The placental epitranscriptome as a novel mechanism behind prenatal metal mixture exposures and child growth and development

PROJECT SUMMARY Maternal exposure to complex metal mixtures during pregnancy may impair child growth and development to impact later health. In New York City (NYC), pregnant individuals from low-income and Hispanic communities are at risk of toxic metals exposure and children from these communities are also more likely to be born small- for-gestational age (SGA) or with low birthweight, dictating later child growth trajectories, educational attainment, and socioeconomic advancement. The placenta is the master regulator of fetal development and a first line of defense against toxic metal exposures. Direct and indirect interactions between toxic (e.g., arsenic [As], cadmium [Cd], lead [Pb]) and essential (e.g., manganese [Mn], selenium [Se], zinc [Zn]) metals in placental tissue may result in cellular and molecular damage that can impact placental function. Defining concrete mechanism(s) for the effects of metals on the placenta will advance efforts to protect millions of children from a widespread threat. Yet, our insight into placental mechanisms linking prenatal metal exposures to impaired growth is limited. The discovery of post-transcriptional modifications of RNA, collectively named the epitranscriptome, as key regulators of placental gene expression provide an innovative avenue to address this gap. N6-methyladenosine (m6A) is the most prevalent epitranscriptomic modification on messenger RNA (mRNA) and modulates mRNA splicing, stability, and translation. m6A and its reader, writer, and eraser proteins (RWEs) that interpret, add, and remove m6A marks, are responsive to toxicant exposures and regulate the cellular response to oxidative stress and inflammation, which are key processes governing metal toxicity to the placenta. These changes in m6A can subsequently regulate downstream proteomic responses to toxicant exposure. We hypothesize that essential (Mn, Se, Zn, etc.) and toxic (As, Cd, Pb, etc.) metals accumulated in the placenta directly influence child health in utero by dysregulating the m6A epitranscriptome and downstream proteome. We will test our hypotheses with a discovery-replication design in two NYC-based, low income, Hispanic birth cohorts, Fair Start (FS) (N=400) and Sibling-Hermanos (Hermanos) (N=100). In Aim 1, we will use placental tissue to investigate 19 metals and their associations with expression of 18 m6A RWEs, transcript-level m6A from m6A-sequencing, and the inflammation and metabolism-related proteome. In Aim 2, we will identify placental m6A epitranscriptome and proteome alterations associated with birth outcomes (SGA, birthweight, gestational length, head circumference, ponderal index) and early child growth trajectories (height, weight, BMI) at ages 0.5, 1, 2, 3, 5, 7, and 9 years. In Aim 3, we will construct a placental “metallome” – a network of the m6A epitranscriptome and proteome linking prenatal metals to birth outcomes and child growth trajectories. Together, these aims will lead to novel insight into the mechanisms linking placental metals, the placental epitranscriptome, and the ensuing effects on child growth and development. It will open new avenues for metals risk assessment and the development of placenta-based therapeutics to avert the harmful impacts of metals on child health.