Effects of oral exposure to the phthalate substitute acetyl tributyl citrate on female reproduction in mice

Abstract

Acetyl tributyl citrate (ATBC), is a phthalate substitute used in food and medical plastics, cosmetics, and toys. Although systemically safe up to 1000 mg/kg/day, its ability to cause reproductive toxicity in females at levels below 50 mg/kg/day has not been examined. This study evaluated the effects of lower ATBC exposures on female reproduction using mice. Adult CD-1 females (n=7–8/treatment) were dosed orally with tocopherol-stripped corn oil (vehicle), 5 or 10 mg/kg/day ATBC daily for 15 days, and then bred with a proven breeder male. ATBC exposure did not alter body weights, estrous cyclicity, and gestational and litter parameters. Relative spleen weight was slightly increased in the 5 mg/kg/day group. ATBC at 10 mg/kg/day targeted ovarian follicles and decreased the number of primordial, primary, and secondary follicles present in the ovary. These findings suggest that low levels of ATBC may be detrimental to ovarian function, thus, more information is needed to better understand the impact of ATBC on female reproduction.

Exposure to endocrine disruptors during adulthood: consequences for female fertility

“…BPF exposure (20 – 500 mg/kg/day) did not alter estrous cycles in rats (Higashihara et al 2007). In contrast, DEHA (1,000 and 2,000 mg/kg/day) decreased average estrous cycle length in rats (Wato et al 2009) and ATBC (5 mg/kg/day) decreased average estrous cycle length in mice (Rasmussen et al 2016). …”

“…DEHA (1,000 and 2,000 mg/kg/day), a phthalate alternative, increased atresia in preantral and antral follicles (Miyata et al 2006; Wato et al 2009). ATBC (5 and 10 mg/kg/day), a phthalate alternative, decreased the numbers of primordial, primary, and secondary follicles, but did not alter the numbers of corpora lutea or atretic follicles in mouse ovaries (Rasmussen et al 2016). In contrast the BPA analogue, BPF (20 – 500 mg/kg/day), did not cause histopathological changes in the rat ovary (Higashihara et al 2007).…”

“…Exposure to ATBC (100 – 1,000 mg/kg/day), a phthalate alternative, decreased the number of implantation sites and litter size in rats (CPSC 2010), but it (5 – 10 mg/kg/day) did not affect implantation rates or litter size in mice (Rasmussen et al 2016). Another phthalate alternative, DEHA (400 – 1080 mg/kg/day), caused prolonged pregnancies, smaller pups, and increased pup mortality rates in rats (CPSC 2010; Dalgaard et al 2003).…”

Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

“…Numerous studies link bisphenol A exposure to aromatase inhibition in granulosa cells and delay or suppression of LH surge resulting in modified ovarian cyclicity (Viguié et al 2018 ). Di-(2-ethylhexyl) adipate can shorten the average length of the estrus cycle in rats (Wato et al 2009 ), whereas acetyl tributyl citrate has been shown to do so in mice (Rasmussen et al 2017 ). In humans, exposure to organophosphate pesticides has been related to a higher risk of irregular menstrual cycles and shorter menstrual bleed duration among Chinese women (Zhang et al 2019 ).…”

Optimization of Process Variables in the Synthesis of Tributyl Citrate Using a Polyvinylpolypyrrolidone-Supported Brønsted Acidic Ionic Liquid Catalyst

“…Tributyl citrate (TBC) is usually applied as a thermally stable, high-performance, and nontoxic plasticizer in toys, medical products, biodegradable polymers, and food additives [1][2][3][4]. Moreover, TBC is a biorenewable and sustainable plasticizer.…”