Further Development 23.4: DES as an Obesogen

Several endocrine disruptors, including DES and BPA, increase the production of adipose (fat) cells and the accumulation of fat therein. These substances are therefore called obesogens. Newbold and colleagues (2005, 2009) demonstrated that mice treated in utero (during the major periods of organogenesis) or soon after birth with as little as 1 part per billion of DES became significantly fatter later in life. The mice became sensitized early in life by the DES. Later, when the large concentrations of estrogen associated with sexual maturity were secreted, the mice became obese. This obesogenic effect has been seen with other estrogenic endocrine disruptors, including BPA (Rubin et al. 2001; vom Saal et al. 2012).

Another obesogen is tributyltin (TBT). This compound was applied to the hulls of ships as an anti-fouling agent until it was found to be an endocrine disruptor that converts testosterone into estrogen and changes the sex of molluscs living near shipyards (Oberdörster and McClellan-Green 2002). TBT is still used in fungicides, wood preservatives, and heat stabilizers in plastics. When ingested by a pregnant mouse, TBT makes her pups obese. It does this by activating the transcription factor PPARγ (Evans et al. 2004; Janesick and Blumberg 2011, 2012). When activated in the liver, PPARγ activates the genes involved in fat synthesis and storage. TBT not only activates the transcription factor but also appears to demethylate the region of DNA regulating the PPARγ gene, making PPARγ even more abundant in the cell (Grün et al. 2006; Kirschner et al. 2010).

The main developmental effect of TBT’s activation of PPARγ, however, is its effect on mesenchymal stem cells. When it is activated in these stem cells, PPARγ instructs the cells’ descendants to become adipose cells instead of bone or cartilage cells, the two other main derivatives of the mesenchymal stem cell. By altering the commitment of mesenchymal cells toward the adipose fate, TBT causes the embryo to make a larger number of adipose cells, and by activating the fat synthesis and storage genes, it makes the fat cells functional. Estrogen mimics such as DES appear to act in a similar manner, activating the synthesis of PPARγ in mesenchymal stem cells (Hao et al. 2012). If the number of adipose cells at birth is a major factor of adult obesity (see Janesick and Blumberg 2011, 2012), then endocrine disruptors may be an important part of the current epidemic of obesity in the industrialized world. As Newbold and her colleagues (2007) have noted, “No longer can we assume that overweight and obesity are simply personal choices, but we have to consider that complex events including environmental chemicals are contributing to this mounting human health problem.”

Literature Cited

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