low doses. Since the original peer review in October 2000, the literature on low-dose chemicals such as bisphenol A has exploded. For just bisphenol A, additional low dose effect have now been reported on mammary gland (Markey et al., 2001Go), vagina (Schönfelder et al., 2002Go), prostate (Ramos et al., 2001Go), sperm production (Sakaue et al., 2001Go), rate of embryonic development (Takai et al., 2000aGoTakai et al., 2000bGo), and reproductive function in both fish (Arukwe et al., 2000Go; Lindholst et al., 2000Go; Yokota et al., 2000Go; Metcalfe et al., 2001Go; Sohoni et al., 2001Go) and snails (Oehlmann et al., 2000Go). We find it odd that Joffe broadly labels this entire field of science concerning the study of chemicals found in plastics, home-care products, pesticides, building materials, etc. as a `myth', but he does not challenge or even comment on our results concerning similar effects of ethinyl estradiol and these supposedly mythical environmental chemicals.

Notes

3 To whom correspondence should be addressed. E-mail: kristina.thayer{at}wwfus.org Back

References

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