Early Life Exposure to Δ ⁹ -Tetrahydrocannabinol Causes Persistent Growth, Behavior, and Bioenergetic Outcomes in Zebrafish

<b>Introduction:</b> Although classified in the United States as Schedule I drugs, medical and recreational cannabis and Δ⁹-tetrahydrocannabinol (THC) are becoming increasingly consumed by pregnant women. Determining the potential adverse effects following exposure during early development is essential for risk communication. <b>Materials and Methods:</b> Following exposure to 0.08, 0.4, or 1 µM THC for 6-96 h post fertilization (hpf) in wild-type zebrafish, latent behavioral effects caused by THC were evaluated at 3 weeks post fertilization (wpf) (juvenile), 11 wpf (onset of sexual maturity), and 24 wpf (adult) and in F1 offspring. Bioenergetics were measured in F0 adult brain mitochondria. <b>Results:</b> Open field tests conducted at 3 wpf and 11 wpf indicated concentration-dependent hyperactivity (increased velocity) and increased thigmotaxis (anxiety-like wall-hugging) at the two highest THC concentrations. The 5D F1 generation of zebrafish (exposed to THC as germ cells) also demonstrated significant dark-phase hyperactivity at 120 hpf in the larval photomotor response. Brain mitochondrial bioenergetics in adults developmentally exposed to THC showed that oxygen consumption rate was significantly increased at the two highest THC concentrations for females and the highest concentration for males. <b>Discussion:</b> Collectively, these results show that exposure to THC during a critical period of development caused behavioral and mitochondrial alterations that persisted into adulthood and across generations.