Low Phytoestrogen Levels in Feed Increase Fetal Serum Estradiol Resulting in the “Fetal Estrogenization Syndrome” and Obesity in CD-1 Mice

Abstract

BackgroundAlthough estrogenic chemicals can disrupt development of the reproductive system, there is debate about whether phytoestrogens in soy are beneficial, benign, or harmful.ObjectivesWe compared reproductive and metabolic characteristics in male and female mice reared and maintained on non-soy low-phytoestrogen feed or soy-based high-phytoestrogen feed.MethodsThe low-phytoestrogen diet was non-soy PMI 5K96 (verified casein diet), and the high-phytoestrogen diet consisted of soy-based PMI 5008 during pregnancy and lactation and soy-based PMI 5001 maintenance feed after weaning.ResultsIn fetuses whose mothers consumed the low-phytoestrogen PMI 5K96 feed, we found a paradoxical significant elevation in endogenous serum estradiol, which was associated postnatally with adverse reproductive outcomes referred to as the “fetal estrogenization syndrome (FES)”. In females, this syndrome included early puberty and increased uterine responsiveness to estrogen, and in males, it included reduced testis, epididymis, and seminal vesicle size, but an enlarged prostate. The low-phytoestrogen–fed males and females were lighter at birth, but, between weaning and adulthood, they became obese and developed abnormally high serum leptin levels; these males, but not females, showed impaired glucose regulation.ConclusionsRemoving phytoestrogens from mouse feed produces an obese phenotype consistent with metabolic syndrome, and the associated reproductive system abnormalities are consistent with FES due to elevated endogenous fetal estradiol. Laboratory rodents may have become adapted to high-phytoestrogen intake over many generations of being fed soy-based commercial feed; removing all phytoestrogens from feed leads to alterations that could disrupt many types of biomedical research.

Withdrawal of dietary phytoestrogens in adult male rats affects hypothalamic regulation of food intake, induces obesity and alters glucose metabolism

“…The high levels of fasting glucose combined with elevated circulating insulin, the consequent high HOMA index and the altered ipGTT reflect that removing phytoestrogens from the diet may induce insulin resistance and diabetes. These results are in agreement with other authors (Ruhlen et al, 2008), who reported that 3 months old male rats exposed to a low phytoestrogen diet from gestation presented impaired glucose clearance compared with males fed a phytoestrogen rich diet. Cederroth et al (2008) reported that dietary phytoestrogens improve glucose metabolism via activation of AMPK, a major sensor of energy status.…”

“…In the present study, male rats that stopped receiving dietary phytoestrogens in adult life displayed significantly increased adipose tissue and body weights compared to HP fed animals. These results are consistent with Ruhlen et al (2008) and Cederroth and Nef (2009a), who reported that removing phytoestrogens from rodent feed during pregnancy and lactation in CD-1 mice produces an obese phenotype in the litter and impairs glucose tolerance. Our work demonstrates for the first time that if male rats consume phytoestrogens until they reach adult life, when the feed is replaced by a low phytoestrogen diet, an obese phenotype with alterations in glucose metabolism emerges.…”

“…As a consequence, experimental animals have been bred and maintained for many generations on soy-containing feed, thus driving selection for traits that allow them to tolerate the relatively high levels of phytoestrogens present in commonly used commercial feeds (Ruhlen et al, 2008). This fact focused our interest on the effects of a commercial diet as a relevant model of phytoestrogen intake, rather than exposing animals to pure phytoestrogens, which would represent a more controlled but less pertinent experimental design.…”

“…LP and HP diets were equivalent in terms of carbohydrate, protein and fat content. Considering reports that the absence of dietary phytoestrogens during pregnancy resulted in obesity during later adulthood in mice (Ruhlen et al, 2008), the last group was fed the same HP diet supplemented with 25 g of lard per 100 g of food as a source of dietary fat [high phytoestrogen-high fat (HP-HF)]. This has been widely reported as a useful model to induce obesity and metabolic syndrome (Buettner et al, 2006).…”

Soybean Phytoestrogens – Friends or Foes?

“…Some studies on rats and mice demonstrated increased testicular weight when animals were treated with soy diet or isoflavone supplements during gestation and lactation or continuous exposure, similar to the effect described above in marmosets treated with soy infant formula during infancy (Akingbemi et al, 2007;McVey et al, 2004;Piotrowska et al, 2011;Ruhlen et al, 2008;Wisniewski et al, 2005). Other authors reported a decrease (Atanassova et al, 1999;Wisniewski et al, 2003) or no effect on testicular weight (Fielden et al, 2003;Kang et al, 2002).…”