Browsing by Subject "Paternal Exposure"

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Open Access
Differential behavioral functioning in the offspring of rats with high vs. low self-administration of the opioid agonist remifentanil.
(European journal of pharmacology, 2021-10) Rezvani, Amir H; Wells, Corinne; Hawkey, Andrew; Blair, Graham; Koburov, Reese; Ko, Ashley; Schwartz, Andrea; Kim, Veronica J; Levin, Edward D
Opioid use disorder (OUD) has a variety of adverse effects on both the users and their offspring. In the current study, a random group of Sprague-Dawley rats (25 females and 15 males) were tested for intravenous self-administration of the opioid agonist remifentanil to determine the range of acquisition for opioid. One-month after the end of self-administration of remifentanil, rats with the highest intake were mated together and rats with lowest intake were mated together. Then, the offspring of the two groups were tested for anxiety-like behavior, locomotor activity, nociception and intravenous remifentanil self-administration. The parents showed a range of remifentanil self-administration, especially in the female rats. The offspring of the parents with low and high remifentanil self-administration showed significant differences in specific behavioral functions. On the hotplate test of nociception, the female offspring parents with high remifentanil self-administration had significantly longer hotplate latencies, indicating reduced nociception, than the female offspring of parents with low remifentanil-self-administration, whereas there was no difference in the male offspring of low and high responding parents. In the elevated plus maze test of anxiety-like behavior, the offspring of the parents with high remifentanil intake showed more anxiety-like behavior than the offspring of the parents with low remifentanil intake regardless of sex. Locomotor activity was not significantly different. Interestingly, no significant differences in remifentanil self-administration in the offspring of parents with low and high remifentanil self-administration were detected. Overall, our data suggest a considerable range in remifentanil self-administration in rats and the offspring of rats with high opioid self-administration exhibit different behaviors vs offspring of rats with low opioid self-administration.
Open Access
Introduction to sex differences in neurotoxic effects.
(Neurotoxicology and teratology, 2021-01) Levin, Edward D; Dow-Edwards, Diana; Patisaul, Heather
Open Access
Paternal cannabis extract exposure in rats: Preconception timing effects on neurodevelopmental behavior in offspring.
(Neurotoxicology, 2020-12) Holloway, Zade R; Hawkey, Andrew B; Torres, Alexandra K; Evans, Janequia; Pippen, Erica; White, Hannah; Katragadda, Vaishnavi; Kenou, Bruny; Wells, Corinne; Murphy, Susan K; Rezvani, Amir H; Levin, Edward D
Maternal toxicant exposure during gestation can have deleterious effects on neurobehavioral development of the offspring. The potential risks engendered by paternal toxicant exposure prior to conception have been largely understudied. Recently, we found that chronic THC exposure prior to conception in male rats causes long-lasting behavioral impairment in their offspring. The current study examined the effects of chronic preconception exposure to cannabis smoke extract in Sprague-Dawley rats at two different phases in sperm development. One group received daily subcutaneous (sc) injections of THC in cannabis extract at 4 mg/kg/day for 28 days until three days prior to mating with untreated females (late exposure group). Another group received the same regimen except they underwent 56 days of drug abstinence prior to mating (early exposure group). These were compared with a control group treated with vehicle. The offspring underwent a battery of tests for behavioral function to assess motor, emotional and cognitive function. On the elevated plus maze test, the offspring of both paternal cannabis smoke extract (CSE) exposure groups had significantly more time on the open arms than control offspring, indicative of greater risk-taking behavior. No significant main effects of CSE exposure were seen on adolescent or adult locomotor activity in the figure-8 apparatus. In the novel object recognition test, there was a significantly greater drop-off in novel object preference across the session in the male, but not female offspring of the late exposure group. There was also a sex-selective effect of paternal CSE treatment in the 16-arm radial maze test of memory function. Female offspring of the late exposure group had significantly more working memory errors than control females in the first half of the 12-session training sequence. No significant effects were seen in the operant visual signal sustained detection test of attention. This study shows that there are long-lasting behavioral consequences of preconception CSE exposure through the paternal lineage in rats.
Open Access
Paternal factors in neurodevelopmental toxicology: THC exposure of male rats causes long-lasting neurobehavioral effects in their offspring.
