Changes in gene expression following long-term in vitro exposure of Macaca mulatta trophoblast stem cells to biologically relevant levels of endocrine disruptors

Abstract

Trophoblast stem cells (TSCs) are crucial for embryo implantation and placentation. Environmental toxicants that compromise TSC function could impact fetal viability, pregnancy, and progeny health. Understanding the effects of low, chronic EDC exposures on TSCs and pregnancy is a priority in developmental toxicology. Differences in early implantation between primates and other mammals make a nonhuman primate model ideal. We examined effects of chronic low-level exposure to atrazine, tributyltin, bisphenol A, bis(2-ethylhexyl) phthalate, and perfluorooctanoic acid on rhesus monkey TSCs in vitro by RNA sequencing. Pathway analysis of affected genes revealed negative effects on cytokine signaling related to anti-viral response, most strongly for atrazine and tributyltin, but shared with the other three EDCs. Other affected processes included metabolism, DNA repair, and cell migration. Low-level chronic exposure of primate TSCs to EDCs may thus compromise trophoblast development in vivo, inhibit responses to infection, and negatively affect embryo implantation and pregnancy.

Transcriptomics and Other Omics Approaches to Investigate Effects of Xenobiotics on the Placenta

“…In vitro culture approaches have aided our understanding of how EDCs affect placental cells. One study used TB stem cells from rhesus monkeys (Macaca mulatta) to screen global transcriptome changes induced by several EDCs, atrazine, tributyltin, bisphenol A, bis(2-ethylhexyl) phthalate, and perfluorooctanoic acid (PFOA) (Midic et al, 2018). Atrazine and tributylin, and to a lesser extent the other three EDCs, suppressed genes involved in cytokine signaling related to antiviral response, along with those involved in metabolism, DNA repair, and cell migration.…”

A Comprehensive Assessment of Associations between Prenatal Phthalate Exposure and the Placental Transcriptomic Landscape

“…2018 ). DEHP treatment resulted in significant changes in the expression of 112 genes in trophoblast stem cell lines from rhesus monkey blastocysts, which was quantified through RNA sequencing ( Midic et al. 2018 ).…”

Maternal exposure to tributyltin during early gestation increases adverse pregnancy outcomes by impairing placental development

“…Prospective studies showed that placental TBT concentrations were positively associated with a risk factor for cryptorchidism and weight gain in the first 3 months of life in boys 8,19 . Furthermore, treatment with TBT significantly increased the secretion of inflammatory factors in placental explant cultures, 20 and attenuated the expression of cell invasive genes in Macaca mulatta trophoblast stem cells, which are essential to embryo implantation and placentation 21 . However, to our knowledge, little is known about the effects of TBT on the early pregnancy and placental development.…”

“…8,19 Furthermore, treatment with TBT significantly increased the secretion of inflammatory factors in placental explant cultures, 20 and attenuated the expression of cell invasive genes in Macaca mulatta trophoblast stem cells, which are essential to embryo implantation and placentation. 21 However, to our knowledge, little is known about the effects of TBT on the early pregnancy and placental development. Thus, this study aimed to observe the effect of maternal exposure to TBT on the early pregnancy and placental development in mice during pregnancy.…”