Gestational triphenyl phosphate exposure in C57Bl/6 mice perturbs expression of insulin‐like growth factor signaling genes in maternal and fetal liver

Abstract

Triphenyl phosphate (TPhP) is an organophosphorus flame retardant and plasticizer that has been added to numerous consumer products in recent years. TPhP is not overtly toxic, however recent studies have suggested that it may have metabolic disrupting effects following developmental exposure. The present study aimed to investigate the developmental and potential metabolic effects of TPhP in a murine model. C57Bl/6 dams were exposed on gestational days (GD) 8, 10, 12, and 14 to 0, 5, 25, or 50 mg/kg TPhP via intraperitoneal injection. Dams were euthanized on GD19, maternal organs excised and weighed, fetal measurements taken, and maternal and fetal livers retained for analysis. A significant increase in placenta size of TPhP exposed mice was found. Maternal and fetal liver gene expression of insulin-like growth factor (Igf) 1 and 2, as well as downstream genes involved in Igf signaling were measured. Additionally, Igf1 protein levels were measured in both maternal and fetal liver. A significant decrease in transcript levels of Igf1 and Irs2 was detected in maternal livers, whereas a significant increase in transcript levels of all genes measured was detected in fetal liver. A significant decrease in Igf1 protein levels was detected in maternal liver, however the increase in Igf1 protein levels in fetal livers was not found to be statistically significant. These results support previous findings that TPhP does not cause overt structural developmental toxicity. These data also support the hypothesis that TPhP could disrupt maternal and fetal metabolism, justifying the need for follow-up studies to investigate further.

Transplacental Behaviors of Organophosphate Tri- and Diesters Based on Paired Human Maternal and Cord Whole Blood: Efficiencies and Impact Factors

“…No significant correlations were found between the C:M ratios of ToCP, TPHP, TCEP and TIPR and the demographic characteristics of the pregnant women. ToCP was reported to elicit delayed neuropathy in humans and hens, as well as liver toxicity and reproductive toxicity in roosters, rats, and mice, and TPHP increase placenta size and disturb maternal and fetal metabolism in mice. , Thus, increased attention should be given to fetal development due to the highly efficient transplacental transfer of ToCP and TPHP.…”

Prenatal exposure to consumer product chemical mixtures and size for gestational age at delivery

“…Toxicologic evidence also supports the biologic plausibility of a relationship between OPE exposure and fetal growth. One study in mice demonstrated that in utero exposure to triphenyl phosphate (TPhP), the parent compound of DPhP, alters fetal and maternal liver insulin growth factor signaling, which is critical to the control of fetal growth and development [ 57 , 58 ]. Additional research using a human placental cell line has also established that TPhP exposure increases both progesterone and human chorionic gonadotropin secretion via activation of the peroxisome proliferator-activated receptor gamma [ 59 ].…”

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

“…However, our implemented dose is lower than that of studies that used a dose (70mg/kg/day) from an old in vivo TPhP exposure study in male Holtzman rats (Sutton et al 1960) to derive a non-regulatory reference dose for TPhP (Ali et al 2012;Li et al 2018). Our TPhP dose is also in the lowermiddle range of recent in vivo exposure studies as one recent study exposed C57Bl/6 dams to 0, 5, 25, or 50 mg/kg TPhP via intraperitoneal injection (Philbrook et al 2018), and National Toxicology Program (NTP) recently exposed male Harlan Sprague Dawley rats to 0, 55, 110, 220, 441, and 881 mg/kg TPHP daily for 4 days by oral gavage (National Toxicology Program 2018). Another important question is whether sex modifies the effect of TPhP exposure.…”