(Neurotoxicology, 2020-05) Holloway, Zade R; Hawkey, Andrew B; Pippin, Erica; White, Hannah; Wells, Corinne; Kenou, Bruny; Rezvani, Amir H; Murphy, Susan K; Levin, Edward D
The potential health risks of cannabis are of growing concern, including effects on reproduction and development. Extensive research has investigated risks associated with maternal exposure to THC during gestation and its impacts on the development of offspring, but little research has been done regarding paternal THC exposure effects prior to conception. We have previously found that paternal THC exposure in rats causes changes in sperm methylation. In an initial study we also showed that a 12-day paternal THC exposure prior to conception alters locomotor activity and impairs cognitive function of their offspring. This study investigated the cross-generational effects of chronic paternal THC exposure in rats (0, 2, or 4 mg/kg/day SC for 28 days) prior to mating with drug naïve females. The offspring of THC-exposed male rats had significant alterations in locomotor activity and cognitive function. Specifically, during adolescence there was significant locomotor hyperactivity in the offspring of males exposed to 2 mg/kg/day of THC. During the novel object recognition task, the controls maintained their relative preference for the novel object across the duration of the ten-min session while the rats whose fathers received THC (2 mg/kg/day) showed a significantly greater drop-off in interest in the novel object during the second half of the session. Learning in the radial-arm maze was significantly delayed in the offspring of males exposed to 4 mg/kg/day of THC. This study shows that premating chronic paternal THC exposure at multiple dose regimens can cause long-lasting detrimental behavioral effects in their offspring, including abnormal locomotor activity and impaired cognitive function. Future studies should investigate the underlying mechanisms driving these aberrant developmental outcomes and seek to identify possible treatments of alleviation in the presence of paternal THC exposure.
Open Access
Paternal THC exposure in rats causes long-lasting neurobehavioral effects in the offspring.
(Neurotoxicology and teratology, 2019-07) Levin, Edward D; Hawkey, Andrew B; Hall, Brandon J; Cauley, Marty; Slade, Susan; Yazdani, Elisa; Kenou, Bruny; White, Hannah; Wells, Corinne; Rezvani, Amir H; Murphy, Susan K
Developmental neurotoxicity of a wide variety of toxicants mediated via maternal exposure during gestation is very well established. In contrast, the impacts of paternal toxicant exposure on offspring neurobehavioral function are much less well studied. A vector for paternal toxicant exposure on development of his offspring has been identified. Sperm DNA can be imprinted by chemical exposures of the father. Most but not all of the epigenetic marks in sperm are reprogrammed after fertilization. The persisting epigenetic marks can lead to abnormal genetic expression in the offspring. We have found that paternal delta-9-tetrohydrocannabinol (THC) exposure in rats causes changes in methylation of sperm (Murphy et al., 2018). This is similar to cannabis-associated changes in sperm DNA methylation we found in human males who smoke cannabis (Murphy et al., 2018). In the current study we investigated the intergeneration effects of THC exposure of young adult male rats (0 or 2 mg/kg/day orally for 12 days) to the neurobehavioral development of their offspring. This paternal THC exposure was not found to significantly impact the clinical health of the offspring, including litter size, sex ratio, pup birth weight, survival and growth. However, it did cause a long-lasting significant impairment in attentional performance in the offspring relative to controls when they were tested in adulthood. There was also a significant increase in habituation of locomotor activity in the adult offspring of the males exposed to THC prior to mating. This study shows that premating paternal THC exposure even at a modest dose for a brief period can cause deleterious long-term behavioral effects in the offspring, notably significant impairment in an operant attention task. Further research should be conducted to determine the degree to which this type of risk is seen in humans and to investigate the mechanisms underlying these effects and possible treatments to ameliorate these long-term adverse behavioral consequences of paternal THC exposure.
Open Access
Paternal Δ9-Tetrahydrocannabinol Exposure Prior to Mating Elicits Deficits in Cholinergic Synaptic Function in the Offspring.
(Toxicological sciences : an official journal of the Society of Toxicology, 2020-04) Slotkin, Theodore A; Skavicus, Samantha; Levin, Edward D; Seidler, Frederic J
Little attention has been paid to the potential impact of paternal marijuana use on offspring brain development. We administered Δ9-tetrahydrocannabinol (THC, 0, 2, or 4 mg/kg/day) to male rats for 28 days. Two days after the last THC treatment, the males were mated to drug-naïve females. We then assessed the impact on development of acetylcholine (ACh) systems in the offspring, encompassing the period from the onset of adolescence (postnatal day 30) through middle age (postnatal day 150), and including brain regions encompassing the majority of ACh terminals and cell bodies. Δ9-Tetrahydrocannabinol produced a dose-dependent deficit in hemicholinium-3 binding, an index of presynaptic ACh activity, superimposed on regionally selective increases in choline acetyltransferase activity, a biomarker for numbers of ACh terminals. The combined effects produced a persistent decrement in the hemicholinium-3/choline acetyltransferase ratio, an index of impulse activity per nerve terminal. At the low THC dose, the decreased presynaptic activity was partially compensated by upregulation of nicotinic ACh receptors, whereas at the high dose, receptors were subnormal, an effect that would exacerbate the presynaptic defect. Superimposed on these effects, either dose of THC also accelerated the age-related decline in nicotinic ACh receptors. Our studies provide evidence for adverse effects of paternal THC administration on neurodevelopment in the offspring and further demonstrate that adverse impacts of drug exposure on brain development are not limited to effects mediated by the embryonic or fetal chemical environment, but rather that vulnerability is engendered by exposures occurring prior to conception, involving the father as well as the mother.