Elevated Maternal Testosterone Levels Alter PFOA Elimination and Tissue Distribution in Pregnant Rats

Abstract

Perfluorooctanoic acid (PFOA) is an enduring synthetic chemical that harms human health. Recent studies indicate heightened bioaccumulation of PFOA, particularly in pregnant women experiencing preeclampsia. Since plasma testosterone levels are elevated in pregnant women with preeclampsia, we hypothesized that hyperandrogenic conditions during pregnancy may hinder PFOA elimination and contribute to their higher body burden. Pregnant Sprague-Dawley rats were s/c injected with vehicle or testosterone propionate from gestational day (GD) 15 to 20 to increase plasma testosterone levels by 2-fold, similar to levels in preeclampsia. On GD 16, [¹⁴C]-PFOA (9.4 pmol/kg) was given intravenously, and subsequently, ¹⁴C radioactivity was measured in maternal blood, urine, feces, and tissues. PFOA was primarily eliminated through urine; however, less PFOA was excreted in urine of pregnant rats with elevated testosterone levels than controls. Fecal excretion of PFOA was minimal and did not significantly differ between groups. The total elimination of PFOA (urine plus feces) was significantly reduced by 12% in pregnant rats with elevated testosterone levels. In controls, PFOA distribution was highest in placenta, followed by the kidneys, liver, brain, heart, lungs, and spleen. Pregnant rats with elevated testosterone levels displayed 12% higher concentrations of PFOA in these tissues than controls. Furthermore, the renal expression of Oat2 and Oat3 was significantly decreased, while Oatp1 and Oat-k expression was significantly increased in pregnant rats with elevated testosterone levels than controls. In conclusion, elevated maternal testosterone levels decrease urinary elimination of PFOA, possibly through altered expression of renal transporters leading to increased tissue concentrations of PFOA in pregnant rats.

Keywords: Bioaccumulation; Kidney; Perfluorooctanoic acid; Pregnant rats; Testosterone; Transporters.

Figure 1:

Elimination of ¹⁴C-PFOA in urine and feces. Vehicle (blue color) and testosterone (red color) treated pregnant rats were administered with ¹⁴C-PFOA (9.4 μmol/kg, i.v.). Feces and urine were collected daily for 4 days. Daily elimination of ¹⁴C-PFOA from urine (A), feces (B), and urine + feces (C) are presented in the top panel. The cumulative percentage of ¹⁴C-PFOA eliminated through urine, feces, and urine + feces over 4 days is presented in the bottom panel. Data are presented in Mean ± SEM, n = 6 in each group. *P<0.05 compared to control.

Figure 2:

Total body burden and blood concentration of ¹⁴C-PFOA. Vehicle (blue color) and testosterone (red color) treated pregnant rats were administered with ¹⁴C-PFOA, and blood was collected daily for 4 days. Daily total ¹⁴C-PFOA accumulation in rat body (A) and blood (B) are presented in the top panel. The bottom panel presents the body burden and blood concentration of ¹⁴C-PFOA after 4 days. Data are presented in Mean ± SEM, n = 6 in each group. *P<0.05 compared to control.

Figure 3:

PFOA distribution in pregnant rats after 4 days of exposure.

Figure 4:

Tissue distribution of ¹⁴C-PFOA in the organs. Vehicle (blue color) and testosterone (red color) treated pregnant rats were administered with ¹⁴C-PFOA, and organs were collected after 4 days. The total accumulation of ¹⁴C-PFOA in the organs is presented in Mean ± SEM, n = 6 in each group. *P<0.05 compared to respective controls.

Figure 5:

Changes in mRNA levels of organo-anion transporters in the kidney of control and testosterone-treated pregnant rats. Real-time PCR was used to assess renal organo-anion transporter mRNA expression. Quantitation of mRNA expression was normalized relative to Gapdh. n=5 in each group. *P<0.05 vs. compared to controls.

Figure 6:

Possible mechanism for PFOA elimination and tissue distribution in pregnant rats with elevated testosterone.