|Newbold, RR, E Padilla-Banks, RJ Snyder and WN Jefferson. 2005. Developmental Exposure to Estrogenic Compounds and Obesity. Birth Defects Research (Part A) 73:478–480.
What did they do?
What did they find?
What does it mean?
With obesity becoming a world-wide epidemic, considerable research has attempted to identify its causes. Most scientific attention has focused on the role of excess calories-- especially fast food-- and decreased exercise as the main culprits, although the evidence for both these has recently been judged 'circumstantial.'
Some researchers have suggested that disruption of hormonal processes controlling weight homeostasis may be contributing factors. This study with mice provides a striking example of how exposure in the womb to an estrogen mimic, diethylstilbestrol, (DES), can lead to grotesque obesity in adulthood.
The level of DES required to cause the effect is extremely low... indeed, previous research by Newbold has shown that higher levels of DES induce weight loss. This may become a classic demonstration of non-monotonic dose-reponse curves.
What did they do? Newbold et al. exposed pregnant mice to 1 part per billion DES and then tracked the weights, activity levels and food consumption of their offspring through to adulthood, comparing them to control offspring that were not exposed. Exposure was via subcutaneous injection to the pregnant female on days 9-16 during pregnancy (the period during which major organs are being formed).
What did they find? From birth through to the age of 5 weeks, DES-treated animals did not differ from controls.
Treated animals differed from controls at Week 6 and for all Weeks thereafter (except Week 8).
Using a mouse densitometer on the animals at 16 weeks of age, Newbold et al. calculated that the treated animals had an average of 11.4 grams of fat vs 6.5 grams in the treated animals.
At 16 weeks, treated animals had an average of 27.6% weight in body fat, vs. 20.9% in control animals.
The mouse on the right was exposed to 1 ppb DES in the womb; control animal on left.
Newbold et al. repeated this experiment using genistein, a phytoestrogen in soy. Genistein is less powerful an estrogen that diethelstilbestrol. Newbold et al. found that animals exposed in the womb to a dose of genistein with the same estrogenic potency as 1 ppb DES (50 parts per million of genistein) were significantly heavier than controls at 3 and 4 months of age.
What does it mean? This experiment with mice demonstrates that fetal exposure to very low concentrations of an estrogenic compound can cause grotesque obesity later in life.
The result is significant in four contexts:
(1) It establishes a clear link between exposure to estrogenic substances and disruption of the hormonal control of weight;
(2) It adds to the emerging body of scientific evidence revealing that adult diseases can have origins in the womb;
(3) With the very low dose causing weight gain compared to earlier work showing weight loss caused by higher doses, it becomes a striking example of a non-monotonic dose response curve. The high dose impact of DES does not predict the low dose response.
(4) Recently Calabrese and his coauthors have been advocating the concept of hormesis, arguing that the same chemical can have harmful effects at high doses and beneficial effects at low doses. They emphasize the beneficial effects of 'low-dose stimulation' and even argue that the widespread nature of 'hormetic responses' justifies relaxing public health standards because of their beneficial effects. These experiments with DES, in combination with the earlier results showing weight loss at higher exposure levels, are a clear example of the adverse effects of a chemical that stimulates estrogenic responses.
The levels of DES used as a drug with pregnant women were significantly higher than the low levels used in these experiments (correcting for body weight). As noted above, prior experiments by Newbold show that DES at levels 10x to 100x that used in this experiment produce weight loss in adulthood. Hence it is not possible to test predictions from these experiments using data from DES sons and daughters.
Exposure to synthetic chemicals with estrogenic properties has increased dramatically over the 20th century. One of the most widespread current exposures is to bisphenol A, used to make polycarbonate plastic and other consumer products. Experiments with mice have shown that BPA exposure in the womb causes large increases in post-pubertal weight, and that exposures to very low levels during adulthood can induce insulin resistance. The CDC estimates that 95% of Americans are exposed to bisphenol A at levels within the range of concentrations used in these animal experiments. US exposure has skyrocketed since the early 1970s when the compound reportedly began to be used to make a resin to line food cans. Today approximately 80% of food cans on US supermarket shelves are lined with BPA, and there is considerable migration of BPA into the food within the cans.