Wednesday, May 09, 2007

Ask A Scientist: Male-Mediated Teratogenesis (and Bupropion)

A correspondent asks: "What are the risks and possible side effects of long-term usage of bupropion in terms of sperm genetic abnormalities?"  (In other words, "Do I need to worry that my husband is taking Wellbutrin?" and "Does Wellbutrin harm sperm?  Does it affect fertility?  Does it cause genetic problems?")

Well, speaking from a scientific standpoint, there's no evidence that bupropion causes DNA damage in any way; bupropion doesn't even cause so-called 'congenital' defects. (Congenital usually means not genetic, but rather caused by environmental or unknown factors.) So probably, bupropion does nothing to sperm.

To broaden the question, what is known about teratogenesis- physical but not genetic changes- caused by sperm abnormalities?

This is a very hard question to study. Any male-mediated effect usually has weaker effects than when female-mediated: a mother's dioxin exposure is more harmful than a father's.* For example, moderate male lead exposure doesn't appear to be associated with birth defects in future offspring, but maternal exposure causes neural tube defects and other nasty things.

Why? The sperm:egg volume ratio is something like 1:1000, so the metabolic organelles are almost all maternally contributed. Only DNA damage (whether direct or 'epigenetic', i.e., non-permanent) in sperm would have an effect on fetal development. That is: if there's something non-genetic wrong with the egg, or if that particular egg is wonky in some way, it can have a huge effect. Not so much with the sperm, because it's mostly a bundle of DNA with a tail attached. Or think of it this way: the father is contributing 23 chromosomes and maybe a mitochondrion, and the mother is contributing everything else. For nine months. Which one do you think matters more? So teratogens have much more severe effects in the female than the male.

(To return briefly to bupropion: lead is a LOT nastier than bupropion. I wouldn't worry about ADs. Really.)

(Also, to digress: women who are breastfeeding often fear drinking. But calculate it out: if your BAC is 0.1%, which is equal to really drunk, then the milk has 0.1% alcohol in it too. Therefore it is 0.2 proof. Like a beer diluted 50 times. This is 2/5 of a cup of beer in a gallon of water. Yeah! That's a lot!!! Similarly, the plasma concentration of the drug is usually equal to the milk concentration, i.e. the breastfeeding child gets some very low percentage of the dose. This is why doctors who categorically refuse to prescribe to breastfeeding women are, in my personal opinion, IDIOTS.)

What if something causes DNA damage in sperm but not eggs- what if there's a drug women use and it's fine, but it's bad for male reproduction? It's theoretically possible- the cell division processes that generate gametes (meiosis) are somewhat different. But it's not likely, because really they're quite similar. (If anyone has a counter-example, please send it.)

It's also possible that nonpermanent genetic changes, which are called epigenetic modifications, are caused by a lot of things. This is really, really hard to study too. If anyone really wants to know why, I can write about it later, but take my word for it.

It's widely thought that many miscarriages are caused by genetic abnormalities. But most drugs don't cause genetic abnormalities, for the simple reason that if they do, they'll raise your rate of cancer (among other things) and be pulled from the market. So sperm-contributed mutations are generally from chance, combined with an inherent error rate in DNA replication, and with the caveat that the error rate may increase with age.** Sometimes from environmental exposure to really nasty stuff, too.***

Interestingly enough, even thalidomide- the stereotypical Bad Scary Teratogenic Drug- caused only 20-30% malformations, and that only when taken between d34 and d50 (i.e. in the second month) by the mother. Motherisk points out that 'When asked, even women exposed to nonteratogenic drugs believe they have a 25% risk of having children with major malformations, apparently the size of the risk with thalidomide itself. This unrealistic perception leads pregnant women to avoid medications even when they clearly need them.' In other words: look at the evidence before freaking out about drugs; it's probably not as bad as you think.

All this aside, there are many chemicals thought to harm sperm - but note that many of their first-line effects are reduced sperm count and motility.

Overall, biologically speaking, there's no evidence that bupropion (Wellbutrin) causes harm to sperm in any way. This doesn't mean it absolutely doesn't under any circumstances, but viewing it scientifically, it is extremely unlikely that the drug is harmful to men or women or fetuses.

*This paper discusses increased risks, but doesn't differentiate well between maternal and paternal exposure- they have historically been quite difficult to assess and track in Vietnam. Take-home message: self-reporting is unreliable, and dioxin is not good for humans. Here's a more careful study. Correlation is not causation.
**This theory, which I so don't have time to go into, has also to do with why the cancer risk increases dramatically with age. In general, all systems degenerate entropically over time. Including the human body.
** But here's a really poorly researched paper on Scary! Bad! Everything. Anecdotal, non-prospective and non-tracking evidence is notoriously bad. I'm just saying.