The liver is the body's main filter, and its workings differ between males and females from the first weeks of life. These differences are set by sex hormones and by the pattern of growth hormone secretion, and they show up in the activity of hundreds of genes: in males, xenobiotic and steroid metabolism genes work harder, while in females it's lipid and bile acid genes. Early toxicant exposures can throw off this tuning during the most sensitive window, which raises the risk of liver disease in adulthood. The work sits somewhat apart: its closest neighbors in the archive study gene-environment links in adolescent behavior, the effects of prenatal hormones on heart rhythm, cell aging, and epithelial plasticity. This paper stands out by systematically comparing seven different toxicants across three levels of molecular regulation and three life stages, and doing so separately for males and females.
The authors used data from the TaRGET II consortium: mice received toxicants from two weeks before the parents were mated until three weeks after birth, then were raised without exposure. In the liver at 3 weeks, 5 months, and 10 months of age, they measured gene expression (RNA-seq), chromatin accessibility (ATAC-seq), and DNA methylation (whole-genome bisulfite sequencing). For each toxicant and sex, exposed animals were compared with controls of the same age. Differentially expressed genes, regions with altered chromatin accessibility, and differentially methylated regions were analyzed separately, then tested for KEGG and GO pathway enrichment, transcription factor motifs, and links to liver sex signatures.
Each toxicant produced its own set of changes, and those in males and females barely overlapped. In males, gene expression changed more often; in females, DNA methylation did. For example, tributyltin produced almost 33,000 differentially methylated regions in females, 95% of which were hypomethylated. Arsenic, by contrast, produced consistent changes in both sexes: 95% of shared chromatin regions became more open, and 99% of shared methylated regions became hypermethylated. The changes were age-dependent: there were almost no genes that stayed altered across all three stages. Only two genes kept a persistent change: Tmem200b in females exposed to PM2.5-CHI and Ces1d in males exposed to lead. Importantly, the toxicants disrupted natural sex differences: in males, many male genes fell silent while female genes switched on. For instance, tributyltin exposure in males lowered the expression of 38 male genes and raised the expression of 10 female genes.
The work shows that early toxicant exposures don't just cause temporary glitches: they remodel the liver's sex program, and males are more vulnerable. This sets it apart from neighboring studies that looked at single exposures or single molecular layers: here, seven toxicants are compared across three levels of regulation and over the course of life. The findings explain why men and women differ in their susceptibility to liver disease after identical environmental exposures, and point to DNA methylation as a potential biomarker of early exposure.
The field will move toward studying the mechanisms through which toxicants affect sex programs. Of particular interest is the growth hormone pathway, which controls male liver genes: if toxicants disrupt its pulsatile secretion, that would explain the observed feminization of the male liver. It will also be important to check whether the epigenetic changes persist across generations and whether they can be reversed.
The results matter for toxicology, epigenetics, hepatology, and the study of sex differences in medicine. They could help in developing biomarkers of exposure and in assessing risks for different population groups.
The next step is to test how toxicants affect growth hormone signaling in the liver, and to run similar studies in other tissues and species, including humans.
The work speaks directly to an unresolved problem in toxicology: why identical doses of toxicants produce different outcomes in males and females, and how early exposures program adult disease. It also contributes to our understanding of liver sexual dimorphism, which remains poorly studied at the epigenome level.
Only two genes kept altered expression across all three life stages: Tmem200b in females exposed to PM2.5-CHI and Ces1d in males exposed to lead. The other thousands of changes came and went with age.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.