Phosphate Overload Inhibits Female Fertility in Mice
Dickson, Addie Smith
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Phosphate (Pi) is a mineral that is essential for life and is found in many important biological molecules as well as comprising the structural material of bone and teeth. However, when animals fail to excrete ingested Pi, Pi overload occurs. Pi overload causes hyperphosphatemia associated with multiple aging-like phenotypes, including infertility. We have employed two mouse models to study the effects of Pi overload on female fertility. The first model is Klotho mutant mice, which suffer Pi overload due to decreased renal Pi excretion. The second model is wild-type mice fed a high Pi diet, which develop Pi overload due to increased intestinal Pi absorption. Both mouse models of Pi overload are infertile, do not undergo proper puberty, do not ovulate, and have hypotrophic uteri. These animals have aberrant hypothalamic-pituitary-gonadal (HPG) axis function typified by low expression of Kiss1 mRNA in the hypothalamus, altered serum luteinizing hormone (LH) levels, and low mRNA expression of steroidogenic enzymes in the ovary. However, the HPG axis in these animals appears to be functional if stimulated with the proper hormonal cues. Estradiol administration stimulates Kiss1 expression in the anteroventral periventricular nucleus while inhibiting Kiss1 expression in the arcuate nucleus of the hypothalamus. Acute administration of Kisspeptin-10 elicits an LH surge. Additionally, gonadotropin administration induces ovulation. These results suggest that the HPG axis in female mouse models of Pi overload is capable of proper function but that upstream hormonal cues may be absent in these mice. We propose that low Kiss1 expression is the primary cause of HPG axis dysfunction in these mice since it is a master regulator of puberty onset in females. Our models of Pi overload-induced female infertility may serve as a novel rodent model system in which to study sexual dysfunction and hormonal aberrations in women and children with chronic kidney disease who suffer from Pi overload due to decreased renal Pi excretion.