Transgenerational effects of perinatal cannabis exposure on female reproductive parameters in mice

Background

Over the past decade, cannabis consumption has increased significantly, especially among young people (Imtiaz et al., 2021). This trend is associated with legalization in many countries, which facilitates access to this drug. Additionally, in the last 10 years, the concentration of delta-9 tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, has doubled (ElSohly et al., 2016), which raises new questions about risks associated with its consumption.

THC disrupts the endocannabinoid system, crucial in reproductive health, neurological development, and behavioural regulation (Di Blasio et al., 2013). Furthermore, THC is lipophilic and can cross the placental barrier to enter the fetal bloodstream (Karschner et al., 2009). Despite the increasing prevalence of cannabis consumption during pregnancy, findings on its impact across generations remain inconsistent. Some human studies have noted higher rates of delinquent behaviours in those exposed to THC in utero (Marchand et al., 2022). However, it is unclear whether this is attributable to cannabis exposure alone or confounded by other lifestyle factors. Rodent studies have shown associations between THC consumption and reproductive issues, including premature births, altered neuronal development, miscarriages, and infertility (Marchand et al., 2022). Yet, much of this work studied the impact of non-inhaled THC exposure, moving away from real-world usage patterns.

This study aims to clarify the potential transgenerational risks of cannabis consumption on female reproductive health (Shi et al., 2025). The authors investigate how inhaled cannabis, administered across gestation and lactation in mice, influences the timing of puberty, estrous cycles, and fertility in the first female generation (F1). They further examine whether reproductive changes persist in the F2 and F3 generations.

Key Findings

Cannabis exposure causes minor gestational disruption in F0 mice, and a delay in puberty onset in F1 mice
Cannabis exposure during gestation and nursing did not disrupt pregnancies in F0 mothers. Litter size and pups’ sex ratios were similar to controls, but F1 pups showed lower birth weights, which is a sign of premature birth. F1 offspring of mothers exposed to the highest THC dose administered (200mg/ml) had delayed puberty onset, as shown by a later vaginal opening day. Furthermore, F1 females experienced longer estrous cycles. However, F1 adult ovarian histology and fertility were similar to controls.

No observed effects of F0 cannabis exposure in F2 and F3 mouse generations
F2 females had longer estrous cycles but showed no other significant disruptions to their development and reproductive health. F3 mice were completely unaffected by F0 cannabis exposure. Indeed for these mice, they found similar birth weights, puberty onset, and adult ovarian health compared to controls.

No observed transgenerational impacts of cannabis exposure on reproductive health
Despite the early puberty disruptions, transgenerational effects of cannabis exposure on fertility or pregnancy were absent. Overall, maternal cannabis exposure impacts early reproductive stages without causing harm throughout mice adulthood and across generations.

Why we highlight this article

This article addresses a growing public health concern, particularly relevant here in Canada, where cannabis legalization has increased accessibility and consumption. Given that THC concentrations have doubled in commercial cannabis products over the past decade, understanding its reproductive health effects is paramount, especially as fertility rates are decreasing around the world.

Furthermore, women were historically excluded from scientific studies, which compels research to focus more of its resources on understanding the complexity of female reproductive health.

This study is also innovative in its methodology, as it uses vapour inhalation rather than conventional injection, which is physiologically relevant to human use. This further enabled the authors to analyze THC’s effects in isolation from the harmful particles associated with cannabis smoking.

Finally, given how rigorous the behavioural neuroscience field is, we believe highlighting negative results is critically important. This is a testament to the author’s willingness for truth-seeking and scientific transparency.

Questions for the Authors

1. Given the potential impact of THC on neonatal neurological and behavioural development, why did you choose not to assess their outcomes in pups who were maternally exposed to THC? Did you observe any incidental differences in the behaviour of control pups and those exposed?
2. Do you think that assessing THC transmission via lactation, by measuring THC concentration therein, could clarify whether observed effects stem predominantly from placental exposure or lactational transmission, offering more profound insights into exposure mechanisms?
3. Many individuals now use cannabis edibles. How might this route-specific difference affect THC excretion into breast milk, and what implications might arise for nursing infants or older offspring?
4. Cannabis is chiefly consumed through joints, and similarly to cigarettes, the tar inhaled from combustion has its host of adverse effects independently of its psychoactive compound. Do you think an administration method similar to combustion would be methodologically feasible? And if so, would you expect different results?

References

Conner SN, Bedell V, Lipsey K, Macones GA, Cahill AG, Tuuli MG (2016) Maternal Marijuana Use and Adverse Neonatal Outcomes: A Systematic Review and Meta-analysis. Obstet Gynecol 128:713–723.

Di Blasio AM, Vignali M, Gentilini D (2013) The endocannabinoid pathway and the female reproductive organs. J Mol Endocrinol 50:R1–R9.

ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC (2016) Changes in Cannabis Potency Over the Last 2 Decades (1995-2014): Analysis of Current Data in the United States. Biol Psychiatry 79:613–619.

Gunn JKL, Rosales CB, Center KE, Nuñez A, Gibson SJ, Christ C, Ehiri JE (2016) Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ Open 6:e009986.

Imtiaz S, Wells S, Rehm J, Hamilton HA, Nigatu YT, Wickens CM, Jankowicz D, Elton-Marshall T (2021) Cannabis Use During the COVID-19 Pandemic in Canada: A Repeated Cross-sectional Study. J Addict Med 15:484–490.

Karschner EL, Schwilke EW, Lowe RH, Darwin WD, Herning RI, Cadet JL, Huestis MA (2009) Implications of Plasma 9-Tetrahydrocannabinol, 11-Hydroxy-THC, and 11-nor-9-Carboxy-THC Concentrations in Chronic Cannabis Smokers. J Anal Toxicol 33:469–477.

Ko JY, Farr SL, Tong VT, Creanga AA, Callaghan WM (2015) Prevalence and patterns of marijuana use among pregnant and nonpregnant women of reproductive age. Am J Obstet Gynecol 213:201.e1-201.e10.

Lo JO, Shaw B, Robalino S, Ayers CK, Durbin S, Rushkin MC, Olyaei A, Kansagara D, Harrod CS (2024) Cannabis Use in Pregnancy and Neonatal Outcomes: A Systematic Review and Meta-Analysis. Cannabis Cannabinoid Res 9:470–485.

Marchand G, Masoud AT, Govindan M, Ware K, King A, Ruther S, Brazil G, Ulibarri H, Parise J, Arroyo A, Coriell C, Goetz S, Karrys A, Sainz K (2022) Birth Outcomes of Neonates Exposed to Marijuana in Utero: A Systematic Review and Meta-analysis. JAMA Netw Open 5:e2145653.

Shi M, Oh Y, Mitchell DA, MacLean JA, McLaughlin RJ, Hayashi K (2025) Transgenerational effects of perinatal cannabis exposure on female reproductive parameters in mice. bioRxiv Available at: https://www.biorxiv.org/content/early/2025/02/28/2025.02.24.639897.

Volkow ND, Han B, Compton WM, McCance-Katz EF (2019) Self-reported Medical and Nonmedical Cannabis Use Among Pregnant Women in the United States. JAMA 322:167.

Tags: cannabis, female reproductive health, health, risks, transgenerational

doi: https://doi.org/10.1242/prelights.40713

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