Either sentence is fine, and the difference between them is very small.
The second sentence is very unambiguous, and it works with essentially every word in the English language (though it would be weird if you used it for one of the words already in the sentence):
What does "_____" mean?
Put any word you want for the blank and it will be a reasonable way to ask for the definition of that word. Sometimes you will not get the desired definition because some words have multiple definitions and without sufficient context someone could give you a different one than you wanted. In writing using quotation marks to indicate that you are talking about the word itself is traditional, but there isn't usually any need to do so in speech and the sentence is unlikely to be misunderstood without them in writing either.
Your first sentence also makes sense and would be interpreted almost identically, but would typically be applied to a much smaller subset of words, specifically nouns referring to a substance or inanimate object. That restriction allows the sentence to be grammatically and semantically correct without quotation marks. Bleach works: "What is bleach?" Other words also work, but can sometimes require an article, and that article could require its own comprehension. For example, if someone tells you "Hand me the wrench." a (potentially) appropriate response could be "What is a wrench?" whereas "What is the wrench?" would be unusual. In this phrasing, the concept you are asking about should fit in the sentence grammatically, which is why quotation marks aren't needed.
Part of the reason to avoid that wording unless you know that the word refers to an object or substance is that it overlaps with a different sentence with the same words but different meaning. If you use the phrase with an adjective instead, there's a good chance you will be interpreted differently. For example, the sentence "What is disgusting?" should be answered with one or more things to which the adjective "disgusting" is applicable, and would typically not be answered by a definition for "disgusting". In spoken English this would typically involve noticeable emphasis on the word "what", and you could encourage the other interpretation by emphasizing the word "disgusting" instead.
Finally, a third phrasing can sometimes sound more fluent than the others and better suits some contexts. In particular, it's recommended if somebody uses a word you do know, but the definition you know for it doesn't make sense with how they used it. For example, if you hear that someone "bleached their hair" but are only familiar with bleach as a household cleaning chemical, the best way to ask for clarification would be "What do you mean by "bleached"?" I can't give an intuitive explanation for why that phrasing works, but it is (in my experience) the best way to get an answer like "Bleaching hair is a cosmetic procedure that lightens hair color dramatically." rather than "Bleach is a household cleaning chemical." which doesn't necessarily help understand the context. It's important to only use this in a context where you are speaking to someone who also heard the same phrase you are asking about, but doesn't exclusively require you to ask the original speaker. If you are asking a friend about something that was said during a speech or lecture which just ended you could ask "What did he mean by "_____"?"