Effects of Exposure to the Endocrine-Disrupting Chemical Bisphenol A During Critical Windows of Murine Pituitary Development

Abstract

Critical windows of development are often more sensitive to endocrine disruption. The murine pituitary gland has two critical windows of development: embryonic gland establishment and neonatal hormone cell expansion. During embryonic development, one environmentally ubiquitous endocrine-disrupting chemical, bisphenol A (BPA), has been shown to alter pituitary development by increasing proliferation and gonadotrope number in females but not males. However, the effects of exposure during the neonatal period have not been examined. Therefore, we dosed pups from postnatal day (PND)0 to PND7 with 0.05, 0.5, and 50 μg/kg/d BPA, environmentally relevant doses, or 50 μg/kg/d estradiol (E2). Mice were collected after dosing at PND7 and at 5 weeks. Dosing mice neonatally with BPA caused sex-specific gene expression changes distinct from those observed with embryonic exposure. At PND7, pituitary Pit1 messenger RNA (mRNA) expression was decreased with BPA 0.05 and 0.5 μg/kg/d in males only. Expression of Pomc mRNA was decreased at 0.5 μg/kg/d BPA in males and at 0.5 and 50 μg/kg/d BPA in females. Similarly, E2 decreased Pomc mRNA in both males and females. However, no noticeable corresponding changes were found in protein expression. Both E2 and BPA suppressed Pomc mRNA in pituitary organ cultures; this repression appeared to be mediated by estrogen receptor-α and estrogen receptor-β in females and G protein-coupled estrogen receptor in males, as determined by estrogen receptor subtype-selective agonists. These data demonstrated that BPA exposure during neonatal pituitary development has unique sex-specific effects on gene expression and that Pomc repression in males and females can occur through different mechanisms.

Re‐evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs

“…one in mice (van Esterik et al, 2014 [RefID 7393]) and six studies in rats (Jiang et al, 2014 [RefID 3190]; Lejonklou et al, 2017 [RefID 3975]; Xia et al, 2014 [RefID 8103]; NTP Clarity Report, 2018/Camacho et al, 2019 [RefID 11370]; Dunder et al, 2018 [RefID 11866]; Greenberg, 2018 (NTP Grantee study) [RefID 13785]); four Tier 2 studies, i.e. three in mice (Eckstrum et al, 2018 [RefID 11874]; Esplugas et al, 2018 [RefID 11900]; Meng et al, 2018a [RefID 12708]) and one in rats (Quan et al, 2017 [RefID 6025]); one Tier 3 study in rats (Sadowski et al, 2014a [RefID 6361]).…”

“…No changes in liver weight were reported in three studies in mice up to doses of 3000 μg/kg bw per day (van Esterik et al, 2014 [RefID 7393]; Eckstrum et al, 2018 [RefID 11874]; Meng et al., 2018a [RefID 12708]) and in six studies in rats up to doses of 50,000 μg/kg bw per day (Jiang et al, 2014 [RefID 3190]; Lejonklou et al, 2017 [RefID 3975]; Sadowski et al, 2014a [RefID 6361]; Xia et al, 2014 [RefID 8103]; Dunder et al, 2018 [RefID 11866] and Greenberg ( 2018 ) (NTP Grantee study) [RefID 13785]). In one rat study, liver weight decreased in males (females not tested) at 1,000 and 100,000 μg/kg bw per day but without dose–response (Quan et al, 2016 [RefID 6024]) and there was a trend indicating an increase of liver weight in male rats treated with doses between 2.5 and 25,000 μg/kg bw per day but not in female rats (NTP Clarity Report, 2018/Camacho et al, 2019 [RefID 11370]).…”

“…There were 23 studies that did not show any effects on body weight at all. Of these, there were 10 studies on mice, of which there were four, three and three studies, respectively, in Tier 1 (Taylor et al., 2018 [RefID 13239]; MacKay et al, 2017 [RefID 4767]; Tucker et al, 2018 [RefID 13275]; Meng et al, 2018b [RefID 12707]), Tier 2 (Ke et al, 2016 [RefID 3447]; Meng et al, 2018a [RefID 12708]; Shi et al, 2018 [RefID 13099]) and Tier 3 (Bodin et al, 2014 [RefID 623]; Eckstrum et al, 2018 [RefID 11874]; Hijazi et al, 2018 [RefID 2707]). There were 11 studies on rats of which there were six, four and one studies, respectively, in Tier 1 (Cao et al, 2015 [RefID 831]; Ding et al, 2014 [RefID 1620]; Lejonklou et al, 2017 [RefID 3975]; Lejonklou et al, 2016 [RefID 3974]; Ferguson et al, 2014b [RefID 1998]; Lind et al, 2017 [RefID 4350]), Tier 2 (Leung et al, 2017 [RefID 3990]; Spörndly‐Nees et al., 2018 [RefID 13164]; Kass et al, 2015 [RefID 3402] and Santamaría et al, 2016 [RefID 6448]) and Tier 3 (Tarapore et al, 2017 [RefID 7128]).…”

Mechanisms of Testicular Disruption from Exposure to Bisphenol A and Phtalates

“…More recently, several authors reported that exposure of neonatal mice to BPA can disrupt pituitary development, with critical effects on their pubertal and hence gonadal development. The described effects comprise a measurable downregulation of the mRNA expression of several genes (including pomc and Icam5) involving different estrogen-related pathways, with sex-specific differences [68,69]. Furthermore, there is evidence from an animal study that the spectrum of reproductive alterations induced by chronic BPA exposure includes reproductive hormone alterations (increased gonadotropins and estradiol, reduced testosterone), spermatogenesis hindrance and increased oxidative stress [70].…”

The Effects of Bisphenol A and Di-Isononyl Phthalate on Conformational Stability and Activity of Lysozyme

“…In contrast to this, irreversible organizational effects were produced in Sprague-Dawley rats after neonatal and perinatal exposure [11]. BPA at high and low doses causes long-term adverse reproductive and carcinogenic effects if exposure occurs during critical periods of differentiation, causing precocious hypothalamic-pituitary maturation and precocious puberty [12,13]. Prenatal exposure to BPA is associated with an increase in the risk for breast cancer [14].…”