Triclosan induces earlier puberty onset in female mice via interfering with L-type calcium channels and activating Pik3cd.

Triclosan (TCS) is a broad-spectrum antibacterial chemical widely presents in people's daily lives. Epidemiological studies have revealed that TCS exposure may affect female puberty development. However, the developmental toxicity after low-dose TCS continuous exposure remains to be confirmed. In our study, 8-week-old ICR female mice were continuously exposed to TCS (30, 300, 3000 µg/kg/day) or vehicle (corn oil) from 2 weeks before mating to postnatal day 21 (PND 21) of F1 female mice, while F1 female mice were treated with TCS intragastric administration from PND 22 until PND 56. Vaginal opening (VO) observation, hypothalamic-pituitary-ovarian (HPO) axis related hormones and genes detection, and ovarian transcriptome analysis were carried out to investigate the effects of TCS exposure on puberty onset. Meanwhile, human granulosa-like tumor cell lines (KGN cells) were exposed to TCS to further explore the biological mechanism of the ovary in vitro. The results showed that long-term exposure to low-dose TCS led to approximately a 3-day earlier puberty onset in F1 female mice. Moreover, TCS up-regulated the secretion of estradiol (E2) and the expression of ovarian steroidogenesis genes. Notably, ovarian transcriptomes analysis as well as bidirectional validation in KGN cells suggested that L-type calcium channels and Pik3cd were involved in TCS-induced up-regulation of ovarian-related hormones and genes. In conclusion, our study demonstrated that TCS interfered with L-type calcium channels and activated Pik3cd to up-regulate the expression of ovarian steroidogenesis and related genes, thereby inducing the earlier puberty onset in F1 female mice.

Perinatal exposure to low doses of cypermethrin induce the puberty-related hormones and decrease the time to puberty in the female offspring.

Pyrethroid insecticides are ubiquitously detected in environmental media, food, and urine samples. Our previous epidemiological study reported a correlation between increased pyrethroid exposure and delayed pubertal development in Chinese girls. In this study, we further investigated the effects of perinatal exposure to low doses of cypermethrin (CP) on pubertal onset and hypothalamic-pituitary-ovarian axis in the female mice offspring. The treatment of CP with 60 µg/kg/day from gestation day 6 (GD6) to postnatal day 21 (PND21) significantly decreased the time to puberty in the female offspring. Exposure of CP increased the serum levels of gonadotropin-releasing hormone (GnRH) and the expression of GnRH genes in a dose-dependent manner in the female offspring. CP also induced the serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as the expression of gonadotropin subunit genes [LHß, FSHß, and chorionic gonadotropin α (Cgα)]. Furthermore, CP induced serum estradiol (E2) levels and the expression of steroidogenesis-related genes [steroidogenic acute regulatory (StAR) and Cytochrome p 450, family 11, subfamily A, polypeptide 1 (CYP11A1)] in the ovary. In accordance with the in vivo tests, administration of CP (6.7, 20, and 60 µg/L) stimulated a dose-dependent increase in the synthesis and secretion of the puberty-related hormones in the explants of hypothalamus, pituitary, and ovary. The interference with calcium channels in the ovary may be responsible for CP-induced pubertal onset. Our study provided evidence that perinatal exposure to low doses of CP induced puberty-related hormones and decreased the time to puberty in the female offspring.