Reduction ofKiss1expression in the anteroventral periventricular nucleus is associated with atrazine-induced attenuation of the luteinizing hormone surge in female rats

Abstract

Atrazine, a commonly used herbicide, suppresses the luteinizing hormone (LH) surge in female rats, although the underlying mechanism remains unclear. Kisspeptin, encoded by the Kiss1 gene, is a hypothalamic peptide that controls gonadotropin-releasing hormone (GnRH) release from the GnRH neurons. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) are involved in regulating pre-ovulatory GnRH and LH surge. To clarify the effect of atrazine on the LH surge in female rats, we investigated its effects on hypothalamic GnRH and kisspeptin. Ovariectomized female rats in a high-dose estradiol supplementation model were orally administered vehicle or 100 mg/kg of atrazine once daily for 5 days. This attenuated the LH surge but did not affect baseline LH levels, with no difference in hypothalamic GnRH levels between the vehicle-treated and atrazine-treated animals. After the fifth treatment, subcutaneous administration of kisspeptin (at 0, 0.1, 1, and 10 nmol/kg) induced a dose-dependent LH release almost equivalent in the vehicle- and atrazine-treated animals, suggesting that GnRH neurons maintain normal responsiveness to kisspeptin. However, Kiss1 mRNA expression levels in the AVPV were significantly reduced in the atrazine-treated animals. Given the normal response of GnRH neurons to exogenously administered kisspeptin, the suppressive effect of atrazine may be explained by suppression of Kiss1 expression in the AVPV leading to the attenuation of kisspeptin release from kisspeptin neurons in the AVPV. Further studies are warranted to elucidate more precisely the mechanism of atrazine's involvement in the suppression of Kiss1 mRNA expression in the AVPV.

Role of kisspeptin neurons as a GnRH surge generator: Comparative aspects in rodents and non‐rodent mammals

“…Atrazine, a commonly used herbicide, is known to impair reproductive function in females including the preovulatory LH surge . It has recently been implicated that the suppression of LH surge by atrazine may be caused by suppressed production of kisspeptin in the AVPV, since Kiss1 expression levels in the AVPV was reduced by atrazine‐treated female rats …”

Mechanisms of Neurotoxicity Associated with Exposure to the Herbicide Atrazine

“…A single exposure at the lower doses of 10, 30, or 100 mg/kg showed an increase in the LH surge as well as an increase in Kiss1 expression in the anteroventral periventricular nucleus (AVPV) following a 1 h exposure, suggesting that atrazine also plays a role in changing the surge [ 45 ]. The Kiss1 gene is responsible for regulating GnRH and in a similar study in the same strain of rats, Kiss1 was inhibited by a series of atrazine exposures at 100 mg/kg in the AVPV [ 46 ]. A decrease in LH levels following atrazine exposure was also witnessed in male rats exposed to atrazine between 1 and 200 mg/kg and was suggested to be the cause of the decrease in testosterone in the same study [ 47 ].…”

“…The literature suggests that kisspeptin expression is intertwined with the HPA axis and its response to stressors [ 112 ]. Crosstalk that occurs between close brain regions such as the HPA axis of the hypothalamus and the hippocampus, mentioned previously, has the potential to induce anxiety-like behavior in the hippocampus through kisspeptin [ 45 , 46 ]. These studies demonstrate how dysfunction in different neurons in the brain can be linked to the dysfunction in the neuroendocrine system, also leading to certain behaviors.…”

Epigenetic modification of <i>Kiss1</i> gene expression in the AVPV is essential for female reproductive aging

“…The Kiss1 gene-encoded neuropeptide kisspeptin in the AVPV potently drives GnRH neuronal activation and the subsequent LH surge (30)(31)(32)(33). Female rats that exhibit reproductive aging display reduced total Kiss1 mRNA (34) and less Kiss1 mRNA per cell in the AVPV as well as decreased Kiss1 cellular activation under E2positive feedback conditions (2).…”