Prenatal exposure to diethylstilbestrol has long-lasting, transgenerational impacts on fertility and reproductive development

Abstract

Significant decreases in fertility have been observed over the past 50 years, with female conception rates dropping by 44% and male sperm counts decreasing by over 50%. This dramatic decrease in fertility can be attributed in part to our increasing exposure to endocrine disrupting chemicals (EDCs). Diethylstilbestrol (DES) is an estrogenic EDC that was prescribed to millions of pregnant women between 1940 and 1970 and resulted in detrimental reproductive effects in the offspring that were exposed in utero. Women who were exposed to DES in utero experienced higher rates of infertility, pregnancy complications, and reproductive cancers. Alarmingly, there is evidence to suggest that these effects may persist in the grandchildren and great grandchildren of exposed women. To define the transgenerational reproductive impacts in females following exposure to DES, gestating mice were exposed to DES and the effects monitored in the female descendants across 3 generations. There was a trend for reduced pregnancy rate and fertility index seen across the generations and moreover, the anogenital distance (AGD) was significantly reduced up until the third, unexposed generation. The onset of puberty was also significantly affected, with the timing of vaginal opening occurring significantly earlier in DES descendants. These results indicate a transgenerational effect of DES on multiple reproductive parameters including fertility, timing of puberty, and AGD. These data have significant implications for more than 50 million DES descendants worldwide as well as raising concerns for the ongoing health impacts caused by exposures to other estrogenic EDCs which are pervasive in our environment.

Keywords: DES; EDC; fertility; transgenerational.

Figure 1.

Schematic representation of DES exposure. The F0 female is exposed to DES every second day from days 9 to 17 of gestation. The F1 has a direct fetal exposure to DES and develops in an altered hormonal environment. The F2 is exposed as germ cells within the F1 fetus, and the F3 generation has no direct exposure to DES and is the first transgenerational generation.

Figure 2.

The effects of prenatal DES exposure on fertility related indices in the F1, F2, and F3 generation. The mating index (A), pregnancy rate (B), fertility index (C), and gestational index (D) are represented.

Figure 3.

The effect of prenatal DES exposure on oocyte number. **p < .01.

Figure 4.

The effects of prenatal DES exposure on litter size (A) and pup death percentage (B). ***p < .001.

Figure 5.

Prenatal DES exposure leads to earlier timing of vaginal opening across multiple generations and doses. *p < .05; **p < .01; ***p < .001.

Figure 6.

DES exposure did not impact body weight (A) but did significantly reduce the AGD across multiple generations and doses (B). *p < .05; **p < .01; ***p < .001; ****p < .0001.