Exposure of female mice to perfluorooctanoic acid suppresses hypothalamic kisspeptin‐reproductive endocrine system through enhanced hepatic fibroblast growth factor 21 synthesis, leading to ovulation failure and prolonged dioestrus

Abstract

Perfluorooctanoic acid (PFOA) is widely used in household applications. High-dose exposure to PFOA has been associated with increased risks of infertility and premature ovarian insufficiency in woman. PFOA can alter hepatic gene expression by activating peroxisome proliferator-activated receptor α (PPARα). The present study investigated whether exposure to PFOA via PPARα activation alters the synthesis of hepatic fibroblast growth factor 21 (FGF21) to disturb female neuroendocrine and reproductive function. In the present study, we show that the oral administration of PFOA (2 or 5 mg kg -1 ) in adult female mice (PFOA mice) caused prolonged dioestrous, a reduction in the number of corpora lutea and decreased levels of hypothalamic gonadotrophin-releasing hormone, serum progesterone and luteinising hormone (LH).Exposure to PFOA decreased the expression of vasopressin in the suprachiasmatic nucleus (SCN) and kisspeptin in the anteroventral periventricular nucleus (AVPV) with deficits in preovulation or oestrogen-induced LH surge. PFOA via activation of PPARα increased dose-dependently hepatic FGF21 expression, leading to elevated serum and hypothalamic FGF21 concentrations. Treatment of PFOA mice with the PPARα antagonist GW6471 or the FGF21 inhibitor PD173074 rescued SCN vasopressin and AVPV-kisspeptin expression. Either administration of GW6471 and PD173074 or treatment with vasopressin and the G protein coupled receptor 54 agonist kisspeptin-10 in PFOA-mice was able to recover the regular oestrous cycle, ovulation ability, LH surge production and reproductive hormone levels. The present study provides in vivo evidence that exposure to PFOA (≥2 mg kg -1 ) in mice causes down-regulation of the kisspeptin-reproductive endocrine system by enhancing PPARα-mediated hepatic FGF21 expression. The liver-brain reproductive endocrine disorder caused by PFOA exposure may lead to prolonged dioestrous and ovulation failure. K E Y W O R D Sfibroblast growth factor 21, kisspeptin neurones, ovulation, perfluorooctanoic acid, peroxisome proliferator-activated receptor α 2 of 16 | ZHANG et Al.

Fibroblast growth factor 21 in dairy cows: current knowledge and potential relevance

“…In this study, overexpression of FGF21 was accompanied by a suppression of the vasopressinkisspeptin signaling cascade, thereby inhibiting the proestrus surge in luteinizing hormone, leading to ovulation failure and protraction of dioestrus [125]. The observation that an increased FGF21 production induced by administration of perfluorooctanoic acid (PFOA) resulted in ovulation failure and prolonged dioestrus supported a direct effect of FGF21 on reproductive function in mice [126]. Another study however showed that the impaired reproductive function in transgenic female mice with overexpression of FGF21 can be restored by feeding a high fat diet [127].…”

Use of kisspeptin to trigger oocyte maturation during in vitro fertilisation (IVF) treatment

“…Kisspeptin neurons in the hypothalamus play an important role in integrating sex-steroid feedback from the periphery to regulate GnRH secretion ( 12 ). It has been demonstrated that kisspeptin signalling is a requisite for the occurrence of the mid-cycle LH surge and resultant ovulation ( 13 ). When a kisspeptin neutralising antibody was applied to the preoptic area of the hypothalamus containing GnRH neurons physiological ovulation was inhibited ( 13 ).…”

“…It has been demonstrated that kisspeptin signalling is a requisite for the occurrence of the mid-cycle LH surge and resultant ovulation ( 13 ). When a kisspeptin neutralising antibody was applied to the preoptic area of the hypothalamus containing GnRH neurons physiological ovulation was inhibited ( 13 ). Kisspeptin was also shown to induce ovulation to a similar extent as hCG in a super-ovulated rodent model ( 14 ), providing early credence to the potential use of kisspeptin as a trigger of oocyte maturation in women undergoing IVF treatment.…”

Chronic exposure to perfluorohexane sulfonate leads to a reproduction deficit by suppressing hypothalamic kisspeptin expression in mice

“…Our research used eight-week-old female ICR (defined as Institute of Cancer Research) mice, which were purchased from Oriental Bio Service, Nanjing, China. These mice were selected based on another perfluorooctanate (PFOA) model in our department [22]. All mice were housed in the Laboratory Animal Research of Nanjing Medical University, where all the instruments and food were supplied to raise the mice.…”