7218 Prenatal Exposure To A Real-Life Environmental Chemical Mixture Via Biosolids Dissipates Sexual Dimorphism Of The Liver Transcriptome In Sheep

Abstract Disclosure: S. Thangaraj: None. M. Bellingham: None. R. Lea: None. N. Evans: None. K. Sinclair: None. V. Padmanabhan: None. Humans are chronically exposed to a mixture of environmental chemicals (ECs), many with endocrine disrupting potential, contributing to the development of non-communicable diseases. The adverse health effects of exposure to single ECs have been extensively studied but less is known about the impact of chronic exposure to low levels of a mixture of ECs, which is the real-life exposure scenario. Biosolids, derived from human wastewater treatment, closely reflects the human exposome in both the array and concentration of ECs and is a novel, real-life model to investigate the health risks posed by developmental exposure to mixtures of ECs. Previous studies using the prenatal biosolids exposure model found an increased accumulation of the endocrine disrupting chemical diethylhexylphthalate in the fetal liver and metabolic perturbations including increased thyroid gland weight in the male fetus and reduced bodyweight in prepubertal male lambs. To understand the basis of this sexually dimorphic metabolic phenotype we investigated the transcriptome of liver, the primary metabolic organ, in prepubertal lambs of both sexes. Since many liver genes show sexual dimorphism, with sex-biased genes playing a pivotal role in lipid and drug metabolism, sex-differences in liver gene expression and the impact of prenatal biosolids exposure on it were examined. We hypothesized that maternal preconceptional and gestational exposure of sheep to biosolids programs sex-specific transcriptional changes in the offspring liver. Ewes (F0) were grazed on either inorganic fertilizer (C) or biosolids-treated pastures (BTP) from 1 month before mating till parturition. All lambs (F1) were raised on control pastures after lambing until euthanasia at 8 weeks of age. RNA from liver from Control male (n=7), Control female (n=8), BTP male (n=7) and BTP female (n=8) lambs were subjected to next generation sequencing and differentially expressed genes (DEG) identified with DESeq2 R package. A stratified sex-differential analysis identified 702 DEG between control males and females validating the sexual dimorphism in hepatic gene expression. A sex-stratified analysis between C and BTP identified 5 downregulated DEG - WNT2B, LCN2, TEAD4, QSOX1 and ITIH4 in male and none among female lambs. Biosolids exposure dissipated the sexual dimorphism seen in hepatic gene expression in the controls barring 3 genes involved in cell growth/differentiation (WNT2B) and chromatin regulation (KDM6A, SS18). This may relate to the increase in androgenic steroids found in F0 maternal circulation (Sci Total Environ 2023, 900:165674). The findings of dissipation of the sex-differences in hepatic gene expression by real-life exposure to ECs in a precocial model with a developmental trajectory similar to humans is of translational significance in the context of sexually dimorphic origin of non-communicable diseases.Funding NIH R01ES030374 Presentation: 6/1/2024