OR04-05 Prenatal Phthalate Exposure Alters The Pattern Of Fetal And Neonatal Endocrine Puberty In A Sex-specific Manner

Abstract

Abstract Disclosure: M.A. Bunnell: None. P. Lin: None. S. Zhou: None. C. Park: None. S. Wang: None. Q. Hu: None. B. Marzbanabbasabadi: None. J. Oh: None. B. Wang: None. M. Laws: None. E. Fletcher: None. Z. Liu: None. E. Joo: None. H. Qiao: None. J. Flaws: None. C. Ko: None. Endocrine puberties (EP) are sex-specific transient elevations of gonadotropins and testosterone (T) in males and estradiol (E2) in females. Fetal EP occurs mid-gestation, neonatal EP is stimulated by the clearance of maternal estrogen after birth, and finally, reproductive function arises during classical puberty. EPs are critical for normal development and the sexual dimorphism of reproductive and some somatic organs. Disrupted T or E2 levels during fetal or neonatal EP lead to reproductive abnormalities in adults. The endocrine disrupting effects of phthalates have been well-documented in humans and animal models. Prepubescent children are highly susceptible to phthalate toxicity. In utero, exposure to phthalates causes gender-specific reproductive abnormalities. In this study, we tested the working hypothesis that in utero exposure to phthalates alters T and E2 levels in fetal and newborn mice in a gender-specific manner. Pregnant CD-1 dams (n=5-6/treatment/time point) were orally administered an environmentally relevant phthalate mixture (20 μg/Kg/day) or vehicle daily from embryonic day (ED) 10.5 until birth. On ED16.5, and postnatal hours (h) 1, 3, and 6, fetal tissues and neonatal sera and tissues were sampled for hormonal assays. Fetal and neonatal gonads were collected for testicular T and ovarian E2 measurements. The amount of serum per embryo was insufficient for determining circulating hormone levels in the fetus. Hence, at ED16.5, hormonal content of the full-body (excluding gonads) was used to assess the impact of phthalate exposure. Hormone levels were quantified by ELISA. At ED16.5, full-body T level was lower in exposed females (2.93 vs. 12.23 pg/body in control, P<0.0001), but higher in exposed males (277 vs. 216 pg/body in control, P=0.022). However, there was no difference in fetal testicular T (871 vs. 1027 pg/2 testes in control, P=0.089), indicating that testicular steroidogenesis was unaltered. A rapid decline in serum T levels occurred in both newborn control (h1= 623 pg/mL, h6= 249 pg/mL, P=0.009) and exposed males (h1= 600 pg/mL, h6= 224 pg/mL, P=0.0015), but serum LH remained constant (Control: h1= 0.83 ng/mL, h6= 0.63 ng/mL, P=0.36; exposed: h1= 0.69 ng/mL, h6= 0.82 ng/mL, P=0.43). Phthalate exposure did not impact neonatal serum T or LH in males. However, at h6, exposed females had lower serum E2 than controls (0.7 vs. 8.51 pg/mL in control, P=0.001). This study found that prenatal phthalate exposure altered T and E2 levels of males and females distinctly, without disrupting LH secretion and gonadal steroidogenesis. The results indicate that T and E2 levels were likely disrupted by altered steroid clearance due to a sex-dependent impact on hepatic T and E2 metabolism, rather than pituitary or gonadal hormone production. In conclusion, prenatal exposure to a phthalate mixture alters the levels of T and E2 during fetal and neonatal EP in a gender-specific manner. Presentation: Thursday, June 15, 2023