Perfluorohexane sulfonate (PFHxS) disturbs the estrous cycle, ovulation rate, oocyte cell communication and calcium homeostasis in mice

Perfluoroalkyl substances are man-made chemicals with ample consumer and industrial applications. They are widely used and are resistant to environmental and metabolic degradation. Several studies have evaluated the effects of Perfluorohexane sulfonate on reproduction. However, there are few reports exploring the cell and molecular mechanisms of its toxicity in the ovary. The aim of this study was to investigate the effects of PFHxS exposure on the estrous cycle, ovulation rate, and the underlying mechanisms of action in female mice in vivo. The animals received a single sub-lethal dose of PFHxS (25.1 mg/kg, 62.5 mg/kg) or vehicle and were stimulated to obtain immature cumulus cell-oocyte complexes (COCs) from the ovaries, or superovulated to develop mature COCs. To evaluate oocyte physiology, Gap-junction intercellular communication (GJIC) was analyzed in immature COCs and calcium homeostasis was evaluated in mature oocytes. PFHxS exposure prolonged the estrous cycle and decreased ovulation rate in female mice. Connexins, Cx43 and Cx37, were downregulated and GJIC was impaired in immature COCs, providing a possible mechanism for the alterations in the estrous cycle and ovulation. No morphological abnormalities were observed in the mature PFHxS-exposed oocytes, but calcium homeostasis was affected. This effect is probably due, at least partially, to deregulation of the endoplasmic reticulum calcium modulator, Stim1. These mechanisms of ovarian injury could explain the reported correlation among PFHxS levels and subfertility in women undergoing fertility treatments.