Multiple Endocrine Disrupting Effects in Rats Perinatally Exposed to Butylparaben

Abstract

Parabens comprise a group of preservatives commonly added to cosmetics, lotions, and other consumer products. Butylparaben has estrogenic and antiandrogenic properties and is known to reduce sperm counts in rats following perinatal exposure. Whether butylparaben exposure can affect other endocrine sensitive endpoints, however, remains largely unknown. In this study, time-mated Wistar rats (n = 18) were orally exposed to 0, 10, 100, or 500 mg/kg bw/d of butylparaben from gestation day 7 to pup day 22. Several endocrine-sensitive endpoints were adversely affected. In the 2 highest dose groups, the anogenital distance of newborn male and female offspring was significantly reduced, and in prepubertal females, ovary weights were reduced and mammary gland outgrowth was increased. In male offspring, sperm count was significantly reduced at all doses from 10 mg/kg bw/d. Testicular CYP19a1 (aromatase) expression was reduced in prepubertal, but not adult animals exposed to butylparaben. In adult testes, Nr5a1 expression was reduced at all doses, indicating persistent disruption of steroidogenesis. Prostate histology was altered at prepuberty and adult prostate weights were reduced in the high dose group. Thus, butylparaben exerted endocrine disrupting effects on both male and female offspring. The observed adverse developmental effect on sperm count at the lowest dose is highly relevant to risk assessment, as this is the lowest observed adverse effect level in a study on perinatal exposure to butylparaben.

Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders

“…Fetal exposure to both the antimicrobial preservative butyl paraben (Boberg et al 2016;Zhang et al 2014) and the industrial plasticizer bisphenol A (Christiansen et al 2014) has been shown to shorten the male AGD around 7-16% in the male offspring, albeit there are studies reporting no effects on AGD for both butyl paraben (Boberg et al 2008) and bisphenol A (Ferguson et al 2011;Howdeshell et al 2008;Takagi et al 2004;Tinwell et al 2002). In the cases where short AGD was observed with these compounds, clear effects on nipple retention or genital malformations were rarely seen.…”

“…In the cases where short AGD was observed with these compounds, clear effects on nipple retention or genital malformations were rarely seen. On the other hand, decreased sperm count or affected prostate development were observed, as were disrupted mammary glands in female offspring (Boberg et al 2016;Hass et al 2016;Mandrup et al 2016). The intuitively appealing explanation for these discrepancies in phenotypic manifestations is that the latter compounds are considered mainly estrogenic.…”

“…There are also examples, where female AGD is shorter than normal following in utero exposure, observations that evoke more questions than answers. The types of compounds capable of shortening female AGD in rodent are also variable and include bisphenol A (Christiansen et al 2014), butyl paraben (Boberg et al 2016), ketoconazole (Taxvig et al 2008), paracetamol (Holm et al 2016), as well as di-n-hexyl phthalate and dicyclohexyl phthalate (Aydoğan Ahbab and Barlas 2015). These studies are not covered in detail herein, and thus not presented with proper weight of evidence as yet any plausible mechanisms-or modes of action are lacking.…”

Pancreatic beta cells are a sensitive target of embryonic exposure to butylparaben in zebrafish (Danio rerio)

“…Butylparaben has been found to act as an endocrine disruptor in numerous studies. Developmental exposures to butylparaben have been shown to affect expression of the estradiol receptor β in fetal ovaries in rats (Boberg et al, ), expression of estrogen receptors α and β and the progesterone receptor in breast cancer cells in vitro (Wrobel & Gregoraszczuk, ), and have also been shown to have anti‐androgenic effects including reduction of sperm counts (Alam, Ohsako, Kanai, & Kurohmaru, ; Boberg et al, ; Zhang et al, ). There are also findings of butylparaben impacting epigenetic mechanisms of gene regulation, including hypermethylation of DNA in rat sperm (Park, Nah, Lee, Oh, & Gye, ) and decreased methylation of the ERα promoter in male rats (Zhang et al, ).…”

Effects of butylparaben on antioxidant enzyme activities and histopathological changes in rat tissues

“…Butylparaben (butyl 4-hydroxybenzoate, BP) from the paraben family has widely been used as antimicrobial/ antifungal preservative in cosmetic products, deodorants, toiletries, face creams, pharmaceuticals, toys, food, and beverages for more than 50 years (1,2). Parabens are endocrine disruptors which impair natural metabolism of hormones by mimicking, interfering, and/or blocking them (3)(4)(5)(6).…”