Full frontal (animated) nudity is shown in several episodes throughout the show. The moments of nudity are muted by context and lack of visual details.
Many episodes in the final season focus on rape and sexual assault, including towards minors.
It is shown in Season 3 that Dr. Potterswheel is sadistic as he gets sexual gratification from inspecting Bloberta's mutilated vagina and goads her to go further with it, which she does. When she overcomes this bout of depression and stops mutilating herself, he immediately loses interest in her.
The show contains from Moderate to Severe sexual innuendo. The sexual content is infrequent until the episode "God's Chef"; from there, the content slowly becomes more suggestive for the later episodes, especially in Season 3. The show deals with various strong adult themes including masturbation, homosexuality, bisexuality, brief jokes about prostitution, adultery, etc.
It is shown early on that Orel's father, Clay, is having an affair with Coach Stopframe. The relationship is more about their suppressed desires than their acting upon them.