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.
Zhang. Yajie Y; Cao. Xinyuan X; Chen. Lin L; Qin. Yaoyao Y; Xu. Ye Y; Tian. Ying Y; Chen. Ling L
Key Findings
- PFOA exposure (≥2 mg/kg) increases hepatic and circulating FGF21 via PPARα activation.
- Elevated FGF21 reduces kisspeptin expression in the AVPV and vasopressin in the SCN, blunting the LH surge and causing ovulation failure.
- Blocking PPARα (GW6471) or FGF21 (PD173074), or directly administering kisspeptin‑10, rescues kisspeptin/vasopressin levels, restores the LH surge, and normalizes the estrous cycle.
Practical Outcomes
- For biohackers, the study highlights that environmental PFAS chemicals can disrupt reproductive hormones through a liver‑brain signaling loop. While kisspeptin‑10 can reverse these effects in mice, human dosing and safety are unknown, so the immediate takeaway is to minimize PFAS exposure rather than rely on kisspeptin supplementation for fertility support.
Summary
In mice, a chemical called PFOA (found in some household products) raises liver levels of a hormone called FGF21, which then suppresses kisspeptin in the brain and leads to messed‑up ovulation and longer non‑fertile cycles. Giving the mice a kisspeptin‑10 peptide (or blocking the FGF21 pathway) restores normal hormone spikes, ovulation, and cycle timing.
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<sup>-1</sup> ) 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<sup>-1</sup> ) 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.
Study Information
pubmed
2020
2020-04-19T00:00:00.000Z
10.1111/jne.12848
22
67