Developmental programming: Prenatal bisphenol A treatment disrupts mediators of placental function in sheep

Abstract

Gestational Bisphenol A (BPA) exposure is associated with low birth weight. We hypothesized that the low birth weight is the consequence of reduced placental efficiency and a function of BPAinduced inflammatory, oxidative, lipotoxic, angiogenic, steroidal and fibrotic changes involving epigenetic alterations. Placentomes were collected during early (day 65) and mid (day 90) gestation (term ~147 days) from control and BPA (gestational day 30-90)-treated pregnant sheep. BPA treatment: reduced placental efficiency and fetal weight; increased interleukin 8, lipid peroxidation marker, antioxidants, aromatase, 17 alpha-hydroxylase, estrogen receptor 2, insulin like growth factor (IGF) 2 receptor and IGF binding proteins (IGFBP), and histone deacetylase 1 and 2; reduced tumor necrosis factor alpha and IGF1 receptor at early gestation (Day 65). Gestational BPA-induced mid-gestational changes include: reduced angiogenic factor hypoxia inducible factor 1 alpha; increased IL1beta, oxidative stress markers, triglyceride, 17alpha hydroxylase, IGFBP 1, DNA methyltransferase 3A and histone deacetylase 1. These findings indicate that gestational BPA, either acting directly or by altering steroidal input, produces early/ mid-gestational-specific epigenetic changes culminating in placental disruptions at several levels, in keeping with time-specific/time-lagged pregnancy-associated changes in placental efficiency and fetal weight. The reduced early-gestational placental efficiency may be a function of increased inflammation/oxidative stress and reduced IGF bioavailability with the mid-gestational restoration of placental efficiency likely driven by improved IGF bioavailability and the time-lagged response to antioxidant increase. This compensation, the result of time-lagged response to increases in negative mediators of placental function must have failed with pregnancy advancement to explain the low birthweight outcome.

Epigenetic signatures underlying inflammation: an interplay of nutrition, physical activity, metabolic diseases, and environmental factors for personalized nutrition

“…Meanwhile, perinatal bisphenol A exposure enhanced the mast cell-mediated production of pro-inflammatory mediators of adult mice, which was associated with pulmonary inflammation and global DNA methylation levels [119]. Similarly, gestational exposure to bisphenol A increased inflammation/oxidative stress markers in sheep through epigenetic alterations [120].…”

Developmental programming of insulin resistance: are androgens the culprits?

“…The observation in sheep models that gestational testosterone treatment increases placental lipid accumulation (Kelley et al 2019b) supports such a possibility. Similar increases in placental lipotoxicity are also observed in sheep models of gestational BPA treatment (Song et al 2020). As BPA exposure during pregnancy can increase maternal androgens (Takeuchi et al 2004, Rutkowska & Rachon 2014 and are known to induce insulin resistance (Veiga-Lopez et al 2016), maternal androgens might contribute to development of later-life insulin resistance through lipotoxicity.…”

“…inflammation (Schmatz et al 2010, Ingvorsen et al 2015, Ozias et al 2015, Alfaradhi et al 2016, Dewi et al 2017, Dudele et al 2017, Bansal et al 2018, Gu et al 2018, Zota et al 2018, Desplats et al 2019, Kelley et al 2019a, Song et al 2020) and an altered androgen milieu (Table 2) (Acromite et al 1999, Takeuchi et al 2004, Whyte et al 2007, Morisset et al 2013, Rutkowska & Rachon 2014, Vejrazkova et al 2014, Barrett & Swan 2015, Arnon et al 2016, Maliqueo et al 2017, Sathyanarayana et al 2017 in both humans and animals. These findings implicate androgens and inflammatory processes in the programming of insulin resistance.…”

“…These findings implicate androgens and inflammatory processes in the programming of insulin resistance. Strong associations exist between inflammatory biomarkers and cortisol in mothers with major depressive disorder (Osborne et al 2018) as well as placental inflammation following maternal exposure to BPA in the sheep (Song et al 2020). As these states are associated with an increased androgenic maternal milieu (Takeuchi et al 2004, Rutkowska & Rachon 2014, Barrett & Swan 2015, it is possible that inflammatory state in these situations also involve androgens.…”

Analysis of the Toxic Effects of Bisphenol A on the Groups of Vertebrate Animals: a Comprehensive Review of Research 2015-2021

“…BPA negatively affected bone metabolism and development 55) ,. dissolved in corn oil and subcutaneously injected) (G) The number of placentomes in first stage increased and body weights of fetus (embryo) decreased but not in gestation day 90 70). A (2~3 years), F A (22 month), F 0.5 (GD 30~90, dissolved in corn oil and subcutaneously injected) (T) Lower lung weight was observed.…”